Novel substituted sulfonylurea compounds as inhibitors of interleukin-1 activity

Abstract

The present application relates to novel substituted sulfonylurea compounds and analogs, their manufacture, pharmaceutical compositions containing them, and their use as medicaments for treating diseases associated with the modulation of cytokines such as IL-1β and IL-18, the modulation of NLRP3, or the inhibition of activation of NLRP3 or related components of the inflammatory process.

Description

[Technical Field]

[0001] Field The present application relates to novel substituted sulfonylurea compounds and analogs, their manufacture, pharmaceutical compositions containing them, and their use as medicaments for treating diseases associated with the modulation of cytokines such as IL-1β and IL-18, the modulation of NLRP3, or the inhibition of activation of NLRP3 or related components of the inflammatory process. [Background technology]

[0002] background Nucleotide-binding oligomerization domain-like receptors (or NOD-like receptors, NLRs) belong to a family of pattern recognition receptors that function as intracellular sensors of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Accumulating evidence indicates that NLRs play an important role in the innate immune response to infection and cellular damage. Among the numerous NOD-like receptors, NLR pyrin domain-containing 3 (NLRP3) has been well characterized in inflammasome formation.

[0003] NLRP3 is primarily expressed in macrophages and several other cell types with some tissue specificity. Formation of the NLRP3 inflammasome activates caspase-1, which catalyzes proteolytic reactions and releases proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 [Nat Rev Immunol. 2013 Jun;13(6) (Non-Patent Document 1)]. Inflammasome activation is also associated with pyroptosis, a rapid, pro-inflammatory form of cell death mediated by membrane-pore-forming gasdermin D fragments.

[0004] Dysregulated inflammasome activation has been shown to be involved in the pathogenesis of several human diseases. Most notably, gain-of-function mutations in NLRP3 cause genetic disorders characterized by IL-1β-mediated systemic inflammation, such as cryopyrin-associated periodic syndromes (CAPS). In addition, aberrant activation of the NLRP3 inflammasome exacerbates chronic human diseases such as neurodegenerative disorders (multiple sclerosis, AD, and PD), metabolic disorders (atherosclerosis and type 2 diabetes), and inflammatory syndromes (gout flares and osteoarthritis). Recently, the role of NLRP3 in the initiation and progression of cancer has been documented [Nat Immunol. 2021 Mar 11. doi:10.1038 / s41590-021-00886-5 (Non-Patent Document 2)].

[0005] Therapeutically targeting the NLRP3 / IL-1β innate immune pathway has proven successful based on findings from the CANTOS study, in which treatment with canakinumab (a monoclonal antibody against IL-1β) resulted in significantly lower rates of recurrent cardiovascular events, demonstrating a clear benefit of targeting inflammation in high-risk patients with cardiovascular disease. Targeting NLRP3 activation with small molecules is also feasible, as exemplified by MCC950, which directly interacts with the Walker B motif within the NLRP3 NACHT domain, blocking ATP hydrolysis and inhibiting NLRP3 activation and inflammasome formation [Nat Chem Biol. 2019 Jun;15(6):556-559 (Non-Patent Document 3)].

[0006] Therefore, inhibition of the NLRP3 / IL-1β innate immune pathway via small molecule modulators may be a useful and practical approach to treat and prevent genetic diseases (cryopyrin-associated periodic syndromes, CAPS), neurodegenerative disorders (multiple sclerosis, AD, and PD), metabolic disorders (atherosclerosis and type 2 diabetes), inflammatory syndromes (gout flares and osteoarthritis), and cancer, among other related human diseases.

[0007] There is a need to provide compounds that have improved pharmaceutical properties and / or that offer useful alternatives to known compounds, which can help achieve therapeutic efficacy while reducing undesirable side effects. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Nat Rev Immunol.2013 Jun;13(6) [Non-patent document 2] Nat Immunol.2021 Mar 11.doi:10.1038 / s41590-021-00886-5 [Non-patent document 3] Nat Chem Biol.2019 Jun;15(6):556-559 Summary of the Invention

[0009] overview This technology provides novel compounds that are effective in inhibiting inflammasomes, such as the NLRP3 inflammasome, and modulating interleukins. In addition, the small molecule compounds disclosed herein exhibit favorable pharmaceutical properties, including solubility, ADME (absorption, distribution, metabolism, and excretion), pharmacokinetics, CYP inhibition, and other safety profiles, which are useful for achieving therapeutic efficacy while minimizing undesirable properties.

[0010] In one aspect, the present technology provides a compound of formula (I)-(III): TIFF2024538602000001.tif80164 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, During the ceremony: A is CH2 or O, Each occurrence of the Q ring is independently selected from 5-membered heteroaryl, 6-membered heteroaryl, C 3-7 cycloalkyl, or 5- to 6-membered heterocyclyl; X 1 and X5 are each independently N or C, and X 2 , X 3 , and X 4 are each independently N or CR 7 and the dashed circle indicates the bond that forms the five-membered aromatic ring, provided that X 1 , X 2 , X 3 , X 4 , and X 5 at least two but not more than three of Y 1 is N or CH, and Y 2 But N, NR 8 or CH, and Y 3 But N, NR 8 or CH, and Y 4 is C or N, and in formula (II), TIFF2024538602000002.tif10128 is TIFF2024538602000003.tif11128, Z 1 is N or CH, and Z 2 But N or CR 9 and Z 3 is N or CH, R 1 Each occurrence of is independently hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cycloalkoxy, NR a R b , C(=O)OR a , OC(=O)R a , C(=O)NR a R b , N.R. b C(=O)R a , C(=O)NHC(=O)R a or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R 11 may be substituted with R 2 Each occurrence of is independently hydrogen, C1-4 Alkyl, HaloC 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, CN, OH, C 1-4 Alkoxy, NR a R b , C(=O)NR a R b or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 2 R 11 may be substituted with R 3 , R 4 , R 5 and R 6 are each independently hydrogen, halogen, CN, C 1-4 Alkyl or haloC 1-4 is alkyl, R 7 each occurrence is independently hydrogen or C 1-4 is alkyl, R 8 each occurrence is independently hydrogen or C 1-4 is alkyl, R 9 Each occurrence of is independently hydrogen, C 1-4 Alkyl or C 1-4 is an alkoxy, R 10 Each occurrence of is independently hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl, or C 1-4 a 4- to 6-membered heterocyclyl optionally substituted with alkyl; R 11 Each occurrence of is independently hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, halogen, CN, OH, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cycloalkoxy, NR a R b , C(=O)OR a , OC(=O)R a , C(=O)NR a R b , N.R. b C(=O)R a , C(=O)NHC(=O)Ra or 4- to 6-membered heterocyclyl; R a and R b Each occurrence of is independently hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, the ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C 1-4 optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; Each occurrence of n is independently 0, 1, or 2.

[0011] The present technology also relates to pharmaceutical compositions comprising compounds of Formulas (I)-(III), their manufacture, and their use as medicaments for treating or preventing diseases associated with the modulation of cytokines such as IL-1β and IL-18, the modulation of NLRP3, or the inhibition of activation of NLRP3 or related components of the inflammatory process. Accordingly, the compounds of Formulas (I)-(III) are useful for the treatment or prevention of genetic diseases (cryopyrin-associated periodic syndromes, CAPS), neurodegenerative disorders (multiple sclerosis, AD, and PD), metabolic disorders (atherosclerosis and type 2 diabetes), inflammatory syndromes (gout flares and osteoarthritis), and cancer, among other related human diseases. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description In one aspect, the present technology provides compounds and pharmaceutically acceptable forms thereof, including, but not limited to, salts, hydrates, solvates, isomers, sterioisomers, enantiomers, prodrugs, and isotopically labeled derivatives thereof.

[0013] In another aspect, the present technology provides methods for treating and / or managing various diseases and disorders, comprising administering to a patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable form thereof (e.g., salt, hydrate, solvate, isomer, sterioisomer, enantiomer, prodrug, and isotopically labeled derivative). Non-limiting examples of diseases and disorders are described herein.

[0014] Also provided herein are pharmaceutical compositions (e.g., single unit dosage forms) that can be used in the methods provided herein. In one embodiment, the pharmaceutical composition comprises a compound provided herein, or a pharmaceutically acceptable form thereof (e.g., salts, hydrates, solvates, isomers, sterioisomers, prodrugs, and isotopically labeled derivatives).

[0015] While specific embodiments are discussed, this specification is illustrative only and not restrictive. Many variations of the disclosure will become apparent to those of skill in the art upon review of this specification.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0017] definition As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0018] As used herein, "drug" or "biologically active agent" refers to a biological, pharmaceutical, or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamins, vitamin derivatives, carbohydrates, toxins, or chemotherapeutic compounds, and their metabolites. A variety of compounds can be synthesized, such as small molecules and oligomers (e.g., oligopeptides and oligonucleotides), as well as synthetic organic compounds based on various core structures. In addition, a variety of natural sources can provide active compounds, such as, for example, plant or animal extracts. One of ordinary skill in the art can readily recognize that there is no limit as to the structural nature of the agents of the present disclosure.

[0019] "Administration" of the disclosed compounds encompasses delivery of a compound as described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, to a subject using any suitable formulation or route of administration, as discussed herein.

[0020] As used herein, the terms "co-administration," "administered in combination with," and their grammatical equivalents include administration of two or more agents to a subject such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0021] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition described herein sufficient to affect the intended use, including, but not limited to, disease treatment, as described below. In some embodiments, this amount is effective for detectable inhibition of NLRP3, as can be determined, for example, by a biological assay described herein. A therapeutically effective amount may vary depending on the intended use (in vitro or in vivo), or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. This term also applies to an amount that will induce a response in target cells, such as reduced cell migration. A particular dosage will vary depending, for example, on the selected compound, the subject's species and their age / existing health conditions or risk to health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0022] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0023] As used herein, the terms "treatment," "treating," "alleviating," "managing," and "ameliorating" are used interchangeably herein. These terms refer to an approach to obtaining beneficial or desired results, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disease being treated. Therapeutic benefit is also achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that improvement is observed in the patient, even though the patient may still suffer from the underlying disease. For prophylactic benefit, pharmaceutical compounds and / or compositions may be administered to patients at risk of developing a disease or to patients who report one or more physiological symptoms of a disease, even if a diagnosis of the disease has not been made.

[0024] As used herein, the terms "preventing" and "prophylaxis" refer to administering a pharmaceutical compound or medicament, or a composition containing a pharmaceutical compound or medicament, to a subject before a disease, disorder, or condition fully manifests itself, to prevent the appearance and / or reduce the severity of one or more symptoms of a disease, disorder, or condition. Those skilled in the art will recognize that the term "prevent" is not an absolute term. In the medical field, it is understood to refer to the prophylactic administration of a drug to reduce the likelihood or severity of a disease, disorder, or condition, or its symptoms, and this is the meaning of such terms as used in this disclosure.

[0025] A "therapeutic effect," as that term is used herein, encompasses therapeutic and / or prophylactic benefits as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0026] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys.

[0027] The term "in vivo" refers to events that take place inside a subject's body. In vivo also includes events that occur in rodents, such as rats, mice, guinea pigs, etc.

[0028] The term "in vitro" refers to events that occur outside of a subject's body. For example, an in vitro assay includes any assay performed outside of a subject. In vitro assays include cell-based assays in which cells, living or dead, are used. In vitro assays also include cell-free assays in which no intact cells are used.

[0029] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or using other methods used in the art, such as ion exchange. For example, pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and the like. Examples of the salts include benzoate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0030] Salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl) 4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Additionally, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt may be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0031] As used herein, the term "solvate" refers to a compound that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Solvates can consist of the disclosed compounds, or pharmaceutically acceptable salts thereof. When the solvent is water, the solvate is a "hydrate." Pharmaceutically acceptable solvates and hydrates are complexes that can include, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. As used herein, the term "compound" will be understood to encompass compounds and solvates of compounds, as well as mixtures thereof.

[0032] In some embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" refers to a compound that is transformed in vivo to yield a pharmaceutically acceptable form of the disclosed compound or compounds. A prodrug may be inactive when administered to a subject but is converted to an active compound in vivo, for example, by hydrolysis (e.g., hydrolysis in the blood). In certain cases, a prodrug has improved physical and / or delivery properties relative to the parent compound. A prodrug can increase the bioavailability of the compound when administered to a subject (e.g., by enabling enhanced absorption into the blood after oral administration) or enhance delivery to a desired biological compartment (e.g., the brain or lymphatic system) compared to the parent compound. Exemplary prodrugs include derivatives of the disclosed compounds that have enhanced aqueous solubility or active transport across the intestinal membrane compared to the parent compound.

[0033] Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced aqueous solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the gastrointestinal tract, or it can enhance drug stability for long-term storage.

[0034] The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a subject. Prodrugs of active compounds as described herein can be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved to the parent active compound, either by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that cleaves to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols, such as active compounds, or acetamide, formamide, and benzamide derivatives of amine functional groups. Other examples of prodrugs include compounds containing -NO, -NO2, -ONO, or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York, 1985).

[0035] Prodrugs also include compounds in which a carboxylic acid is bonded to any group that cleaves to form the free carboxylic acid when the prodrug of the active compound is administered to a subject. For example, if a disclosed compound or a pharmaceutically acceptable form of the compound contains a carboxylic acid functional group, the prodrug can be a compound obtained by bonding the hydrogen atom of the acid group to a (C 1-8 ) alkyl, (C 1-12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 10 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4-yl, di-N,N-(C 1-2 ) Alkylamino(C 2-3 ) alkyl (e.g., [3-dimethylaminoethyl], carbamoyl-(C 1-2 ) alkyl, N,N-di(C 1-2 ) alkylcarbamoyl-(C 1-2 ) alkyl, and piperidino-, pyrrolidino-, or morpholino (C 2-3 ) alkyl, or the like, to form pharmaceutically acceptable esters.

[0036] Similarly, when a disclosed compound contains an alcohol functional group, the prodrug may be a compound selected from the group consisting of a hydrogen atom of the alcohol group and a (C 1-6 ) alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 ) alkoxycarbonylaminomethyl, succinoyl, (C 1-6 ) alkanoyl, α-amino (C 1-4 ) alkanoyl, arylacyl, and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from naturally occurring L-amino acids, -P(O)(OH), -P(O)(O(C 1-6) alkyl) 2, or glycosyl (a radical resulting from removal of the hydroxyl group of a carbohydrate in hemiacetal form).

[0037] When the disclosed compounds incorporate an amine functional group, prodrugs can be prepared by combining a hydrogen atom in the amine group with a hydroxyl group in which R and R′ are each independently: (C 1-10 ) alkyl, (C 3-7 ) cycloalkyl, benzyl, natural α-aminoacyl, or natural α-aminoacyl-natural α-aminoacyl, -C(OH)C(O)OW 1 and W may be formed by replacement with a group such as R-carbonyl, RO-carbonyl, NRR′-carbonyl, or the like, selected from 1 However, H, (C 1-6 ) alkyl, or benzyl, -C(OW 2 )W 3 and W 2 However, (C 1-4 ) alkyl, and W 3 However, (C 1-6 ) alkyl, carboxy (C 1-6 ) alkyl, amino (C 1-4 ) alkyl, or mono-N- or di-N,N-(C 1-6 ) alkylaminoalkyl, and -C(W 4 )W 5 and W 4 is H or methyl, and W 5 However, mono-N- or di-N-(C 1-6 ) alkylamino, morpholino, piperidin-1-yl, or pyrrolidin-1-yl.

[0038] In some embodiments, the disclosed compounds may include isomers. "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. As used herein, the term "isomer" includes any and all geometric and stereoisomers. For example, "isomer" includes geometric double bond cis and trans isomers, also referred to as E and Z isomers, R and S enantiomers, diastereomers, (d) isomers and (l) isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the present disclosure.

[0039] Geometric isomers are represented by the symbols representing bonds which may be single, double or triple bonds as described herein: TIFF2024538602000004.tif2128. Provided herein are various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbon ring. Substituents around a carbon-carbon double bond are designated as being of the "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers.

[0040] Alternatively, substituents around a carbon-carbon double bond may be designated "cis" or "trans," with "cis" representing substituents on the same side of the double bond and "trans" representing substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring may also be designated "cis" or "trans." The term "cis" represents substituents on the same side of the plane of the ring and the term "trans" represents substituents on opposite sides of the plane of the ring. A mixture of compounds in which substituents are disposed on both the same and opposite sides of the plane of the ring is designated "cis / trans."

[0041] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportions may be known as a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is an enantiomer, the stereochemistry at each chiral carbon may be specified as either R or S. Resolved compounds of unknown absolute configuration may be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) that the compound rotates plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and may therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R)- or (S)- in terms of the absolute stereochemistry at each asymmetric atom. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared using, for example, chiral synthons or chiral reagents, or resolved using conventional techniques.

[0042] In some embodiments, an enantiomer is provided partially or substantially free of the corresponding enantiomer and may be referred to as "optically enriched," "enantiomerically enriched," "enantiomerically pure," and "non-racemic," when used interchangeably herein. The "enantiomeric excess" or "% enantiomeric excess" of a composition may be calculated using the equation shown below. In the example shown below, the composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, e.g., the R enantiomer. ee=(90-10) / 100=80%. Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. In some embodiments, the compositions described herein contain an enantiomeric excess of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% of the S enantiomer, or a range between and including any two of the foregoing values ​​(e.g., 50-99.5% ee). In other words, the composition contains an enantiomeric excess of the S enantiomer over the R enantiomer. In other embodiments, some compositions described herein contain an enantiomeric excess of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% of the R enantiomer, or a range between any two of the foregoing values ​​(e.g., 50-99.5% ee). In other words, the composition contains an enantiomeric excess of the R enantiomer over the S enantiomer. When the enrichment of one enantiomer is much greater than about 80% by weight, the composition is referred to as a "substantially enantiomerically enriched," "substantially enantiomerically pure," or "substantially non-racemic" preparation.

[0043] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. In some embodiments, the compositions described herein contain an enantiomeric excess of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% of the S enantiomer, or a range between and including any two of the foregoing values ​​(e.g., 50-99.5% ee). In other words, the composition contains an enantiomeric excess of the S enantiomer over the R enantiomer. In other embodiments, some compositions described herein contain an enantiomeric excess of at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% of the R enantiomer, or a range between any two of the foregoing values ​​(e.g., 50-99.5% ee). In other words, the composition contains an enantiomeric excess of the R enantiomer over the S enantiomer. When the enrichment of one enantiomer is much greater than about 80% by weight, the composition is referred to as a "substantially enantiomerically enriched," "substantially enantiomerically pure," or "substantially non-racemic" preparation.

[0044] Optical isomers can be obtained according to conventional processes, for example, by the formation of diastereomeric salts, by treatment with optically active acids or bases, or by resolution of racemic mixtures. Examples of suitable acids include, but are not limited to, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Separation of the diastereomeric mixture by crystallization, followed by liberation of the optically active base from the salt, results in separation of the isomers. Another method involves the synthesis of covalent diastereomeric molecules by reacting the disclosed compounds with optically pure acids in activated form or with optically pure isocyanates. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to deliver enantiomerically enriched compounds. Optically active compounds can also be obtained by using active starting materials. In some embodiments, these isomers can be in the form of free acids, free bases, esters, or salts.

[0045] In any embodiment, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" refers to a type of isomer comprising two or more interconvertible compounds resulting from the formal migration of at least one of the hydrogen atoms and at least one change in valence (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). "Tautomerism" includes prototropic tautomerism or prototropic tautomerism, which are considered a subset of acid-base chemistry. "Prototropic tautomerism" or "prototropic tautomerism" involves the migration of a proton with a change in bond order. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. When tautomerism is possible (e.g., in solution), a chemical equilibrium of the tautomers can be reached. Tautomerism (i.e., the reaction providing the tautomeric pair) can be catalyzed by an acid or base, or can occur without the action or presence of an external agent. Exemplary tautomers include, but are not limited to, keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different) enamine tautomers. A specific example of keto-enol tautomerism is the interconversion of the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of the tautomers of pyridin-4-ol and pyridin-4(1H)-one.

[0046] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0047] The present disclosure also encompasses pharmaceutically acceptable forms that are "isotopically labeled derivatives," which are compounds identical to those enumerated herein except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include, respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes can allow for ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, can confer certain therapeutic benefits (e.g., increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability. Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, provided herein are compounds that may also contain unnatural proportions of atomic isotopes at one or more of the atoms comprising such compounds. All isotopic variations of compounds as disclosed herein, whether radioactive or not, are encompassed within the scope of the present disclosure. In some embodiments, radiolabeled compounds are useful for studying the metabolism and / or tissue distribution of compounds, or for altering the rate or pathway of metabolism or other aspects of biological function.

[0048] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. A pharmaceutically acceptable carrier or excipient does not destroy the pharmacological activity of the disclosed compounds and is non-toxic when administered in dosages sufficient to deliver a therapeutic amount of the compound. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated.Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and non-toxic compatible lubricants such as sodium lauryl sulfate and stearin. magnesium stearate; colorants; release agents; coating agents; sweetening agents, flavors, and fragrances; preservatives; antioxidants; ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as da tocopherol polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, such as Tween or other similar polymeric delivery matrices; serum proteins, such as human serum albumin; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyacrylates, waxes, and polyethylene-polyoxypropylene-block polymers. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrin, or other solubilized derivatives, can also be used to enhance delivery of the compounds described herein.

[0049] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sansalito, 1999; Smith and March's Advanced Organic Chemistry, 5th ed., John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge University Press, Cambridge, 1987.

[0050] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value and subrange falling within the range, unless otherwise stated herein, and each separate value and subrange is incorporated herein as if it were individually recited herein. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6Similarly, 1 to 4 substituents will be understood to include 1, 2, 3, 4, 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4 substituents.

[0051] "Alkyl" refers to a straight or branched hydrocarbon chain radical (e.g., C 1-10 Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; for example, "1 to 10 carbon atoms" means that the alkyl group can consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, although this definition also covers occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated linear alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups, while saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, etc. The alkyl is attached to the parent molecule by a single bond. Unless otherwise stated herein, the alkyl group may be optionally substituted with one or more of the substituents disclosed herein. In a non-limiting embodiment, the substituted alkyl may be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0052] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from 2 to 10 carbon atoms (i.e., C 2-10 Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range; for example, "2 to 10 carbon atoms" means that the alkenyl group can consist of up to 10 carbon atoms, such as 2 carbon atoms, 3 carbon atoms, etc. In some embodiments, the alkenyl comprises 2 to 8 carbon atoms. In other embodiments, the alkenyl comprises 2 to 6 carbon atoms (e.g., C 2-6 Alkenyls include alkyl groups such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, and penta-1,4-dienyl. The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), 2-methylprop-2-enyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), 2,3-dimethyl-2-butenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless stated otherwise herein, alkenyl groups may be optionally substituted with one or more of the substituents disclosed herein.

[0053] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, and having from 2 to 10 carbon atoms (i.e., C 2-10Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range; for example, "2 to 10 carbon atoms" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, or up to 10 carbon atoms. In some embodiments, the alkynyl comprises 2 to 8 carbon atoms. In other embodiments, the alkynyl comprises 2 to 6 carbon atoms (e.g., C 2-6 Alkynyl groups include alkynyl groups, which are attached to the parent molecular structure by a single bond and are, for example, ethynyl, propynyl, butynyl, pentynyl, 3-methyl-4-pentynyl, hexynyl, and the like. Unless stated otherwise herein, alkynyl groups may be optionally substituted with one or more of the substituents disclosed herein.

[0054] "Alkoxy" refers to the group -O-alkyl containing 1 to 10 carbon atoms of a straight, branched, saturated, cyclic configuration, and combinations thereof, attached to the parent molecular structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, cyclopropyloxy, cyclohexyloxy, and the like. "Lower alkoxy" refers to an alkoxy group containing 1 to 6 carbons. In some embodiments, C 1-4 Alkoxy is an alkoxy group that includes both straight- and branched-chain alkyls of 1 to 4 carbon atoms. Unless otherwise stated herein, an alkoxy group may be optionally substituted with one or more of the substituents disclosed herein. The terms "alkenoxy" and "alkynoxy" mirror the above description of "alkoxy," with the prefix "alk" replacing "alkene" or "alkyne," respectively, and the parent "alkenyl" or "alkynyl" terms as described herein.

[0055] "Aromatic" or "aryl" refers to a radical having 6 to 14 ring atoms (e.g., C 6-14In some embodiments, aryl refers to C 6-10 An aryl group. For example, a divalent radical formed from a substituted benzene derivative and having a free valence on a ring atom is named a substituted phenylene radical. In another embodiment, a divalent radical derived from a monovalent polycyclic hydrocarbon radical ending in "-yl" by removing one hydrogen atom from the carbon atom having the free valence is named by adding "idene" to the name of the corresponding monovalent radical; for example, a naphthyl group having two attachment points is called naphthylidene. Whenever it appears herein, a numerical range such as "6 to 14 aryl" refers to each integer in the given range; for example, "6 to 14 ring atoms" means that the aryl group can consist of up to 14 ring atoms, such as 6 ring atoms, 7 ring atoms, etc. This term includes monocyclic or fused-ring polycyclic (i.e., rings sharing pairs of adjacent ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In polycyclic groups, only one ring is required to be aromatic, and thus groups such as indanyl are encompassed by the definition of aryl. Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl, indanyl, and the like. Unless otherwise stated herein, aryl groups may be optionally substituted with one or more of the substituents disclosed herein.

[0056] "Cycloalkyl" and "carbocyclyl" each refer to a monocyclic or polycyclic radical that contains only carbon and hydrogen and can be saturated or partially unsaturated. A partially unsaturated cycloalkyl group can be referred to as a "cycloalkenyl" if the carbocyclic ring contains at least one double bond, or as a "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. A cycloalkyl group is a group having 3 to 13 ring atoms (i.e., C 3-13

[0023] Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range; for example, "3 to 13 carbon atoms" means that the cycloalkyl group can consist of up to 13 carbon atoms, such as 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" refers to a C 3-8 In some embodiments, "cycloalkyl" is a C 3-5 Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-7 An example of a carbocyclyl group is norbornyl (C7). 3-8 Examples of carbocyclyl groups include the aforementioned C 3-7 Examples include carbocyclyl groups, as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. 3-13 Examples of carbocyclyl groups include the aforementioned C 3-8Examples of cycloalkyl groups include carbocyclyl groups, and octahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless stated otherwise herein, cycloalkyl groups may be optionally substituted with one or more of the substituents disclosed herein. The terms "cycloalkenyl" and "cycloalkynyl" reflect the above description of "cycloalkyl," with the prefix "alk" replacing "alkene" or "alkyne," respectively, and the parent "alkenyl" or "alkynyl" terms as described herein. For example, cycloalkenyl groups can have 3 to 13 ring atoms, e.g., 5 to 8 ring atoms. In some embodiments, cycloalkynyl groups can have 5 to 13 ring atoms.

[0057] "Halo," "halide," or alternatively, "halogen" means fluoro, chloro, bromo, or iodo. The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halo groups or combinations thereof, preferably substituted with one, two, or three halo groups. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where the halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2 trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, -O-CHF2, and the like. Each of the alkyl, alkenyl, alkynyl, and alkoxy groups is as defined herein and may be optionally further substituted as defined herein.

[0058] "Heteroaryl," or alternatively, "heteroaromatic," refers to a radical of a 5- to 18-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring system (e.g., having 6, 10, or 14 π-electrons shared in a cyclic arrangement) having one or more ring carbon atoms and one to six ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 18-membered heteroaryl"). Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range; for example, "5 to 18 ring atoms" means that the heteroaryl group can consist of up to 18 ring atoms, such as 5 ring atoms, 6 ring atoms, etc. In some cases, a heteroaryl can have 5 to 14 ring atoms. In some embodiments, heteroaryls have divalent radicals derived from monovalent heteroaryl radicals whose names end in "-yl", e.g., by removing one hydrogen atom from the atom with the free valence, and are named by adding "-ene" to the name of the corresponding monovalent radical, e.g., a pyridyl group with two points of attachment is pyridylene.

[0059] For example, an N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. One or more heteroatoms in a heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, may be optionally quaternized. Heteroaryl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridinyl N-oxide. A heteroaryl is attached to the parent molecular structure through any atom of the ring.

[0060] "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment to the parent molecular structure being on either the aryl or heteroaryl ring, or in which a heteroaryl ring, as defined above, is fused to one or more cycloalkyl or heterocyclyl groups, with the point of attachment to the parent molecular structure being on the heteroaryl ring. For polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment to the parent molecular structure can be on either ring, i.e., either the ring containing a heteroatom (e.g., 2-indolyl) or the ring containing no heteroatoms (e.g., 5-indolyl). In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having one or more ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur (a "5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur (a "5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1 ring heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur.

[0061] Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzopyranonyl, and benzofuranyl. Lazanil, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzyl benzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8- Methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2, Examples of heteroaryl groups include, but are not limited to, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e., thienyl). Unless otherwise stated herein, heteroaryl groups may be optionally substituted with one or more of the substituents disclosed herein.

[0062] "Heterocyclyl," "heterocycloalkyl," or "heterocarbocyclyl" each refer to any 3- to 18-membered non-aromatic radical monocyclic or polycyclic moiety containing at least one carbon atom and at least one heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. Heterocyclyl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and polycyclic ring systems can be fused, bridged, or spiro ring systems. Heterocyclyl polycyclic ring systems can contain one or more heteroatoms in one or both rings. Heterocyclyl groups can be saturated or partially unsaturated. Partially unsaturated heterocycloalkyl groups can be referred to as "heterocycloalkenyl" if the heterocyclyl contains at least one double bond, or "heterocycloalkynyl" if the heterocyclyl contains at least one triple bond. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range; for example, "5 to 18 ring atoms" means that the heterocyclyl group can consist of up to 18 ring atoms, such as 5 ring atoms, 6 ring atoms, etc. Divalent radicals derived from monovalent heterocyclyl radicals whose names end in "-yl", e.g., by removing one hydrogen atom from the atom having the free valence, are named by adding "-ene" to the name of the corresponding monovalent radical; e.g., a piperidine group having two points of attachment is piperidylene.

[0063] An N-containing heterocyclyl moiety refers to a non-aromatic group in which at least one of the ring atoms is a nitrogen atom. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, may be optionally quaternized. Heterocyclyl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as piperidinyl N-oxide. A heterocyclyl is attached to the parent molecular structure through any atom of any of the rings.

[0064] "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, with the point of attachment being on either the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment to the parent molecular structure being on the heterocyclyl ring. In some embodiments, a heterocyclyl group is a 5- to 14-membered non-aromatic ring system having one or more ring carbon atoms and one to four ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur (a "5- to 14-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 3- to 10-membered non-aromatic ring system having one or more ring carbon atoms and one to four ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur (a "3- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, phosphorus, and sulfur (a "5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, phosphorus, and sulfur (a "5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1 ring heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur.

[0065] A "heterocyclyl" may contain one or more ketone groups (-C(=O)-) as part of the ring. Examples of ketone-containing heterocycles include, but are not limited to, pyridin-2(1H)-one, pyrazin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, pyridin-4(1H)-one, imidazolidin-2-one, 1,3-dihydro-2H-imidazol-2-one, 2,4-dihydro-3H-1,2,4-triazol-3-one, oxazol-2(3H)-one, and oxazolidin-2-one. Ketone-containing heterocyclyls can be obtained by removing a hydrogen atom from the corresponding ketone-containing heterocycle at any available NH or CH position.

[0066] Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyls containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, thiazolidinyl, and dithiolanyl. Exemplary 5-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazolinyl, diazolonyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, and triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, benzothianyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, 3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, phenanthridinyl, indolyl, and the like. nyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH- These include, but are not limited to, pyrrolo[2,3-b]pyridinyl, hydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0067] Unless stated otherwise specifically, a heterocyclyl group may be optionally substituted with one or more of the substituents disclosed herein.

[0068] Substituents, when specified by their conventional chemical formula written from left to right, equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0069] A "leaving group or atom" is any group or atom that, under reaction conditions, is cleaved from a starting material, thereby facilitating reaction at a specific site. Suitable non-limiting examples of such groups, unless otherwise specified, include halogen atoms, mesyloxy, p-nitrobenzenesulfonyloxy, trifluoromethyloxy, and tosyloxy groups.

[0070] The term "protecting group" has its traditional meaning in organic synthesis: a group that selectively blocks one or more reactive sites in a multifunctional compound so that a chemical reaction can be selectively performed at an otherwise unprotected reactive site, and so that the group can be easily removed after the selective reaction is complete. Non-limiting examples of functional groups that can be masked by a protecting group include amine, hydroxy, thiol, carboxylic acid, and aldehyde. For example, a hydroxy-protected form is when at least one of the hydroxy groups present in a compound is protected by a hydroxy-protecting group. Various protecting groups are disclosed, for example, in Greene's Protective Groups in Organic Synthesis, Fifth Edition, Wiley (2014), which is incorporated herein by reference in its entirety. For additional background information regarding protecting group methodology (materials, methods, and strategies for protection and deprotection) and other synthetic chemical transformations useful in producing the compounds described herein, see R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), Greene's Protective Groups in Organic Synthesis, Fifth Edition, Wiley (2014), L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). These references are incorporated herein by reference in their entireties.

[0071] The term "substituted" or "substituted" means that at least one hydrogen present on a group atom (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon displacement by hydrogen, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group can have a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position. Substituents include acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (wherein t is 1 or 2), -P(=O)(R a )(Ra ), or -OP(=O)(OR a )2, wherein each R a are independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties (other than hydrogen) can be optionally substituted with one or more substituents (up to six, valences allowed) independently selected from OH, NH, oxo, halo, nitro, COOH, C(O)NH, or cyano. For example, a cycloalkyl substituent can have a halide substituted on one or more ring carbons, etc. Protecting groups that can form the protective derivatives of the above substituents are known to those of skill in the art and can be found in references such as Greene and Wuts, above.

[0072] Suitable substituents include haloalkyl and trihaloalkyl, alkoxyalkyl, halophenyl, -M-heteroaryl, -M-heterocycle, -M-aryl, -M-OR a , -M-SR a , -MN(R a )2, -M-OC(O)N(R a )2, -MC(=NR a )N(R a )2, -MC(=NR a ) OR a , -MP(O)(R a )2, Si(R a )3, -M-NR a C(O)R a , -M-NR a C(O)OR a , -MC(O)R a , -MC(=S)R a , -MC(=S)NR a R a , -MC(O)N(R a )2, -MC(O)NR a -MN(R a )2, -M-NR a C(NR a)N(R a )2, -M-NR a C(S)N(R a )2, -MS(O)2R a , -MC(O)R a , -M-OC(O)R a , -MC(O)SR a , -MS(O)2N(R a )2, -C(O)-MC(O)R a , -MCO2R a , -MC(=O)N(R a )2, -MC(=NH)N(R a )2, and -M-OC(=NH)N(R a ) 2 (wherein M is C 1-6 Examples of suitable alkyl groups include, but are not limited to, alkyl groups.

[0073] When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl) is substituted with several substituents varying within an explicitly defined range, it is understood that the total number of substituents does not exceed the normally available valences under the existing conditions. Thus, for example, a phenyl ring substituted with a "p" substituent (where "p" ranges from 0 to 5) can have 0 to 5 substituents, while a pyridinyl ring substituted with a "p" substituent is understood to have several substituents ranging from 0 to 4. The maximum number of substituents that a group in the disclosed compounds may have can be readily determined. Substituted groups encompass only those combinations of substituents and variables that result in stable or chemically feasible compounds. Stable or chemically feasible compounds are those that have sufficient stability to permit their preparation and detection, among other factors. In some embodiments, the disclosed compounds are sufficiently stable that they remain substantially unchanged when maintained at a temperature of 40° C. or less in the absence of moisture (e.g., less than about 10%, less than about 5%, less than about 2%, less than about 1%, or less than about 0.5%) or other chemically reactive conditions for, e.g., at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 4 weeks, or at least about 6 weeks.

[0074] The terms "combining, combining, to combine, combination" refer to the act of adding at least one chemical to another chemical, either sequentially or simultaneously. In some embodiments, bringing these chemicals together can result in the conversion of the first chemical into one or more different chemicals. This conversion can occur through one or more chemical reactions, such as, for example, covalent bonds being formed, broken, or rearranged. A non-limiting example can include hydrolysis of an ester to an alcohol and a carboxylic acid, which can result from combining an ester with a suitable base. In another non-limiting example, an aryl fluoride can be combined with an amine to provide an aryl amine through a substitution process. These terms also include changes associated with charged chemicals and the production of charged chemicals, such as, but not limited to, N-oxide formation, acid addition salt formation, base addition salt formation, etc. These terms include the production and / or conversion of radical chemicals and isotopically labeled chemicals.

[0075] The terms "convert, converting, to convert, conversion" refer to a subset of "combination" and its grammatical equivalents, where the action of one or more reagents converts one or more functional groups on a chemical to another functional group. For example, conversion includes, but is not limited to, using a reducing agent to convert a nitro functional group on a chemical to an amine. Conversion also includes the alteration of charged chemicals, radical chemicals, and isotopically labeled chemicals. However, the term "convert" does not include the alteration of conserved bonds in the disclosed genera and compounds.

[0076] compound In one aspect, the present technology provides a compound of formula (I)-(III): TIFF2024538602000005.tif80164 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, During the ceremony: A is CH2 or O, Each occurrence of the Q ring is independently selected from 5-membered heteroaryl, 6-membered heteroaryl, C3-7 cycloalkyl, or 5- to 6-membered heterocyclyl; X 1 and X 5 are each independently N or C, and X 2 , X 3 , and X 4 are each independently N or CR 7 and the dashed circle indicates the bond that forms the five-membered aromatic ring, provided that X 1 , X 2 , X 3 , X 4 , and X 5 at least two but not more than three of Y 1 is N or CH, and Y 2 But N, NR 8 or CH, and Y 3 But N, NR 8 or CH, and Y 4 is C or N, and in formula (II), TIFF2024538602000006.tif10128 is TIFF2024538602000007.tif11128, Z 1 is N or CH, and Z 2 But N or CR 9 and Z 3 is N or CH, R 1 Each occurrence of is independently hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cycloalkoxy, NR a R b , C(=O)OR a , OC(=O)R a , C(=O)NR a R b , N.R. b C(=O)R a , C(=O)NHC(=O)R a or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R11 may be substituted with R 2 Each occurrence of is independently hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, CN, OH, C 1-4 Alkoxy, NR a R b , C(=O)NR a R b or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 2 R 11 may be substituted with R 3 , R 4 , R 5 and R 6 are each independently hydrogen, halogen, CN, C 1-4 Alkyl or haloC 1-4 is alkyl, R 7 each occurrence is independently hydrogen or C 1-4 is alkyl, R 8 each occurrence is independently hydrogen or C 1-4 is alkyl, R 9 Each occurrence of is independently hydrogen, C 1-4 Alkyl or C 1-4 is an alkoxy, R 10 Each occurrence of is independently hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl, or C 1-4 a 4- to 6-membered heterocyclyl optionally substituted with alkyl; R 11 Each occurrence of is independently hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, halogen, CN, OH, C 3-7 Cycloalkyl, C 1-4 Alkoxy, C 3-7 Cycloalkoxy, NR a R b , C(=O)OR a , OC(=O)R a , C(=O)NRa R b , N.R. b C(=O)R a , C(=O)NHC(=O)R a or 4- to 6-membered heterocyclyl; R a and R b Each occurrence of is independently hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, the ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C 1-4 optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; Each occurrence of n is independently 0, 1, or 2.

[0077] In some embodiments, the present technology provides a compound of formula (I): TIFF2024538602000008.tif39128 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein A, Q, X 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R a , R b , and n can each be as defined above or have any of the values ​​disclosed herein.

[0078] In any embodiment of the compound of formula (I), TIFF2024538602000009.tif18128 is TIFF2024538602000010.tif45155, where R 5 and R 6 , may each be as defined above or have any of the values ​​disclosed herein.

[0079] In some embodiments, the present technology provides a compound of formula (II): TIFF2024538602000011.tif37128 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, Q and Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 11 , R a , R b , and n can each be as defined above or have any of the values ​​disclosed herein.

[0080] In any embodiment of the compound of formula (II), TIFF2024538602000012.tif18128 is TIFF2024538602000013.tif23128, where R 5 , R 6 and R 8 , may each be as defined above or have any of the values ​​disclosed herein.

[0081] In some embodiments, the present technology provides a compound of formula (III): TIFF2024538602000014.tif34128 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, Q, Z 1 , Z 2 , Z 3, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , R a , R b , and n can each be as defined above or have any of the values ​​disclosed herein.

[0082] In any embodiment of the compound of formula (III), TIFF2024538602000015.tif16128 is TIFF2024538602000016.tif20128, where R 5 , R 6 , R 9 and R 8 , may each be as defined above or have any of the values ​​disclosed herein.

[0083] In any embodiment of the present compounds (including but not limited to compounds of Formula I, II, and III), Q, at each occurrence, is independently a 5-membered heteroaryl. In some embodiments, Q, at each occurrence, is independently a thiophene, pyrazole, imidazole, thiazole, oxazole, iso-oxazole, or triazole. In some embodiments, Q, at each occurrence, is independently In some embodiments, Q, in each occurrence, is independently TIFF2024538602000018.tif9128. In some embodiments, Q is R 1 together with, in each occurrence, independently In some embodiments, Q, in each occurrence, is independently TIFF2024538602000020.tif18128. In some embodiments, Q is R 1 together with, in each occurrence, independently In some embodiments, Q, in each occurrence, is independently TIFF2024538602000022.tif18128. In some embodiments, Q is R 1 together with, in each occurrence, independently The file is TIFF2024538602000023.tif16128.

[0084] In some embodiments, Q, at each occurrence, is independently a 6-membered heteroaryl. In some embodiments, Q, at each occurrence, is independently pyridine, pyridazine, pyrimidine, or pyrazine. In some embodiments, Q, at each occurrence, is independently TIFF2024538602000024.tif13139. In some embodiments, Q is R 1 together, in each occurrence independently, The file is TIFF2024538602000025.tif19128.

[0085] In some embodiments, Q, in each occurrence, is independently C 3-7 In some embodiments, Q is independently at each occurrence cyclobutyl.

[0086] In some embodiments, Q, at each occurrence, is independently a 5- to 6-membered heterocyclyl. In some embodiments, the 5- to 6-membered heterocyclyl contains 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, Q is R 1 together, in each occurrence independently, The file is TIFF2024538602000026.tif15128.

[0087] In some embodiments, the present technology provides a compound of formula (Ia): TIFF2024538602000027.tif38128 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein A, X 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R a , R b , and n can each be as defined above or have any of the values ​​disclosed herein.

[0088] In some embodiments, the present technology provides a compound of formula (Ib): TIFF2024538602000028.tif38128 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R a , R b , and n can each be as defined above or have any of the values ​​disclosed herein.

[0089] In some embodiments, the present technology provides a compound of formula (IIa): TIFF2024538602000029.tif37128 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein Y 1 , Y 2 , Y 3 , Y4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 11 , R a , R b , and n can each be as defined above or have any of the values ​​disclosed herein.

[0090] In some embodiments, the present technology provides a compound of formula (IIb): TIFF2024538602000030.tif37128 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 11 , R a , R b , and n can each be as defined above or have any of the values ​​disclosed herein.

[0091] In some embodiments, the present technology provides a compound of formula (IIIa): TIFF2024538602000031.tif35128 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein Z 1 , Z 2 , Z 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , R a , R b, and n can each be as defined above or have any of the values ​​disclosed herein.

[0092] In some embodiments, the present technology provides a compound of formula (IIIb): TIFF2024538602000032.tif35128 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein Z 1 , Z 2 , Z 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 10 , R 11 , R a , R b , and n can each be as defined above or have any of the values ​​disclosed herein.

[0093] In any embodiment of the compound, R 1 is, in each occurrence independently, C 1-4 Alkyl, HaloC 1-4 Alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy, cyclobutyloxy, NR a R b or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R 11 In some embodiments, R 1 is, in each occurrence independently, C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, NR a R b or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R 11 In some embodiments, C 3-5 Cycloalkyl is cyclopropyl or cyclobutyl, C3-5 Cycloalkoxy is cyclopropyloxy or cyclobutyloxy. In some embodiments, R 1 is, in each occurrence independently, C 1-4 In some embodiments, R 1 is, in each occurrence independently, C 1-4 alkyl, which is one to three R 11 In some embodiments, R 1 is, independently at each occurrence, methyl. In some embodiments, R 1 is, independently in each occurrence, methyl, which is 11 In some embodiments, R 1 is, independently at each occurrence, cyclopropyl. In some embodiments, R 1 is, independently in each occurrence, cyclopropyl, which is 11 In some embodiments, R 1 is, independently at each occurrence, cyclobutyl. In some embodiments, R 1 is independently, in each occurrence, cyclobutyl, which is 11 In some embodiments, R 1 is, in each occurrence independently, TIFF2024538602000033.tif12128. In some embodiments, R 1 is, in each occurrence independently, TIFF2024538602000034.tif15128. In some embodiments, R 1 is, in each occurrence independently, The file is TIFF2024538602000035.tif15128.

[0094] In any embodiment of the compound, R 2 is, in each occurrence, independently hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, C3-5 Cycloalkyl, halogen, CN, OH, C 1-4 Alkoxy, NR a R b or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 2 R 11 In some embodiments, R 3 is, at each occurrence, independently hydrogen, methyl, F, or Cl. In some embodiments, R 4 is, at each occurrence, independently hydrogen, methyl, or halogen. In some embodiments, R 5 is, at each occurrence, independently hydrogen or methyl. In some embodiments, R 6 is, at each occurrence, independently hydrogen or methyl. In some embodiments, R 7 is, at each occurrence, independently hydrogen or methyl. In some embodiments, R 8 is, at each occurrence, independently hydrogen or methyl. In some embodiments, R 9 is, at each occurrence, independently hydrogen, methyl, or methoxy. In some embodiments, R 10 is, in each occurrence, independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, or C 1-4 and 4-6 membered heterocyclyl optionally substituted with alkyl, the 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from N, O, and S. In some embodiments, R 11 is, in each occurrence, independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, halogen, CN, OH, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, NR a R b or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl contains 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, R 11 is, independently at each occurrence, cyclopropyl. In some embodiments, R 11is, independently at each occurrence, cyclobutyl. In some embodiments, R 11 is, independently in each occurrence, an oxetane.

[0095] In any embodiment of the compounds of the invention, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0096] In any embodiment, the compound is TIFF2024538602000036.tif62133.

[0097] In any embodiment, the compound is TIFF2024538602000037.tif62128 is an example.

[0098] In any embodiment, the compound is Selected from TIFF2024538602000038.tif62130.

[0099] In some embodiments, the present technology relates to compounds of formulas (I), (II), and (III), including each exemplary compound, in which at least one hydrogen (H) is replaced with deuterium (D). Enriching with deuterium may provide certain therapeutic advantages, such as increased in vivo half-life or reduced dosage requirements, or may provide compounds useful as standards for characterization of biological samples. In some other embodiments, the compounds provided herein may have an isotopic enrichment factor for each deuterium present at a site designated as a potential deuterium site on the compound of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0100] In another aspect, the present technology relates to pharmaceutical compositions comprising compounds disclosed herein (including, but not limited to, compounds of Formulas (I), (II), and (III)) and a pharmaceutically acceptable carrier.

[0101] In yet another aspect, the present technology relates to a method for treating or preventing a disease or condition responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein (including, but not limited to, compounds of Formulas (I), (II), and (III)).

[0102] In yet another aspect, the present technology relates to methods for treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein (including but not limited to compounds of Formulas (I), (II), and (III)), wherein the disease or condition is a genetic disease, a neurodegenerative disorder, a metabolic disorder, an inflammatory syndrome, or cancer. In some embodiments, the genetic disease is cryopyrin-associated periodic syndrome. In some embodiments, the neurodegenerative disorder is multiple sclerosis, Alzheimer's disease, or Parkinson's disease. In some embodiments, the metabolic disorder is atherosclerosis or type 2 diabetes. In some embodiments, the inflammatory syndrome is a gout flare or osteoarthritis.

[0103] In yet another aspect, the present technology relates to processes for making compounds of Formulas (I), (II), and (III), including each of the exemplary compounds and intermediates described herein. [Example]

[0104] General synthesis method The compounds of the present technology can be synthesized using the methods described herein, together with synthetic methods known in the field of synthetic organic chemistry, or by variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, the exemplary schemes and working examples thereof described below. All substituents are as defined herein above unless otherwise indicated. Reactions are carried out in a solvent or solvent mixture appropriate to the reagents and materials used and suitable for the proposed transformation. This will often require judgment to modify the order of synthetic steps or select a particular process scheme over another to obtain the desired compound of the present technology.

[0105] It will be recognized that another major consideration in planning any synthetic route in this field is the judicious selection of protecting groups used to protect reactive functional groups present in the compounds described in this technology. An authoritative description describing many alternatives for the trained practitioner is provided by Greene et al., "Greene's Protective Groups in Organic Synthesis," Fifth Edition, Wiley (2014). It will also be recognized that the names of compounds referred to in the descriptions of Schemes 1-3 are for convenience only and do not necessarily reflect the actual chemical names of those compounds. TIFF2024538602000039.tif54165

[0106] Scheme 1 describes a general synthetic route to compounds of Formula (I). Treatment of compounds 1 and 2 under Suzuki coupling conditions in a suitable solvent (e.g., 1,4-dioxane / water) in the presence of a Pd catalyst (e.g., Pd(dppf)Cl) and a base (e.g., KCO) provides compound 3. Treatment of compound 3 with triphosgene in the presence of a base (e.g., TEA, DIPEA) in a suitable solvent (e.g., DCM, THF) provides an isocyanate intermediate, which then reacts with compound 4 in the presence of a base (e.g., NaH, t-BuONa) in a suitable solvent (e.g., THF, CHCN) to provide the desired compound of Formula (I). TIFF2024538602000040.tif54165

[0107] Scheme 2 describes a general synthetic route to compounds of formula (II). Compounds 1 and 5 are treated under Suzuki coupling conditions in a suitable solvent (e.g., 1,4-dioxane / water) in the presence of a Pd catalyst (e.g., Pd(dppf)Cl) and a base (e.g., KCO) to give compound 6. Treatment of compound 6 with triphosgene in the presence of a base (e.g., TEA, DIPEA) in a suitable solvent (e.g., DCM, THF) gives an isocyanate intermediate, which then reacts with compound 4 in the presence of a base (e.g., NaH, t-BuONa) in a suitable solvent (e.g., THF, CHCN) to give compounds of formula (II). TIFF2024538602000041.tif53166

[0108] Scheme 3 describes a general synthetic route to compounds of formula (III). Compounds 1 and 7 are treated under Suzuki coupling conditions in a suitable solvent (e.g., 1,4-dioxane / water) in the presence of a Pd catalyst (e.g., Pd(dppf)Cl) and a base (e.g., KCO) to give compound 8. Treatment of compound 8 with triphosgene in the presence of a base (e.g., TEA, DIPEA) in a suitable solvent (e.g., DCM, THF) gives the isocyanate intermediate, which then reacts with compound 4 in the presence of a base (e.g., NaH, t-BuONa) in a suitable solvent (e.g., THF, CHCN) to give compounds of formula (III).

[0109] Pharmaceutical Compositions and Methods The compounds utilized in the methods described herein can be formulated into pharmaceutically acceptable compositions together with a pharmaceutically acceptable carrier or adjuvant prior to administration to a subject. In another embodiment, such pharmaceutically acceptable compositions further comprise an effective amount of an additional therapeutic agent, including those described herein, to achieve modulation of the disease or disease symptoms.

[0110] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a subject together with a compound of the present technology, which does not destroy its pharmacological activity and which is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the compound.

[0111] Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions of the present technology include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tween or other similar polymer delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilized derivatives, may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0112] The pharmaceutical compositions of the present technology can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir, preferably by oral administration or injection. The pharmaceutical compositions of the present technology can contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation can be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the formulated compound or its delivery form. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0113] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated using suitable dispersing or wetting agents (such as Tween 80) and suspending agents according to techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any smooth fixed oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethylcellulose, or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. Other commonly used surfactants, such as Tween or Span, and / or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0114] The pharmaceutical compositions of the present technology can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. For oral tablets, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. For aqueous suspensions and / or emulsions, the active ingredient can be suspended or dissolved in an oily phase combined with an emulsifying and / or suspending agent. If necessary, certain sweeteners and / or flavorings and / or coloring agents can be added.

[0115] The pharmaceutical composition of the present technology can also be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the compound of the present technology with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the active ingredient.Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0116] Topical administration of the pharmaceutical composition of the present technology is useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredients suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present technology include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifiers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of the present technology can also be applied topically to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topical transdermal patches are also included in the present technology.

[0117] The pharmaceutical compositions of the present technology can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0118] When the compositions of the present technology include a combination of a compound of the formula described herein with one or more additional therapeutic or prophylactic agents, both the compound and the additional agents should be present at dosage levels of about 1-100%, and more preferably about 5-95%, of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately from the compounds of the present technology as part of a multiple-dose regimen. Alternatively, the agents may be part of a single dosage form and mixed together with the compounds of the present technology in a single composition.

[0119] The compounds described herein can be administered, for example, by injection, intravenous, intraarterial, subdermal, intraperitoneal, intramuscular, or subcutaneous administration, or in oral, buccal, nasal, transmucosal, topical, or ophthalmic preparations, or by inhalation, at dosages ranging from about 0.5 to about 100 mg / kg of body weight every 4 to 120 hours, alternatively at dosages of 1 mg to 1000 mg / dose, or according to the requirements of the drug. The methods herein contemplate administering an effective amount of a compound or compound composition to achieve the desired or described effect. Typically, pharmaceutical compositions of the present technology will be administered about 1 to about 6 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the mode of administration. A typical preparation will contain about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound.

[0120] Lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any subject will depend on a variety of factors, including the activity of the particular compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition, or symptom, the subject's disposition to the disease, condition, or symptom, and the judgment of the treating physician.

[0121] To improve the condition of the subject, the compound, composition or combination of the present technology can be administered in a maintenance dose as needed.Then, the dosage or frequency of administration, or both, can be reduced according to the function of symptoms, when the condition is alleviated to the desired level, until the improved condition is maintained.However, the subject may need to be treated intermittently on a long-term basis based on any recurrence of disease symptoms.

[0122] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0123] The examples herein are provided to illustrate the advantages of the present technology and to further assist those skilled in the art in preparing or using the compounds of the present technology or their salts, pharmaceutical compositions, derivatives, solvates, metabolites, prodrugs, racemic mixtures, or tautomeric forms. The examples herein are also presented to more fully illustrate preferred aspects of the present technology. The examples should not be construed in any way as limiting the scope of the present technology, as defined by the appended claims. The examples may include or incorporate any of the variations, aspects, or embodiments of the present technology described above. The variations, aspects, or embodiments described above may also each further include or incorporate any or all other variations, aspects, or variations of embodiments of the present technology.

[0124] Example The abbreviations used herein are as follows: TIFF2024538602000042.tif254167TIFF2024538602000043.tif46167

[0125] General Conditions and Procedures In the following examples, chemical reagents were purchased from commercial sources (e.g., Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Company) and used without further purification. THF was continuously refluxed and freshly distilled from sodium and benzophenone under nitrogen, and dichloromethane was continuously refluxed and freshly distilled from CaH2 under nitrogen.

[0126] Flash chromatography was performed on an Ez Purifier III column with 200-300 mesh silica gel particles. Analytical and preparative thin-layer chromatography plates (TLC) were HSGF254 (0.15-0.2 mm thick, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were recorded at approximately 20-30 °C using a Brucker AMX-300 or AMX-400 NMR (Brucker, Switzerland) unless otherwise specified. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublet; ddd, doublet of doublet of doublet; dt, doublet of triplet; bs, broad signal. Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were performed by electrospray ionization (ESI) from a Waters LCT TOF mass spectrometer (Waters, USA). Compound purification was performed using a variety of conventional methods, including, but not limited to, preparative chromatography using either normal-phase or reverse-phase HPLC or flash columns, or Prep-TLC plates, under acidic, neutral, or basic conditions as appropriate.

[0127] Preparative HPLC: Unless otherwise noted, compounds were purified using a WATERS Fractionlynx system equipped with a YMC Pack Pro d8 column (5 μm, 120 A, 50 × 20 mm) and the following solvent systems: HO, AcCN, and 2% TFA in HO. The specific elution gradients were based on retention times obtained by analytical LC-MS; however, generally, all elution gradients of HO and MeCN were performed over a 7-minute run time using a flow rate of 35 mL / min. An autoblend method was used to ensure a TFA concentration of 0.1% throughout each run. The specific elution gradients were based on retention times obtained by analytical LC-MS; however, generally, all elution gradients of HO and MeCN were performed over an 8-minute run time using a flow rate of 50 mL / min.

[0128] Analytical LC-MS: Analytical LC-MS was performed on a WATERS Acquity UPLC-MS instrument equipped with an ACQUITY UPLC BEH Ci8 column (2.1 × 50 mm, 1.7 μηι) at a column temperature of 45 °C and using the following solvent systems: Solvent A: 0.1% HCOOH in HO, and Solvent B: 0.1% HCOOH in AcCN. All compounds were run using the same elution gradient, i.e., 5% to 95% solvent B, with a flow rate of 0.6 mL / min over a run time of 1.5 min.

[0129] Preparative chiral SFC separation: Stereoisomeric mixtures were separated using a Berger Minigram SFC instrument on one of the following columns: ChiralPak AS-H (10 x 250 mm), ChiralPak IA (10 x 250 mm), ChiralPak AD-H (21 x 250 mm), Phenomenex Lux-2 (21.2 x 250 mm), or ChiralPak IC (10 x 250 mm), using a flow rate of 2.5 mL / min and a column temperature of 35 °C, eluting with either 0.1% diethylamine in MeOH / CO, or 0.1% diethylamine in EtOH / CO, or 0.1% diethylamine in isopropanol / CO.

[0130] Analytical chiral SFC separations: Stereoisomeric mixtures or single enantiomers were analyzed using a JASCO analytical SFC instrument on one of the following columns: ChiralPak AS-H (4.6 x 250 mm), ChiralPak IA (4.6 x 250 mm), ChiralPak AD-H (4.6 x 250 mm), Phenomenex Lux-2 (4.6 x 250 mm), or ChiralPak IC (4.6 x 250 mm), eluting with either 0.1% diethylamine in MeOH / CO, or 0.1% diethylamine in EtOH / CO, or 0.1% diethylamine in isopropanol / CO, using a flow rate of 6.0 mL / min and a column temperature of 35°C.

[0131] Preparation of intermediates Intermediate A1: 1-(cyclopropylmethyl)-1H-pyrazole-3-sulfonamide TIFF2024538602000044.tif54128 Step 1: Lithio 1-(oxan-2-yl)-1H-pyrazole-5-sulfinate (2) To a solution of 1-(oxan-2-yl)-1H-pyrazole (5 g, 32.8 mmol) in THF (80 mL) at −70° C., n-BuLi (14.4 mL, 36.1 mmol, 2.5 M in THF) was added dropwise, and the mixture was stirred at −70° C. for 1 h. Sulfur dioxide gas was bubbled through the mixture for 10 min, and the resulting mixture was stirred at −70° C. for 1 h to room temperature. The mixture was concentrated to dryness, and the residue was triturated with MTBE (40 mL). The mixture was filtered, and the filter cake was dried under vacuum to give the title compound (6.4 g, 87.6% yield) as a pale yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.26(d,J=1.3 Hz,1H),6.12(d,J=1.5 Hz,1H),5.97(dd,J=10.0,2.4 Hz,1H),3.93-3.88(m,1H),3.56-3.50(m,1H),2.25-2.16(m,1H),1.99-1.93 (m,1H),1.75-1.70(m,1H),1.61-1.48(m,3H).LC / MS(ESI)(m / z):215(M-Li) - .

[0132] Step 2: N,N-bis[(4-methoxyphenyl)methyl]-1-(oxan-2-yl)-1H-pyrazole-5-sulfonamide (3) To a solution of 1-(oxan-2-yl)-1H-pyrazole-5-sulfinic acid (200 mg, 0.92 mmol) in DCM (6 mL) was added NCS (135 mg, 1.01 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with DCM (2 × 10 mL). The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was dissolved in DCM (5 mL), and bis[(4-methoxyphenyl)methyl]amine (238 mg, 0.92 mmol) and TEA (0.4 mL, 2.77 mmol) were added at 0 °C. After stirring at room temperature for 1 h, the mixture was diluted with EtOAc, washed with water and brine, dried over NaSO, filtered, and concentrated to dryness to give the title compound (0.4 g, 91.7% yield) as a yellow solid. LC / MS(ESI)m / z:472(M+H) + .

[0133] Step 3: N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide To a solution of N,N-bis[(4-methoxyphenyl)methyl]-1-(oxan-2-yl)-1H-pyrazole-3-sulfonamide (400 mg, 0.85 mmol) in THF (10 mL) was added 1 N aqueous HCl (1.6 mL, 1.6 mmol), and the mixture was stirred at 25 °C for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (0.32 g, 97.4% yield) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 7.88(d,J=2.4 Hz,1H),7.01(t,J=5.7 Hz,4H),6.76-6.72(m,4H),6.61(d,J=2.4 Hz,1H),4.27(s,4H),3.75(s,6H).LC / MS(ESI)(m / z):388(M+H) + .

[0134] Step 4: 1-(cyclopropylmethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (480 mg, 1.23 mmol) in DMF (5 mL) was added methyl(bromomethyl)cyclopropane (334 mg, 2.47 mmol) and K2CO3 (513 mg, 3.71 mmol), and the mixture was stirred at 80 °C for 2 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) to give the title compound (480 mg, 87.4% yield) as a white solid. 1 H NMR(400 MHz,CDCl3)δ 7.54(d,J=2.3 Hz,1H),7.05(d,J=8.6 Hz,4H),6.76(d,J=8.6 Hz,4H),6.66(d,J=2.3 Hz,1H),4.32(s,4H),4.04(d,J=7.2 Hz,2H),3.78(s,6H),1.35-1.25(m,1H),0.69(q,J=5.8 Hz,2H),0.41(q,J=5.0 Hz,2H).LC / MS(ESI)m / z:442(M+H) + .

[0135] Step 5: 1-(cyclopropylmethyl)-1H-pyrazole-3-sulfonamide A solution of 1-(cyclopropylmethyl)-N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-3-sulfonamide (480 mg, 1.08 mmol) in TFA (5 mL) was stirred at 35 °C for 1 h. The reaction mixture was concentrated to dryness, and the residue was neutralized with saturated aqueous NaHCO3. The mixture was extracted with DCM (2 × 10 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (190 mg, 87.4% yield) as a white solid. LC / MS (ESI) m / z: 202 (M+H). + .

[0136] Intermediate A2: 1-Cyclopropyl-1H-pyrazole-3-sulfonamide TIFF2024538602000045.tif21128 Step 1: 1-Cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (200 mg, 0.52 mmol) in 1,4-dioxane (5 mL) was added cyclopropylboronic acid (49 mg, 0.57 mmol), 2,2'-bipyridine (80 mg, 0.52 mmol), and sodium carbonate (82 mg, 0.77 mmol) at room temperature, and the mixture was stirred at 25 °C for 0.5 h. Cu(OAc) (94 mg, 0.52 mmol) was then added, and the mixture was stirred at 70 °C for 16 h in air. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (140 mg, 63.4% yield) as a yellow solid. LC / MS(ESI)(m / z):428(M+H) + .

[0137] Step 2: 1-Cyclopropyl-1H-pyrazole-3-sulfonamide To a solution of 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (130 mg, 0.30 mmol) in DCM (2 mL) was added TFA (4 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated to dryness, and the residue was neutralized with saturated aqueous NaHCO and extracted with DCM (2 × 10 mL). The combined organic layers were washed with water and brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (45 mg, 79.1% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.91(d,J=1.9 Hz,1H),7.38(s,2H),6.55(d,J=2.1 Hz,1H),3.86-3.75(m,1H),1.10-1.04(m,2H),1.03-0.98(m,2H).LC / MS(ESI)(m / z):188(M+H) + .

[0138] Intermediate A3: 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide TIFF2024538602000046.tif83128 Step 1: 4-Iodo-1-(oxan-2-yl)-1H-pyrazole To a mixture of 4-iodo-1H-pyrazole (7 g, 36 mmol) and p-toluenesulfonic acid (620 mg, 3.6 mmol) in DCM (40 mL) was added 3,4-dihydro-2H-pyran (4.6 g, 54.1 mmol), and the reaction was stirred at room temperature for 3 h. The mixture was diluted with DCM (50 mL), washed with saturated aqueous NaHCO and brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (6.5 g, 64.8% yield) as a yellow solid. LC / MS (ESI) m / z: 279 (M+H). + .

[0139] Step 2: S-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzothioate To a solution of 4-iodo-1-(oxan-2-yl)-1H-pyrazole (6.5 g, 23.4 mmol) in toluene (100 mL), benzenecarbothioic acid (3.9 g, 28.0 mmol), 1,10-phenanthroline (840 mg, 4.7 mmol), DIPEA (6.0 g, 46.7 mmol), and CuI (450 mg, 2.3 mmol) were added under N atmosphere. The mixture was degassed three times under N atmosphere and stirred at 110 °C for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (5.1 g, 75.7% yield) as a yellow solid. LC / MS(ESI)m / z:289(M+H) + .

[0140] Step 3: 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-sulfonyl chloride To a solution of benzyltrimethylammonium chloride (10.8 g, 58.4 mmol) in CHCN (30 mL) was added 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (4.52 g, 19.5 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered, and the filtrate was added dropwise to a solution of S-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzothioate (5.1 g, 17.7 mmol) in CHCN (30 mL) at 0 °C. 1N aqueous NaCO solution (5.2 mL) was added to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc, washed with water and brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (4.3 g, 96.9% yield) as a colorless oil.

[0141] Step 4: N,N-bis(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-sulfonamide To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-sulfonyl chloride (4.3 g, 17.1 mmol) in THF (80 mL) was added bs(4-methoxybenzyl)amine (6.8 g, 26.5 mmol) followed by DIPEA (6.9 g, 53.1 mmol) in THF (80 mL) at 0 °C, and the mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc (50 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (5.6 g, 69.4% yield) as a white solid. LC / MS (ESI) m / z: 472 (M+H). + .

[0142] Step 5: N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-4-sulfonamide To a solution of N,N-bis[(4-methoxyphenyl)methyl]-1-(oxan-2-yl)-1H-pyrazole-4-sulfonamide (5.6 g, 11.9 mmol) in THF (40 mL) and EtOH (40 mL) was added 1N aqueous HCl (23.7 mL, 23.7 mmol), and the mixture was stirred at room temperature for 16 h. The reaction was diluted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (3.6 g, 78.2% yield) as a white solid. LC / MS (ESI) m / z: 472 (M+H). + .

[0143] Step 6: 1-(cyclopropylmethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide To a mixture of N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-4-sulfonamide (2 g, 5.16 mmol) and (bromomethyl)cyclopropane (836 mg, 6.19 mmol) in DMF (10 mL) was added K2CO3 (2.14 g, 15.5 mmol), and the reaction solution was stirred at 90 °C for 4 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give the title compound (1.8 g, 78.9% yield) as a yellow solid. LC / MS (ESI) m / z: 442 (M+H). + .

[0144] Step 7: 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide A mixture of 1-(cyclopropylmethyl)-N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-4-sulfonamide (1.8 g, 4.08 mmol) in TFA (10 mL) was stirred at room temperature for 16 hours. The mixture was concentrated to dryness, and the residue was neutralized with saturated aqueous NaHCO. The mixture was extracted with EtOAc (2 x 20 mL), and the combined organic layers were washed with water and brine, dried over NaSO, filtered, and concentrated to dryness to give the title compound (310 mg, 94.5% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.20(s,1H),7.71(s,1H),7.23(s,2H),4.00(d,J=7.2Hz,2H),1.27-1.21 (m,1H),0.56-0.51(m,2H),0.41-0.33(m,2H).LC / MS(ESI)m / z:202(M+H) + .

[0145] Intermediate A4: 1-(cyclobutylmethyl)-1H-pyrazole-3-sulfonamide TIFF2024538602000047.tif23128 Step 1: 1-(cyclobutylmethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (400 mg, 1.03 mmol) in DMF (5 mL) were added (bromomethyl)cyclobutane (0.17 mL, 1.55 mmol) and K2CO3 (428 mg, 3.1 mmol) at room temperature, and the mixture was stirred at 80 °C for 30 min. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (330 mg, 70.2% yield) as a yellow solid. LC / MS (ESI) (m / z): 456 (M+H). + .

[0146] Step 2: 1-(cyclobutylmethyl)-1H-pyrazole-3-sulfonamide To a solution of 1-(cyclobutylmethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (330 mg, 0.72 mmol) in DCM (4 mL) was added TFA (2 mL) at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated to dryness, and the residue was neutralized with saturated aqueous NaHCO3. The mixture was extracted with DCM (2 × 10 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (110 mg, 70.9% yield) as a pale yellow solid. LC / MS (ESI) (m / z): 216 (M+H). + .

[0147] Intermediate A5: 1-Cyclobutyl-1H-pyrazole-4-sulfonamide TIFF2024538602000048.tif23128 Step 1: 1-Cyclobutyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide To a mixture of N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (150 mg, 0.38 mmol) and bromocyclobutane (78 mg, 0.58 mmol) in DMF (3 mL) was added K2CO3 (160 mg, 1.16 mmol), and the mixture was stirred at 80 °C for 1 h. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (150 mg, 93.2% yield) as a white solid. LC / MS (ESI) (m / z): 442 (M+H). + .

[0148] Step 2: 1-Cyclobutyl-1H-pyrazole-4-sulfonamide A solution of 1-cyclobutyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (150 mg, 0.34 mmol) in TFA (2 mL) was stirred at 50° C. for 2 hours. The reaction mixture was concentrated to dryness, and the residue was neutralized with saturated aqueous NaHCO. The mixture was extracted with DCM (2×10 mL), and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness to give the title compound (60 mg, 87.8% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.24(s,1H),7.75(s,1H),7.21(s,2H),4.94-4.85(m,2H),2.45(d,J=9.7H z,2H),2.41-2.30(m,2H),1.87-1.71(m,2H).LC / MS(ESI)(m / z):202(M+H) + .

[0149] Intermediate A6: 1-Cyclopropyl-1H-pyrazole-4-sulfonamide TIFF2024538602000049.tif24128 Step 1: 1-Cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (140 mg, 0.36 mmol) in 1,4-dioxane (5 mL) was added cyclopropylboronic acid (34 mg, 0.40 mmol), 2,2'-bipyridine (56 mg, 0.36 mmol), NaCO (61 mg, 0.58 mmol), and Cu(OAc) (65 mg, 0.36 mmol), and the mixture was stirred at 70 °C under an O atmosphere for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (130 mg, 84.2% yield) as a yellow solid. LC / MS (ESI) (m / z): 428 (M+H). + .

[0150] Step 2: 1-Cyclopropyl-1H-pyrazole-4-sulfonamide To a solution of 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (130 mg, 0.30 mmol) in DCM (2 mL) was added TFA (4 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated to dryness. The residue was neutralized with saturated aqueous NaHCO and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness to give the title compound (80 mg, 45.5% yield) as a yellow solid. 1 H NMR(400 MHz,CDCl3-d6)δ 7.93(s,1H),7.77(s,1H),5.17(s,2H),3.70-3.59(m,1H),1.17-1.12(m,2H),1.10-1.05(m,2H).LC / MS(ESI)(m / z):188(M+H) + .

[0151] Intermediate A7: 5-(cyclopropyl(methoxy)methyl)-1-methyl-1H-pyrazole-3-sulfonamide TIFF2024538602000050.tif57128 Step 1: (3-Bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methanol To a solution of 3-bromo-1-methyl-1H-pyrazole (5 g, 31.0 mmol) in THF (10 mL) was added LDA (18.6 mL, 37.2 mmol) dropwise at −70°C, and the mixture was stirred at −70°C for 0.5 h. A solution of cyclopropanecarbaldehyde (3.4 mL, 46.5 mmol) in THF (10 mL) was added dropwise to the mixture at −70°C, and the resulting mixture was stirred at −70°C for 2 h until room temperature. The reaction mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (2.1 g, 29.3% yield) as a pale yellow oil. LC / MS(ESI)(m / z):231(M+H) + .

[0152] Step 2: 3-Bromo-5-(cyclopropyl(methoxy)methyl)-1-methyl-1H-pyrazole To a solution of (3-bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methanol (500 mg, 2.1 mmol) in DMF (5 mL) was added NaH (104 mg, 4.3 mmol, 60% dispersion in mineral oil) at 0 °C, and the mixture was stirred at this temperature for 30 min. Iodomethane (0.6 mL, 10.8 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice water and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (0–20% EtOAc in PE) to give the title compound (500 mg, 94.2% yield) as a pale yellow oil. LC / MS (ESI) (m / z): 245 (M+H). + .

[0153] Step 3: 3-(benzylthio)-5-(cyclopropyl(methoxy)methyl)-1-methyl-1H-pyrazole To a solution of 3-bromo-5-[(R)-cyclopropyl(methoxy)methyl]-1-methyl-1H-pyrazole (500 mg, 2.1 mmol) in 1,4-dioxane (10 mL) was added phenylmethanethiol (0.24 mL, 2.0 mmol), Pd(dba) (187 mg, 0.2 mmol), Xant-Phos (236 mg, 0.4 mmol), and DIPEA (1.0 mL, 6.1 mmol), and the mixture was stirred at 120 °C for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (300 mg, 50.9% yield) as a pale yellow oil. LC / MS (ESI) (m / z): 289 (M+H). + .

[0154] Step 4: 5-(cyclopropyl(methoxy)methyl)-1-methyl-1H-pyrazole-3-sulfonyl chloride To a solution of 3-(benzylsulfanyl)-5-[cyclopropyl(methoxy)methyl]-1-methyl-1H-pyrazole (150 mg, 0.5 mmol) in HO (1 mL) and AcOH (5 mL) was added NCS (347 mg, 2.6 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was poured into water and extracted with DCM (2 × 5 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (100 mg, 72.6% yield) as a pale yellow oil. LC / MS (ESI) (m / z): 265 (M+H). + .

[0155] Step 5: 5-(cyclopropyl(methoxy)methyl)-1-methyl-1H-pyrazole-3-sulfonamide To a solution of 5-(cyclopropyl(methoxy)methyl)-1-methyl-1H-pyrazole-3-sulfonyl chloride (100 mg, 0.38 mmol) in THF (2 mL) was added NH3 / THF (2 mL, 1 M), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative TLC (10% MeOH in DCM) to give the title compound (80 mg, 86.3% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 6.58(s,1H),4.25(t,J=7.0Hz,2H),3.86(s,3H),3.20(s,3H),1.28-1.22(m,1H),0. 70-0.64(m,1H),0.56-0.44(m,2H),0.22-0.18(m,1H).LC / MS(ESI)(m / z):246(M+H) + .

[0156] Intermediate A8: Cyclopropyl(1-methyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl acetate TIFF2024538602000051.tif60128 Step 1: (3-Bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methyl acetate A solution of (3-bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methanol (1 g, 4.33 mmol) in AcO (2.21 g, 21.6 mmol) was stirred at 90 °C for 16 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give the title compound (610 mg, 51.6% yield) as a colorless oil. LC / MS (ESI) (m / z): 273 (M+H). + .

[0157] Step 2: [3-(benzylsulfanyl)-1-methyl-1H-pyrazol-5-yl](cyclopropyl)methyl acetate To a mixture of (3-bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methyl acetate (600 mg, 2.19 mmol) and phenylmethanethiol (545 mg, 4.39 mmol) in 1,4-dioxane (10 mL) was added Xant-Phos (254 mg, 0.44 mmol), Pd(dba) (201 mg, 0.22 mmol), and DIPEA (1.09 mL, 6.59 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 95 °C for 12 h under a N atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (420 mg, 60.5% yield) as a yellow solid. LC / MS (ESI) (m / z): 317 (M+H). + .

[0158] Step 3: [3-(chlorosulfonyl)-1-methyl-1H-pyrazol-5-yl](cyclopropyl)methyl acetate To a solution of [3-(benzylsulfanyl)-1-methyl-1H-pyrazol-5-yl](cyclopropyl)methyl acetate (400 mg, 1.26 mmol) in AcOH (4 mL, 69.8 mmol), 1,3-dichloro-5,5-dimethylhydantoin (1.24 g, 6.32 mmol) and HO (1 mL) were added at 0 °C, and the mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (80 mg, 21.6% yield) as a yellow solid. LC / MS (ESI) (m / z): 293 (M+H). + .

[0159] Step 4: Cyclopropyl(1-methyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl acetate To a solution of [3-(chlorosulfonyl)-1-methyl-1H-pyrazol-5-yl](cyclopropyl)methyl acetate (50 mg, 0.17 mmol) in DCM (5 mL) was added NH3 / THF (5 mL, 1 M) at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was concentrated to dryness to give (35 mg, 75% yield) as a yellow solid. LC / MS (ESI) m / z: 274 (M+H). + .

[0160] Intermediate A9: 5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-3-sulfonamide TIFF2024538602000052.tif66128 Step 1: (3-Bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methanol To a solution of 3-bromo-1-methyl-1H-pyrazole (2 g, 12.4 mmol) in THF (15 mL) was added LDA (6.5 mL, 13 mmol, 2 M in THF) dropwise at −70°C, and the mixture was stirred at −70°C for 1 h. A solution of cyclopropanecarbaldehyde (0.9 mL, 12.4 mmol) in THF (5 mL) was added to the mixture at −70°C, and the resulting mixture was stirred at −70°C for 1 h until room temperature. The reaction mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (700 mg, 24.3% yield) as a pale yellow oil. LC / MS(ESI)(m / z):231(M+H) + .

[0161] Step 2: 3-Bromo-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole To a solution of (3-bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methanol (700 mg, 3.0 mmol) in DCM (5 mL) was added triethylsilane (2.9 mL, 18.1 mmol) and TFA (1.3 mL, 18.1 mmol) at room temperature, and the mixture was stirred at 40 °C for 16 h. The reaction mixture was poured into saturated aqueous NaHCO and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (330 mg, 50.6% yield) as a pale yellow oil. LC / MS (ESI) (m / z): 215 (M+H). + .

[0162] Step 3: 3-(benzylthio)-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole To a solution of 3-bromo-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole (150 mg, 0.7 mmol) in 1,4-dioxane (5 mL) was added phenylmethanethiol (0.1 mL, 0.7 mmol), Pd(dba) (127.7 mg, 0.1 mmol), Xant-Phos (161.4 mg, 0.2 mmol), and DIPEA (0.3 mL, 2.0 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 120 °C for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (70 mg, 38.8% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 7.33-7.21(m,5H),6.08(s,1H),4.11(s,2H),3.67(s,3H),2.48(d,J=7.2Hz,2H),0. 97-0.91(m,1H),0.51-0.46(m,2H),0.16-0.13(m,2H).LC / MS(ESI)(m / z):259(M+H) +

[0163] Step 4: 5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-3-sulfonyl chloride To a solution of 3-(benzylsulfanyl)-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole (70 mg, 0.27 mmol) in AcOH (5 mL) and HO (1 mL) was added NCS (144 mg, 1.1 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (60 mg, 94.4% yield) as a pale yellow oil. LC / MS (ESI) (m / z): 235 (M+H). + .

[0164] Step 5: 5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-3-sulfonamide To a solution of 5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-3-sulfonyl chloride (60 mg, 0.2 mmol) in DCM (5 mL) was added NH3 / THF (5 mL, 1 M) at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (50 mg, 90% yield) as a yellow solid. LC / MS (ESI) (m / z): 216 (M+H). +

[0165] Intermediate A10: 1-Cyclobutyl-1H-pyrazole-3-sulfonamide TIFF2024538602000053.tif26128 Step 1: 1-Cyclobutyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (500 mg, 1.29 mmol) in DMF (5 mL) was added NaH (67 mg, 1.68 mmol, 60% dispersion in mineral oil) at 0 °C under a N atmosphere, and the mixture was stirred at 25 °C for 0.5 h. Bromocyclobutane (0.13 mL, 1.42 mmol) was added to the mixture, and the mixture was stirred at 50 °C for 3 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (400 mg, 70.2% yield) as a colorless oil. LC / MS(ESI)(m / z):442(M+H) + .

[0166] Step 2: 1-Cyclobutyl-1H-pyrazole-3-sulfonamide To a solution of 1-cyclobutyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (300 mg, 0.68 mmol) in DCM (2 mL) was added TFA (4 mL) at 0° C., and the mixture was stirred at 25° C. for 1 h. The mixture was concentrated to dryness under vacuum to give the title compound (100 mg, 73.5% yield) as a yellow solid. LC / MS (ESI) (m / z): 202 (M+H). + .

[0167] Intermediate A11: (S)-1-(2-methoxypropyl)-1H-pyrazole-3-sulfonamide TIFF2024538602000054.tif58128 Step 1: (S)-1-(2-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide To a stirred solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (300 mg, 0.77 mmol) in MeCN (5 mL) was added (S)-2-methyloxirane (0.11 mL, 1.55 mmol) and K2CO3 (214.0 mg, 1.55 mmol) at room temperature. The mixture was then stirred in a sealed tube at 65 °C for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to give the title compound (300 mg, 86.9% yield) as a yellow oil. LC / MS (ESI) (m / z): 345 (M+H). + .

[0168] Step 2: (S)-N,N-bis(4-methoxybenzyl)-1-(2-methoxypropyl)-1H-pyrazole-3-sulfonamide To a solution of (S)-1-(2-hydroxypropyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (300 mg, 0.673 mmol) in DMF (3 mL) was added NaH (19.4 mg, 0.81 mmol, 60% dispersion in mineral oil) at 0 °C under a N atmosphere, and the mixture was stirred at room temperature for 30 min. MeI (382 mg, 2.69 mmol) was added, and the resulting mixture was stirred at 25 °C for 2 h. The mixture was quenched with aqueous NH4Cl and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (200 mg, 64.6% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.51(d,J=2.2Hz,1H),7.04(d,J=8.5Hz,4H),6.76(d,J=8.6Hz,4H),6.62(d,J=2.2Hz,1H),4.29(s,3H),4.22(dd,J=14.0,3 .7Hz,1H),4.10(dd,J=14.0,7.4Hz,1H),3.75-3.67(m,1H),3.25(s,3H),1.14(d,J=6.3Hz,3H).LC / MS(ESI)(m / z):460(M+H) + .

[0169] Step 3: (S)-1-(2-Methoxypropyl)-1H-pyrazole-3-sulfonamide To a solution of (S)-N,N-bis(4-methoxybenzyl)-1-(2-methoxypropyl)-1H-pyrazole-3-sulfonamide (130 mg, 0.30 mmol) in DCM (2 mL) was added TFA (4 mL) at 0° C., and the mixture was stirred at 25° C. for 1 h. The mixture was concentrated to dryness under reduced pressure and dried to give the title compound (60 mg, 62.9% yield) as a yellow solid. LC / MS (ESI) (m / z): 220 (M+H). + .

[0170] Intermediate A12: (R)-1-(2-methoxypropyl)-1H-pyrazole-3-sulfonamide TIFF2024538602000055.tif59128 Step 1: 1-[(2R)-2-hydroxypropyl]-N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-3-sulfonamide To a mixture of N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-3-sulfonamide (500 mg, 1.29 mmol) and (2R)-2-methyloxirane (0.18 mL, 2.58 mmol) in MeCN (5 mL) was added KCO (357 mg, 2.58 mmol) at room temperature, and the mixture was stirred at 65 °C in a sealed tube for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) to give the title compound (440 mg, 76.5% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.48(d,J=2.2Hz,1H),7.06(d,J=8.6Hz,4H),6.66(d,J=2.2Hz,1H),4.32(s,4H),4.23-4.15 (m,2H),4.05-4.00(m,1H),3.78(s,6H),1.23(d,J=6.3Hz,3H).LC / MS(ESI)(m / z):446(M+H) + .

[0171] Step 2: N,N-bis[(4-methoxyphenyl)methyl]-1-[(2R)-2-methoxypropyl]-1H-pyrazole-3-sulfonamide To a solution of 1-[(2R)-2-hydroxypropyl]-N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-3-sulfonamide (240 mg, 0.54 mmol) in DMF (3 mL) was added NaH (25.9 mg, 0.65 mmol, 60% dispersion in mineral oil) at 0 °C under a N atmosphere, and the mixture was stirred at room temperature for 30 min. MeI (0.13 mL, 2.16 mmol) was added at 0 °C, and the mixture was stirred at room temperature for an additional 1 h. The mixture was quenched with ice water and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (210 mg, 84.8% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.52(d,J=1.8Hz,1H),7.05(d,J=8.5Hz,4H),6.76(d,J=8.5Hz,4H),6.63(d,J=1.8Hz,1H),4.30(s,4H),4.26-4.20(m,1 H),4.14-4.08(m,1H),3.78(s,6H),3.74-3.69(m,1H),3.26(s,3H),1.15(d,J=6.2Hz,3H).LC / MS(ESI)(m / z):460(M+H) + .

[0172] Step 3: (R)-1-(2-Methoxypropyl)-1H-pyrazole-3-sulfonamide To a solution of N,N-bis[(4-methoxyphenyl)methyl]-1-[(2R)-2-methoxypropyl]-1H-pyrazole-3-sulfonamide (210 mg, 0.46 mmol) in DCM (2 mL) was added TFA (1 mL) at 0 °C, and the mixture was stirred at room temperature for 3 h. The mixture was concentrated to dryness and coevaporated twice with DCM. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to give the title compound (93 mg, 92.8% yield) as a white solid. 1H NMR(400 MHz,CDCl3)δ 7.53(d,J=2.1 Hz,1H),6.70(d,J=2.1 Hz,1H),5.21(s,2H),4.23(dd,J=14.0,3.3 Hz,1H),4.10(dd,J=14.0,7.6 Hz,1H),3.75-3.68(m,1H),3.26(s,3H),1.16(d,J=6.2 Hz,3H).LC / MS(ESI)(m / z):220(M+H) + .

[0173] Intermediate A13: 1-(cyclobutylmethyl)-1H-pyrazole-4-sulfonamide TIFF2024538602000056.tif21128 Step 1: 1-(cyclobutylmethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (150 mg, 0.38 mmol) in MeCN (3 mL) were added (bromomethyl)cyclobutene (86.5 mg, 0.58 mmol) and K2CO3 (161 mg, 1.16 mmol) at room temperature, and the mixture was stirred at 85 °C for 3 h. The mixture was diluted with water and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to give the title compound (150 mg, 85% yield) as a yellow oil. LC / MS (ESI) (m / z): 321 (M+H). + .

[0174] Step 2: 1-(cyclobutylmethyl)-1H-pyrazole-4-sulfonamide A solution of 1-(cyclobutylmethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-4-sulfonamide (150 mg, 0.33 mmol) in TFA (5 mL) was stirred at 55° C. for 2 hours. The mixture was concentrated to dryness, and the residue was neutralized with saturated aqueous NaHCO. The mixture was extracted with EtOAc (3×10 mL), and the combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (70.9 mg, 100% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.81(s,2H),4.14(d,J=7.4Hz,2H),2.87-2.79(m,1H),2.14-2.07(m,2H),1.97-1.88(m,2H),1.83-1.76(m,2H).LC / MS(ESI)m / z:216(M+H) + .

[0175] Intermediate A14: 5-(cyclopropyl(methyl)amino)pyridine-3-sulfonamide TIFF2024538602000057.tif48128 Step 1: 5-Bromo-N-cyclopropylpyridin-3-amine To a mixture of 3-bromo-5-fluoropyridine (5 g, 0.028 mol) and cyclopropanamine (1.90 mL, 0.056 mol) in NMP (50 mL) was added K2CO3 (11.6 g, 0.084 mol), and the reaction mixture was stirred at 180 °C for 3 h. The reaction mixture was poured into ice water and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (1.3 g, 45.3% yield) as a pale yellow solid. LC / MS (ESI) (m / z): 214 (M+H). + .

[0176] Step 2: 5-Bromo-N-cyclopropyl-N-methylpyridin-3-amine To a solution of 5-bromo-N-cyclopropylpyridin-3-amine (780 mg, 3.66 mmol) in dry DMF (10 mL) was added NaH (176 mg, 4.4 mmol, 60% dispersion in mineral oil) at 0 °C, and the mixture was stirred at this temperature for 20 min. Iodomethane (0.27 mL, 4.39 mmol) was added dropwise to the mixture, and the resulting mixture was stirred at room temperature for 30 min. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (600 mg, 92.3% yield) as a colorless oil. LC / MS (ESI) (m / z): 228 (M+H). + .

[0177] Step 3: 5-(benzylthio)-N-cyclopropyl-N-methylpyridin-3-amine To a mixture of 5-bromo-N-cyclopropyl-N-methylpyridin-3-amine (200 mg, 0.88 mmol) and phenylmethanethiol (0.13 mL, 1.14 mmol) in anhydrous 1,4-dioxane (5 mL) was added DIPEA (0.3 mL, 1.76 mmol), Xant-Phos (25 mg, 0.044 mmol), and Pd(dba) (16 mg, 0.017 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 120 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–17% EtOAc in PE) to give the title compound (220 mg, 93.2% yield) as a yellow solid. LC / MS(ESI)(m / z):272(M+H) + .

[0178] Step 4: 5-(cyclopropyl(methyl)amino)pyridine-3-sulfonamide To a solution of 5-(benzylthio)-N-cyclopropyl-N-methylpyridin-3-amine (100 mg, 0.37 mmol) in AcOH (4 mL) and water (1 mL) was added NCS (197 mg, 1.48 mmol) and 1N aqueous HCl (2 mL) under a N atmosphere, and the mixture was stirred at room temperature for 1 h. The mixture was poured into water and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over NaSO, and filtered. The filtrate was added to a NH / THF solution (10 mL, 1 M) at −50° C., and the resulting mixture was stirred at this temperature for 30 min. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by flash chromatography (silica gel, 0–60% EtOAc in PE) to give the title compound (80 mg, 50% yield) as a white solid. LC / MS (ESI) (m / z): 228 (M+H). + .

[0179] Intermediate A15: 5-(cyclopropylamino)pyridine-3-sulfonamide TIFF2024538602000058.tif36128 Step 1: 5-(benzylthio)-N-cyclopropylpyridin-3-amine To a stirred solution of 5-bromo-N-cyclopropylpyridin-3-amine (2.0 g, 8.81 mmol) in 1,4-dioxane (25 mL) under a N atmosphere was added phenylmethanethiol (1.3 mL, 11.4 mmol), Pd(dba) (0.14 g, 0.18 mmol), Xant-Phos (250 mg, 0.44 mmol), and DIPEA (2.3 g, 17.6 mmol). The mixture was degassed three times under a N atmosphere and stirred at 100 °C for 3 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (1.2 g, 50.4% yield) as a brown solid. LC / MS(ESI)(m / z):257(M+H) + .

[0180] Step 2: 5-(Cyclopropylamino)pyridine-3-sulfonyl chloride To a stirred solution of 5-(benzylthio)-N-cyclopropylpyridin-3-amine (200 mg, 0.78 mmol) in AcOH (4 mL) / HO (1 mL) was added NCS (416 mg, 3.12 mmol) in portions at 0° C. After stirring at room temperature for 1 h, the mixture was poured into water and extracted with DCM (3×10 mL). The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated to dryness to give the title compound (120 mg, 66.0% yield) as a yellow solid, which was used directly in the next reaction without purification. LC / MS (ESI) (m / z): 233 (M+H). + .

[0181] Step 3: 5-(cyclopropylamino)pyridine-3-sulfonamide A mixture of 5-(cyclopropylamino)pyridine-3-sulfonyl chloride (120 mg, 0.48 mmol) in NH3 / THF solution (5 mL, 1 M) was stirred at room temperature for 1 h. The mixture was poured into water and extracted with DCM (3 × 10 mL). The combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (40 mg, 36.0% yield) as a white solid. LC / MS (ESI) (m / z): 214 (M+H). + .

[0182] Intermediate A16: 2-morpholinopyridine-4-sulfonamide TIFF2024538602000059.tif68128 Step 1: 4-(4-Bromopyridin-2-yl)morpholine To a stirred solution of 4-bromo-2-fluoropyridine (0.6 mL, 5.68 mmol) in NMP (15 mL) was added morpholine (0.5 mL, 5.68 mmol) at room temperature, and the mixture was stirred at 100° C. for 2 h. The mixture was diluted with water and extracted with EtOAc (2×15 mL). The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (1.2 g, 86.9% yield) as a yellow oil. LC / MS (ESI) (m / z): 243 (M+H). + .

[0183] Step 2: 4-(4-(benzylthio)pyridin-2-yl)morpholine To a stirred solution of 4-(4-bromopyridin-2-yl)morpholine (800 mg, 3.29 mmol) in 1,4-dioxane (8 mL) was added phenylmethanethiol (0.5 mL, 4.28 mmol) and DIPEA (849 mg, 6.58 mmol), followed by Pd(dba) (53 mg, 0.07 mmol) and XantPhos (95 mg, 0.17 mmol) at room temperature under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 100 °C for 3 h under a N atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (500 mg, 53.1% yield) as a yellow oil. LC / MS(ESI)(m / z):287(M+H) + .

[0184] Step 3: 2-Morpholinopyridine-4-sulfonyl chloride To a stirred solution of 4-(4-(benzylthio)pyridin-2-yl)morpholine (500 mg, 1.75 mmol) in AcOH (4 mL) and HO (1 mL) was added NCS (932 mg, 6.98 mmol) in portions at 0° C., and the mixture was stirred at room temperature for 1 h. The mixture was poured into ice water and extracted with DCM (3×10 mL). The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to give the title compound (300 mg, 65.5% yield) as a yellow oil. LC / MS (ESI) (m / z): 263 (M+H). + .

[0185] Step 4: 2-Morpholinopyridine-4-sulfonamide A mixture of 2-morpholinopyridine-4-sulfonyl chloride (300 mg, 1.14 mmol) in NH3 / THF (10 mL, 1 M) was stirred at room temperature for 1 h. The mixture was poured into water and extracted with DCM (3 × 10 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (200 mg, 47.1% yield) as a white solid. LC / MS (ESI) (m / z): 244 (M+H). + .

[0186] Intermediate A17: 2-Cyclopropoxypyridine-4-sulfonamide TIFF2024538602000060.tif62128Step 1: 4-Bromo-2-cyclopropoxypyridine To a solution of cyclopropanol (0.73 g, 12.5 mmol) in DMF (20 mL) was added NaH (0.75 g, 18.6 mmol, 60% dispersion in mineral oil) at 0 °C under a N atmosphere, and the mixture was stirred at 0 °C for 30 min. 4-Bromo-2-fluoropyridine (1.17 mL, 11.36 mmol) was added at 25 °C, and the mixture was stirred at 25 °C for 2 h. The mixture was quenched with saturated aqueous NH Cl and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (1.4 g, 57.6% yield) as a yellow solid.

[0187] Step 2: 4-(benzylsulfanyl)-2-cyclopropoxypyridine To a mixture of 4-bromo-2-cyclopropoxypyridine (1 g, 4.67 mmol), phenylmethanethiol (0.71 mL, 6.07 mmol), Xantphos (0.54 g, 0.93 mmol), and DIPEA (1.54 mL, 9.34 mmol) in 1,4-dioxane (15 mL) was added Pd(dba) (0.43 g, 0.47 mmol) under N atmosphere. The mixture was degassed three times under N atmosphere and stirred at 120 °C for 3 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (850 mg, 70.7% yield) as a yellow solid. LC / MS(ESI)(m / z):258(M+H) + .

[0188] Step 3: 2-Cyclopropoxypyridine-4-sulfonamide To a solution of 4-(benzylsulfanyl)-2-cyclopropoxypyridine (800 mg, 3.11 mmol) in AcOH (4 mL), HO (1 mL), and 1 N aqueous HCl (2 mL, 2.00 mmol) was added NCS (2.15 g, 16.2 mmol) in portions at 0 °C, and the mixture was stirred at 25 °C for 2 h. The mixture was poured into ice water and extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO and filtered. The filtrate was added to a NH / THF solution (50 mL, 1 M) at −50 °C, and the resulting mixture was stirred at 25 °C for 3 h. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0–60% EtOAc in PE) to give the title compound (100 mg, 15.0% yield) as a brown oil. LC / MS(ESI)(m / z):215(M+H) + .

[0189] Intermediate A18: 5-Cyclopropoxypyridine-3-sulfonamide TIFF2024538602000061.tif56128Step 1: 3-Bromo-5-cyclopropoxypyridine To a mixture of 5-bromopyridin-3-ol (3.0 g, 17.2 mmol) and bromocyclopropane (4.17 mL, 51.7 mmol) in DMF (30 mL) was added CsCO (16.9 g, 51.7 mmol) and KI (2.86 g, 17.2 mmol), and the reaction mixture was stirred in an autoclave at 140 °C for 3 h. The reaction mixture was poured into water and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (800 mg, 32.3% yield) as a pale yellow solid. LC / MS (ESI) (m / z): 214 / 216 (M+H). + .

[0190] Step 2: 3-(benzylthio)-5-cyclopropoxypyridine To a mixture of 3-bromo-5-cyclopropoxypyridine (800 mg, 3.72 mmol) and phenylmethanethiol (0.56 mL, 4.83 mmol) in 1,4-dioxane (5.0 mL) under N atmosphere, DIPEA (1.30 mL, 7.44 mmol), Xant-Phos (108 mg, 0.05 mmol), and Pd(dba) (85 mg, 0.02 mmol) were added. The mixture was degassed three times under N atmosphere and stirred at 120 °C for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–15% EtOAc in PE) to give the title compound (950 mg, 93.2% yield) as a yellow solid. LC / MS(ESI)(m / z):258(M+H) + .

[0191] Step 3: 3-(benzylthio)-5-cyclopropoxypyridine To a solution of 3-(benzylthio)-5-cyclopropoxypyridine (100 mg, 0.37 mmol) in AcOH (4.0 mL) and water (1.0 mL) was added NCS (197 mg, 1.48 mmol) and 1N aqueous HCl (2.0 mL), and the mixture was stirred at room temperature for 1 h. The mixture was poured into ice water and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was added to NH / THF (10 mL, 1N) at −50° C., and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0–60% EtOAc in PE) to give the title compound (45 mg, 54% yield) as a white solid. LC / MS (ESI) (m / z): 215 (M+H). + .

[0192] Intermediate A19: 5-cyclobutoxypyridine-3-sulfonamide TIFF2024538602000062.tif61128Step 1: 3-(benzylthio)-5-cyclobutoxypyridine To a stirred solution of 3-bromo-5-cyclobutoxypyridine (1.0 g, 4.38 mmol) in 1,4-dioxane (15 mL) was added phenylmethanethiol (0.7 mL, 5.69 mmol) and DIPEA (1.1 g, 8.77 mmol), followed by Pd(dba) (70 mg, 0.09 mmol) and XantPhos (130 mg, 0.22 mmol) at room temperature under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred overnight at 100 °C under a N atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (1.0 g, 84.1% yield) as a yellow oil. LC / MS(ESI)(m / z):272(M+H) + .

[0193] Step 2: 5-Cyclobutoxypyridine-3-sulfonyl chloride To a stirred solution of 3-(benzylthio)-5-cyclobutoxypyridine (200 mg, 0.74 mmol) in AcOH (4 mL) and HO (1 mL) was added NCS (394 mg, 2.95 mmol) in portions at 0° C., and the mixture was stirred at room temperature for 1 h. The mixture was poured into ice water and extracted with DCM (3×10 mL). The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (150 mg, 82.4% yield) as a yellow oil. LC / MS (ESI) (m / z): 248 (M+H). + .

[0194] Step 3: 5-Cyclobutoxypyridine-3-sulfonamide A mixture of 5-cyclobutoxypyridine-3-sulfonyl chloride (150 mg, 0.61 mmol) in NH3 / THF (10 mL, 1 M) was stirred at room temperature for 1 h. The mixture was poured into water and extracted with DCM (3 × 10 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to give the title compound (120 mg, 71.3% yield) as a white solid. LC / MS (ESI) (m / z): 229 (M+H). + .

[0195] Intermediate A20: 5-(cyclobutyl(methyl)amino)pyridine-3-sulfonamide TIFF2024538602000063.tif70128 Step 1: 5-Bromo-N-cyclobutylpyridin-3-amine To a solution of 3-bromo-5-fluoropyridine (3.5 g, 19.9 mmol) and cyclobutanamine (3.41 mL, 39.8 mmol) in NMP (35 mL) was added K2CO3 (8.25 g, 59.7 mmol) at room temperature, and the mixture was stirred in an autoclave at 200 °C for 3 h. The mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (570 mg, 12.6% yield) as a yellow solid. LC / MS (ESI) (m / z): 227 (M+H). + .

[0196] Step 2: 5-Bromo-N-cyclobutyl-N-methylpyridin-3-amine To a solution of 5-bromo-N-cyclobutylpyridin-3-amine (300 mg, 1.32 mmol) in DMF (3 mL) was added NaH (79 mg, 1.98 mmol, 60% dispersion in mineral oil) at 0 °C under a N atmosphere, and the mixture was stirred at room temperature for 0.5 h. CHCl (0.12 mL, 1.98 mmol) was added at 0 °C, and the mixture was stirred at room temperature under a N atmosphere for 2 h. The mixture was quenched with saturated aqueous NHCl and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (210 mg, 65.9% yield) as a colorless oil. LC / MS (ESI) (m / z): 241 (M+H). + .

[0197] Step 3: 5-(benzylsulfanyl)-N-cyclobutyl-N-methylpyridin-3-amine To a mixture of 5-bromo-N-cyclobutyl-N-methylpyridin-3-amine (200 mg, 0.83 mmol), phenylmethanethiol (0.13 mL, 1.08 mmol), and DIPEA (214 mg, 1.66 mmol) in 1,4-dioxane (3 mL) was added XantPhos (48 mg, 0.08 mmol) and Pd(dba) (38 mg, 0.04 mmol) under N atmosphere. The mixture was degassed three times under N atmosphere and stirred at 120 °C for 3 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (210 mg, 89.0% yield) as a yellow solid. LC / MS(ESI)(m / z):285(M+H) +

[0198] Step 4: 5-[Cyclobutyl(methyl)amino]pyridine-3-sulfonamide To a solution of 5-(benzylsulfanyl)-N-cyclobutyl-N-methylpyridin-3-amine (100 mg, 0.35 mmol) in AcOH (4 mL) and HO (1 mL) was added NCS (141 mg, 1.06 mmol) and 1 N aqueous HCl (2 mL, 2.00 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h and poured into ice water. The mixture was extracted with DCM (2 × 5 mL), and the combined organic layers were washed with water and brine, dried over anhydrous NaSO, and filtered. The filtrate was poured into NH / THF (10 mL, 1 M) at 0 °C, and the resulting mixture was stirred at 25 °C for 2 h. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (40 mg, 47.1% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.42(s,1H),8.27(s,1H),7.41(s,1H),4.94(s,2H),4.13-4.05(m,1H),2.94(s,3H), 2.35-2.29(m,2H),2.18-2.10(m,2H),1.79-1.70(m,2H).LC / MS(ESI)(m / z):242(M+H) + .

[0199] Intermediate A21: 2-Cyclobutylpyridine-4-sulfonamide TIFF2024538602000064.tif65128 Step 1: tert-Butyl 1-(4-bromopyridin-2-yl)cyclobutane-1-carboxylate To a solution of tert-butyl cyclobutanecarboxylate (1.4 g, 8.96 mmol) in THF (20 mL) was added LiHMDS (13.44 mL, 1 M in THF) at −78 °C under a N atmosphere, and the mixture was stirred at −78 °C for 1 h. Then, a solution of 4-bromo-2-fluoropyridine (1.58 g, 8.96 mmol) in THF (5 mL) was added. The resulting mixture was stirred at −78 °C to room temperature for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (1.2 g, 42.9% yield) as a yellow oil. LC / MS(ESI)m / z:312(M+H) + .

[0200] Step 2: 1-(4-bromopyridin-2-yl)cyclobutane-1-carboxylic acid To a solution of tert-butyl 1-(4-bromopyridin-2-yl)cyclobutane-1-carboxylate (1.2 g, 3.84 mmol) in DCM (10 mL) was added TFA (3 mL) and the mixture was stirred at 30° C. for 2 h. The mixture was concentrated to dryness to give the title compound (0.8 g, 81.3% yield) as a brown oil, which was used directly in the next step. LC / MS (ESI) (m / z): 256 (M+H). + .

[0201] Step 3: 4-Bromo-2-cyclobutylpyridine A solution of 1-(4-bromopyridin-2-yl)cyclobutane-1-carboxylic acid (0.8 g, 3.12 mmol) in toluene (6 mL) was stirred at 90 °C for 16 h. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (620 mg, 93.6% yield) as a yellow oil. LC / MS (ESI) m / z: 212 (M+H). + .

[0202] Step 4: 4-(benzylthio)-2-cyclobutylpyridine To a mixture of 4-bromo-2-cyclobutylpyridine (620 mg, 2.92 mmol) and phenylmethanethiol (0.52 mL, 4.39 mmol) in 1,4-dioxane (6 mL), Pd(dba) (268 mg, 0.29 mmol) was added, followed by XantPhos (338 mg, 0.59 mmol) and DIEA (1.45 mL, 8.77 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 100 °C for 3 h. The reaction was washed with saturated aqueous NHCl and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–60% EtOAc in PE) to give the title compound (550 mg, 73.7% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.33(d,J=5.3Hz,1H),7.02-7.38(m,2H),7.35-7.31(m,2H),7.29-7.28(m,1H),6.99-6.98(m,1H),6.93(dd,J=5.3,1.8H z,1H),4.20(s,2H),3.63-3.54(m,1H),2.35-2.22(m,4H),2.10-1.9(m,1H),1.91-1.83(m,1H).LC / MS(ESI)m / z:256(M+H) + .

[0203] Step 5: 2-Cyclobutylpyridine-4-sulfonamide To a solution of 4-(benzylthio)-2-cyclobutylpyridine (100 mg, 0.39 mmol) in AcOH (3 mL) and HO (1 mL) was added 1,3-dichloro-5,5-dimethylhydantoin (154 mg, 0.78 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1.5 h. The mixture was diluted with water and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was added to NH / THF solution (10 mL, 1 M) at 0 °C, and the resulting mixture was stirred at room temperature for 1 h. The mixture was washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (50 mg, 60.2% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.78(d,J=5.1Hz,1H),8.08(s,2H),7.62(s,1H),7.57(dd,J=5.1,1.6Hz,1H),3.81-3.73(m ,1H),2.42-2.32(m,4H),2.17-2.05(m,1H),1.97-1.90(m,1H).LC / MS(ESI)(m / z):213(M+H) + .

[0204] Intermediate A22: 1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide TIFF2024538602000065.tif65128 Step 1: 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]pyridine-3-sulfonamide To a solution of 6-chloropyridine-3-sulfonyl chloride (2.3 g, 10.9 mmol) in DCM (25 mL) were added bis(4-methoxybenzyl)amine (2.73 mL, 11.4 mmol) and TEA (1.96 mL, 14.1 mmol) at 0° C., and the mixture was stirred at room temperature for 2 h. The mixture was washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was triturated with MTBE, filtered, and the filter cake was dried under vacuum to give the title compound (4.4 g, 93.7% yield) as a white solid. LC / MS (ESI) (m / z): 433 (M+H). + .

[0205] Step 2: 6-Hydroxy-N,N-bis[(4-methoxyphenyl)methyl]pyridine-3-sulfonamide To a solution of 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]pyridine-3-sulfonamide (4.4 g, 10.2 mmol) in ethane-1,2-diol (80 mL) was added KOH (40 mL, 80 mmol) at room temperature, and the mixture was stirred at 150 °C for 2 h. The mixture was diluted with water and extracted with CHCl / i-PrOH (3 × 40 mL, v / v = 3 / 1). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–20% MeOH in DCM) to give the title compound (4 g, 94.9% yield) as a white solid.

[0206] Step 3: 1-(cyclopropylmethyl)-N,N-bis[(4-methoxyphenyl)methyl]-6-oxo-1,6-dihydropyridine-3-sulfonamide To a mixture of 6-hydroxy-N,N-bis[(4-methoxyphenyl)methyl]pyridine-3-sulfonamide (1 g, 2.41 mmol) and LiBr (0.03 mL, 0.48 mmol) in DME (16 mL) and DMF (4 mL) was added NaH (0.09 g, 3.62 mmol, 60% dispersion in mineral oil) at 0 °C under a N atmosphere, and the mixture was stirred at 25 °C for 10 min. Then, (bromomethyl)cyclopropane (0.25 mL, 2.58 mmol) was added to the mixture, and the resulting mixture was stirred at 60 °C for 16 h. The mixture was quenched with saturated aqueous NH Cl and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (490 mg, 43.3% yield) as a colorless oil. LC / MS (ESI) (m / z): 469 (M+H). + .

[0207] Step 4: 1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide A mixture of 1-(cyclopropylmethyl)-N,N-bis[(4-methoxyphenyl)methyl]-6-oxo-1,6-dihydropyridine-3-sulfonamide (490 mg, 1.05 mmol) and TFA (10 mL) was stirred at 70 °C for 3 h. The mixture was concentrated to dryness and co-evaporated twice with DCM. The residue was neutralized with saturated aqueous NaHCO and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (200 mg, 83.7% yield) as a yellow solid. LC / MS (ESI) (m / z): 229 (M+H). + .

[0208] Intermediate A23: 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide TIFF2024538602000066.tif47128 Step 1: Methyl 5-(chlorosulfonyl)thiophene-3-carboxylate To a solution of methylthiophene-3-carboxylate (5.0 g, 35.17 mmol) in CHCl (70 mL) was added ClSOH (6.15 g, 52.75 mmol) and PCl (14.65 g, 70.33 mmol) at 0 °C under a N atmosphere. After the addition, the mixture was stirred at 60 °C for 2 h. The mixture was poured into ice water and extracted with DCM (2 × 50 mL). The combined organic layers were washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (6.5 g, 76.8% yield) as a yellow oil, which was used directly in the next reaction.

[0209] Step 2: Methyl 5-sulfamoylthiophene-3-carboxylate To a solution of methyl 5-(chlorosulfonyl)thiophene-3-carboxylate (6.5 g, 27 mmol) in DCM (50 mL) was added NH3 / THF solution (150 mL, 1 M), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give the title compound (3.7 g, 61.9% yield) as a yellow solid. LC / MS (ESI) m / z: 219 (MH) - .

[0210] Step 3: 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide To a solution of methyl 5-sulfamoylthiophene-3-carboxylate (3.7 g, 16.7 mmol) in THF (100 mL) was added MeMgBr solution (25.0 mL, 75 mmol, 3 M in THF) dropwise at 0 °C, and the mixture was stirred at room temperature under a N atmosphere for 2 h. The mixture was quenched with aqueous NH4Cl and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–5% MeOH in DCM) to give the title compound (2.78 g, 75.1% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.60(s,2H),7.56(d,J=1.7Hz,1H),7.53(d,J=1.7Hz,1H),5.22(s,1H),1.42(s,6H).LC / MS(ESI)m / z:222(M+H) + .

[0211] Intermediate A24: 1-Isopropyl-1H-pyrazole-3-sulfonamide TIFF2024538602000067.tif43128 Step 1: 3-Nitro-1-(propan-2-yl)-1H-pyrazole To a solution of 3-nitro-1H-pyrazole (5 g, 44.2 mmol) in DMF (50 mL) was added NaH (1.95 g, 48.6 mmol, 60% dispersion in mineral oil) in small amounts at 0 °C, and the mixture was stirred at room temperature for 0.5 h. To the above mixture was added 2-bromopropane (5.0 mL, 53 mmol) at 0 °C, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with MTBE (4 × 50 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–35% EtOAc in PE) to give the title compound (3.75 g, 54.7% yield) as a yellow solid. LC / MS (ESI) m / z: 156 (M+H). + .

[0212] Step 2: 1-(propan-2-yl)-1H-pyrazol-3-amine To a solution of 3-nitro-1-(propan-2-yl)-1H-pyrazole (7.7 g, 49.63 mmol) in EtOH (100 mL) and water (25 mL), NH4Cl (7.97 g, 149 mmol) and Fe (8.34 g, 149 mmol) were added, and the mixture was stirred at 80 °C for 1 h. After completion, the reaction mixture was filtered through a pad of Celite. The filter cake was washed with EtOH (2 × 20 mL). The filtrate was diluted with DCM (100 mL), washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to give the title compound (4.4 g, 70.8% yield) as a pale yellow solid. LC / MS (ESI) m / z: 126 (M+H). + .

[0213] Step 3: 1-(propan-2-yl)-1H-pyrazole-3-sulfonamide To a solution of 1-(propan-2-yl)-1H-pyrazol-3-amine (2 g, 16 mmol) in 6 N aqueous HCl (40 mL) was added dropwise a solution of NaNO (1.66 g, 24 mmol) in water (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. The mixture was added dropwise to saturated SO / AcOH solution (40 mL) at 0 °C, followed by CuCl (2.1 g, 16 mmol), and the resulting mixture was stirred at 0 °C to room temperature for 2 h. The mixture was poured into ice water and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over NaSO, and filtered. The filtrate was added dropwise to NH / THF solution (60 mL, 1 M) at 0 °C, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give the title compound (860 mg, 28.4% yield) as a white solid. LC / MS (ESI) m / z: 190 (M+H) + .

[0214] Intermediate A25: 3-Cyclopropoxycyclobutane-1-sulfonamide TIFF2024538602000068.tif77146 Step 1: 3-(benzyloxy)cyclobutan-1-ol To a solution of 3-(benzyloxy)cyclobutan-1-one (4.50 mL, 28.4 mmol) in MeOH (50 mL) was added NaBH (1.44 g, 42.5 mmol) portionwise at 0 °C, and the mixture was stirred at 0 °C for 3 h. The reaction was quenched with saturated aqueous NH Cl and extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over Na SO , filtered, and concentrated to dryness to give the title compound (5 g, 98.9% yield) as a yellow oil. LC / MS (ESI) m / z: 179 (M+H) + .

[0215] Step 2: ((3-(1-ethoxyethoxy)cyclobutoxy)methyl)benzene To a solution of 3-(benzyloxy)cyclobutan-1-ol (2.5 g, 14.0 mmol) in ethyl vinyl ether (15 mL) was added TFA (0.02 mL, 0.28 mmol) at 0 °C under a N atmosphere, and the mixture was stirred at 25 °C overnight. The mixture was diluted with saturated aqueous NaHCO and extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness to give the title compound (3.5 g, 99.7% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.37-7.26(m,5H),4.66(q,J=5.3 Hz,1H),4.42(s,2H),3.85-3.75(m,1H),3.70-3.57(m,2H),3.49-3.42(m,1H), 2.70-2.58(m,2H),2.09-1.93(m,2H),1.28(d,J=5.4Hz,3H),1.22-1.12(m,4H).

[0216] Step 3: ((3-(vinyloxy)cyclobutoxy)methyl)benzene To a solution of {[3-(1-ethoxyethoxy)cyclobutoxy]methyl}benzene (3.5 g, 14.0 mmol) in DCM (35 mL) was added TEA (5.90 mL, 42.6 mmol) and TMSOTf (7.60 mL, 41.9 mmol) under a N atmosphere at 0 °C, and the mixture was stirred at 25 °C for 3 h. The mixture was quenched with 1 N aqueous NaOH (42 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–2% EtOAc in PE) to give the title compound (1 g, 35.0% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.38-7.28(m,5H),6.34(dd,J=14.4,6.8Hz,1H),4.44(s,2H),4.14-4.06(m,1H ),4.04-3.95(m,2H),3.79-3.71(m,1H),2.80-2.69(m,2H),2.13-2.02(m,2H).

[0217] Step 4: ((3-cyclopropoxycyclobutoxy)methyl)benzene EtZn (5.40 mL, 1 M in toluene) was added to DCM (5 mL) followed by ClCHI (0.90 mL, 12.2 mmol) at 0 °C under a N atmosphere. The mixture was stirred at 0 °C for 10 min, and a solution of {[3-(ethenyloxy)cyclobutoxy]methyl}benzene (500 mg, 2.45 mmol) in DCM (3.5 mL) was added. The mixture was stirred at 0 °C for 1 h and quenched with saturated aqueous NHCl. The mixture was extracted with DCM (2 × 10 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–5% EtOAc in PE) to give the title compound (400 mg, 74.9% yield) as a colorless oil. 1H NMR(400MHz,CDCl3)δ 7.38-7.27(m,5H),4.42(s,2H),3.73-3.65(m,2H),3.24-3.19(m,1H),2. 62-2.62(m,2H),2.07-1.96(m,2H),0.58-0.54(m,2H),0.45-0.41(m,2H).

[0218] Step 5: 3-Cyclopropoxycyclobutan-1-ol To a solution of [(3-cyclopropoxycyclobutoxy)methyl]benzene (400 mg, 1.83 mmol) in MeOH (4 mL) was added Pd / C (20 mg, 10 wt%) at room temperature under a N atmosphere, and the mixture was stirred at 40 °C under a H balloon for 2 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (230 mg, 97.9% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 3.95-3.86(m,1H),3.68-3.61(m,1H),3.23-3.18(m,1H),2.76-2.70(m,2H) ,1.98(s,1H),1.93-1.87(m,2H),0.55(t,J=7.3Hz,2H),0.45-0.42(m,2H).

[0219] Step 6: 3-Cyclopropoxycyclobutyl methanesulfonate To a solution of 3-cyclopropoxycyclobutan-1-ol (150 mg, 1.17 mmol) in DCM (4 mL) was added TEA (0.32 mL, 2.34 mmol) and MsCl (0.10 mL, 1.29 mmol) under a N atmosphere at 0 °C, and the mixture was stirred at 30 °C for 2.5 h. The mixture was quenched with water and extracted with DCM (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness to give the title compound (240 mg, 99.9% yield) as a brown oil, which was used directly in the next step without further purification.

[0220] Step 7: S-(3-cyclopropoxycyclobutyl)ethanethioate To a solution of [3-(cyclopropylmethyl)cyclobutyl]methanesulfonic acid (240 mg, 1.17 mmol) in MeCN (1 mL) and DMF (4 mL) was added KSAc (534 mg, 4.68 mmol) at room temperature under a N atmosphere, and the mixture was stirred at 90 °C for 2 h. The mixture was diluted with EtOAc, washed with water and brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% EtOAc in PE) to give the title compound (217 mg, 99.9% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.30-4.24(m,1H),3.99-3.92(m,1H),3.21-3.18(m,1H),2.62-2.52(m,2H),2.32-2.23(m,5H),0.58-0.53(m,2H),0.45-0.41(m,2H).

[0221] Step 8: 3-Cyclopropoxycyclobutane-1-sulfonamide To a solution of 1-[(3-cyclopropoxycyclobutyl)sulfanyl]ethan-1-one (100 mg, 0.537 mmol) in AcOH (1 mL) and HO (0.2 mL) was added NCS (233 mg, 1.75 mmol) at 0 °C under a N atmosphere, and the mixture was stirred at 30 °C for 2 h. The mixture was poured into NH HO (10 mL, 15 wt%) at 0 °C, and the mixture was stirred at 30 °C overnight. The mixture was concentrated to dryness, and the residue was triturated with THF. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0–5% MeOH in DCM) to give the title compound (70 mg, 68.2% yield) as a colorless solid. 1H NMR(400MHz,CDCl3)δ 4.74(d,J=4.0Hz,2H),4.41-4.35(m,1H),4.06-3.98(m,1H),3.79-3.76(m,1H),3.46-3.42(m,1H),3.25-3.22 (m,1H),2.74-2.65(m,2H),2.50-2.35(m,2H),0.59-0.53(m,2H),0.48-0.43(m,2H).LC / MS(ESI)m / z:192(M+H) + .

[0222] Intermediate A26: (R)-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfonamide To a solution of 1-[(2R)-2-hydroxypropyl]-N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-3-sulfonamide (200 mg, 0.45 mmol) in DCM (3 mL) was added TFA (2 mL) at 0 °C, and the mixture was stirred at 25 °C for 3 h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% MeOH in DCM) to give the title compound (38 mg, 41.3% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.51(d,J=2.0Hz,1H),6.72(d,J=2.0Hz,1H),5.30(s,2H),4.29-4.15(m,2H),4.04(dd,J=14.4,8.8Hz,1H),1.25(s,3H).LC / MS(ESI)m / z:206(M+H) + .

[0223] Intermediate A27: (S)-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfonamide To a solution of 1-[(2S)-2-hydroxypropyl]-N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-3-sulfonamide (130 mg, 0.28 mmol) in DCM (3 mL) was added TFA (2 mL) at 0 °C, and the mixture was stirred at 25 °C for 3 h. The mixture was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% MeOH in DCM) to give the title compound (50 mg, 84.7% yield) as a colorless oil. LC / MS (ESI) m / z: 206 (M+H) + .

[0224] Intermediate A28: 5-Cyclopropoxypyridazine-3-sulfonamide TIFF2024538602000071.tif59128Step 1: 3-Chloro-5-cyclopropoxypyridazine To a mixture of 3,5-dichloropyridazine (1.0 g, 6.7 mmol) and CsCO (3.3 g, 10 mmol) in MeCN (10 mL) was added cyclopropanol (780 mg, 13.5 mmol) at room temperature under a N atmosphere. The mixture was stirred at 80 °C overnight under a N atmosphere. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (320 mg, 33.2% yield) as a pale yellow oil.

[0225] Step 2: 3-(benzylthio)-5-cyclopropoxypyridazine To a mixture of 5-chloro-3-cyclopropoxypyridazine (300 mg, 1.8 mmol) and DIEA (460 mg, 3.6 mmol) in 1,4-dioxane (10 mL) was added Xantphos (105 mg, 0.18 mmol) and Pd(dba) (72 mg, 0.1 mmol) at room temperature under a N atmosphere. The mixture was stirred at 100 °C for 5 h under a N atmosphere. The mixture was poured into ice water and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (320 mg, 70.4% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.65(d,J=2.6Hz,1H),7.45(d,J=7.2Hz,2H),7.31(t,J=7.3Hz,2H),7.22(dd,J=20.4,4.9Hz,1H),6.95(d,J= 2.6Hz,1H),4.61(s,2H),3.82-3.71(m,1H),0.88-0.84(m,2H),0.82-0.77(m,2H).LC / MS(ESI)m / z:259(M+H) + .

[0226] Step 3: 5-Cyclopropoxypyridazine-3-sulfonamide To a mixture of 3-(benzylsulfanyl)-5-cyclopropoxypyridazine (130 mg, 0.5 mmol) and 1N aqueous HCl (3 mL, 3.0 mmol) in DCM (5 mL) was added dropwise NaClO solution (1.5 mL, 10-15 wt%) at 0 °C under a N atmosphere. The mixture was stirred at 0 °C for 2 h under a N atmosphere. The layers were separated, and the organic layer was added dropwise to NH / THF solution (3 mL, 2 M) at 0 °C under a N atmosphere. The mixture was stirred at 0 °C for 2 h. The residue was purified by preparative HPLC to give the title compound (32 mg, 29.6% yield) as a yellow solid. 1H NMR(400MHz,CDCl3)δ 9.00(d,J=2.2Hz,1H),7.78(d,J=2.4Hz,1H),5.69(s,2H),4.02-3.93(m,1H),1.04-0.96(m,2H),0.93-0.86(m,2H).LC / MS(ESI)m / z:216(M+H) + .

[0227] Intermediate A29: 1-(1-cyclopropylethyl)-1H-pyrazole-3-sulfonamide TIFF2024538602000072.tif31128 Step 1: 1-(1-cyclopropylethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide To a solution of N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-3-sulfonamide (700 mg, 1.81 mmol) in THF (10 mL) was added PPh3 (949 mg, 3.62 mmol) and 1-methylcyclopropan-1-ol (234 mg, 2.72 mmol), followed by dropwise addition of DIAD (732 mg, 3.62 mmol) at room temperature under a N2 atmosphere. The mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (650 mg, 79.0% yield) as a colorless oil. LC / MS (ESI) m / z: 456 (M+H). + .

[0228] Step 2: 1-(1-cyclopropylethyl)-1H-pyrazole-3-sulfonamide To a solution of 1-(1-cyclopropylethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (650 mg, 1.43 mmol) in MeCN (8 mL) was added CAN (3.95 g, 7.14 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (50 mg, 16.3% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.55(d,J=1.5Hz,1H),6.73(d,J=1.9Hz,1H),5.18(s,2H),4.19-4.12(m,1H),1.60(d,J=6.7Hz,4H),1 .55-1.47(m,1H),0.72-0.65(m,1H),0.50-0.40(m,2H),0.38-0.31(m,1H).LC / MS(ESI)m / z:216(M+H) + .

[0229] Intermediate A30: 5-Cyclobutylpyridine-3-sulfonamide TIFF2024538602000073.tif74142 Step 1: N'-Cyclobutylidene-4-methylbenzene-1-sulfonohydrazide A mixture of cyclobutanone (2.69 mL, 35.6 mmol) and 4-methylbenzenesulfonhydrazide (6.64 g, 35.6 mmol) in MeOH (25 mL) was stirred at 50° C. for 1 h. The mixture was concentrated in vacuo to give the title compound (8.5 g, 99.0% yield) as a white solid, which was used directly in the next step without further purification. LC / MS (ESI) (m / z): 239 (M+H). + .

[0230] Step 2: 3-Bromo-5-cyclobutylpyridine To a mixture of (5-bromopyridin-3-yl)boronic acid (3 g, 14.8 mmol) and N'-cyclobutylidene-4-methylbenzene-1-sulfonohydrazide (4.25 g, 17.8 mmol) in 1,4-dioxane (30 mL) was added K2CO3 (6.16 g, 44.6 mmol) at room temperature, and the mixture was stirred at 100 °C for 16 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 to 50% EtOAc in PE) to give the title compound (800 mg, 25.4% yield) as a brown oil. 1 H NMR(400MHz,DMSO-d6)δ 8.69(s,1H),8.61(s,1H),8.00(s,1H),3.68-3.61(m,1H),2.84(d,J=7.2Hz,2H),1.97-1.82(m,4H).

[0231] Step 3: 3-(benzylsulfanyl)-5-cyclobutylpyridine To a mixture of 3-bromo-5-cyclobutylpyridine (300 mg, 1.41 mmol) and phenylmethanethiol (0.20 mL, 1.70 mmol) in 1,4-dioxane (5 mL) at room temperature under a N atmosphere, Xantphos (81.8 mg, 0.14 mmol), Pd(dba) (64.76 mg, 0.071 mmol), and DIPEA (0.47 mL, 2.83 mmol) were added, and the mixture was stirred at 120 °C under a N atmosphere for 3 h. The mixture was diluted with EtOAc (20 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (170 mg, 47.1% yield) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δ 8.69(s,1H),8.61(s,1H),8.00(s,1H),7.41-7.23(m,5H),4.96(s,2H),3.68-3.61(m,1H),2.84(d,J=7.2Hz,2H),1.97-1.82(m,4H).

[0232] Step 4: 5-Cyclobutylpyridine-3-sulfonamide To a solution of 3-(benzylsulfanyl)-5-cyclobutylpyridine (170 mg, 0.67 mmol) in AcOH (8 mL) and HO (2 mL) were added NCS (267 mg, 1.99 mmol) and aqueous HCl (4 mL, 4.00 mmol, 1 M) at 0 °C, and the mixture was stirred at 25 °C for 2 h. The mixture was poured into water (30 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered. The filtrate was added to a NH / THF solution (5 mL, 2 M), and the mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0–20% MeOH in DCM) to give the title compound (48 mg, 34.0% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 8.79(s,1H),8.66(s,1H),8.05(s,1H),7.57(s,2H),3.77-3.61(m,1H),2.39-2 .33(m,2H),2.21-2.00(m,3H),1.88(t,J=9.1Hz,1H).LC / MS(ESI)m / z:213(M+H) + .

[0233] Intermediate A31: 1-(rel-(1R,2S)-2-hydroxycyclobutyl)-1H-pyrazole-3-sulfonamide TIFF2024538602000074.tif65142 Step 1: 2-(benzyloxy)cyclobutan-1-one To a solution of phenylmethanol (2.70 mL, 26.0 mmol) in HCl / 1,4-dioxane (30 mL) was added 1,2-bis((trimethylsilyl)oxy)cyclobut-1-ene (5.57 mL, 21.70 mmol) at 0 °C. The mixture was stirred at 80 °C for 2 h. The mixture was diluted with water and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (2.3 g, 60.2% yield) as a yellow oil. LC / MS (ESI) (m / z): 177 (M+H). + .

[0234] Step 2: rel-(1R,2S)-2-(benzyloxy)cyclobutan-1-ol and rel-(1S,2S)-2-(benzyloxy)cyclobutan-1-ol To a solution of 2-(benzyloxy)cyclobutan-1-one (2.3 g, 13.05 mmol) in MeOH (20 mL) was added NaBH (0.99 g, 26.1 mmol) in portions at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated aqueous NH Cl (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–60% EtOAc in PE) to give compound 3a (1.0 g, 43.0% yield) and compound 3b (1.1 g, 47.3% yield) as a yellow oil. Compound 3a: 1 H NMR(400MHz,CDCl3)δ 7.37-7.29(m,5H),4.60-4.51(m,2H),4.11-4.05(m,1H),3.81-3.76(m,1H),2.08-1.96(m,2H),1.40-1.31(m,2H);LC / MS(ESI)(m / z):179(M+H) + .Compound 3b: 1H NMR(400MHz,CDCl3)δ 7.38-7.28(m,5H),4.58-4.49(m,2H),4.30-4.26(m,1H),4.13-4.08(m,1H),2.09-1.92(m,4H).LC / MS(ESI)(m / z):179(M+H) + .

[0235] Step 3: 1-(rel-(1R,2S)-2-(benzyloxy)cyclobutyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide To a mixture of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (350 mg, 0.90 mmol) and rel-(1S,2S)-2-(benzyloxy)cyclobutan-1-ol (161 mg, 0.90 mmol) in toluene (10 mL) was added CMBP (654 mg, 2.71 mmol) at 0 °C under a N atmosphere. The mixture was stirred at 110 °C for 16 h. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (140 mg, 28.3% yield) as a yellow oil. LC / MS (ESI) (m / z): 548 (M+H). + .

[0236] Step 4: 1-(rel-(1R,2S)-2-(benzyloxy)cyclobutyl)-1H-pyrazole-3-sulfonamide A solution of 1-(rel-(1R,2S)-2-(benzyloxy)cyclobutyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (140 mg, 0.26 mmol) in TFA (5 mL) was stirred at 50° C. for 5 h. The mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (45 mg, 57.3% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ 8.05(s,2H),7.61(s,1H),7.32-7.26(m,3H),7.22-7.20(m,2H),6.69-6.68(m,1H),5.19(q,J=8.4Hz,1H),4.63-4.58(m ,1H),4.41(d,J=11.7Hz,1H),4.30(d,J=11.6Hz,1H),2.28-2.13(m,2H),1.89-1.65(m,2H).LC / MS(ESI)(m / z):308(M+H) + .

[0237] Step 5: 1-(rel-(1R,2S)-2-hydroxycyclobutyl)-1H-pyrazole-3-sulfonamide To a solution of 1-(rel-(1R,2S)-2-(benzyloxy)cyclobutyl)-1H-pyrazole-3-sulfonamide (45 mg, 0.15 mmol) in EtOAc (3 mL) was added Pd / C (15.6 mg, 10 wt%) at room temperature under a N atmosphere, and the mixture was stirred at room temperature under a H balloon for 2 h. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (23 mg, 72.3% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.47(s,1H),6.74(s,1H),6.43(s,2H),5.18-5.11(m,1H),4.99(s,1H),4.25-4.21(m,1H ),2.46-2.39(m,1H),2.25-2.20(m,2H),1.76-1.69(m,1H).LC / MS(ESI)(m / z):218(M+H) + .

[0238] Intermediate A32: (S)-1-(oxetan-2-ylmethyl)-1H-pyrazole-3-sulfonamide TIFF2024538602000075.tif36128 Step 1: N,N-bis(4-methoxybenzyl)-1-(oxetan-2-ylmethyl)-1H-pyrazole-3-sulfonamide To a stirred solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (300 mg, 0.77 mmol) in MeCN (3 mL) were added (S)-oxetan-2-yl methanesulfonate (154 mg, 0.93 mmol) and CsCO (1 g, 3.09 mmol) at room temperature, and the reaction mixture was stirred at 90 °C for 3 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (170 mg, 48.0% yield) as a yellow solid. LC / MS (ESI) (m / z): 458 (M+H). + .

[0239] Step 2: 1-(oxetan-2-ylmethyl)-1H-pyrazole-3-sulfonamide To a solution of N,N-bis(4-methoxybenzyl)-1-(oxetan-2-ylmethyl)-1H-pyrazole-3-sulfonamide (170 mg, 0.37 mmol) in DCM (2 mL) was added TFA (1 mL) at 0 °C, and the mixture was stirred at 0 °C for 3 h. The mixture was quenched with saturated aqueous NaHCO and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–20% MeOH in DCM) to afford the title compound (30 mg, 37.2% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.66(d,J=2.3Hz,1H),6.77(d,J=2.3Hz,1H),5.18-5.11(m,1H),4.68-4.62(m,1H),4.43-4.39(m,1H),4 .37-4.28(m,1H),2.81-2.60(m,1H),2.45-2.34(m,1H),1.46-1.39(m,1H).LC / MS(ESI)(m / z):218(M+H) + .

[0240] Intermediate A33: 1-(3-hydroxycyclobutyl)-1H-pyrazole-3-sulfonamide TIFF2024538602000076.tif52141 Step 1: 3-(benzyloxy)cyclobutan-1-ol To a solution of 3-(benzyloxy)cyclobutan-1-one (1.8 g, 10.2 mmol) in MeOH (20 mL) was added NaBH (0.69 g, 20.4 mmol) in portions at 0 °C under a N atmosphere, and the mixture was stirred at room temperature for 3 h under a N atmosphere. The mixture was quenched with saturated aqueous NH Cl and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (1.7 g, 93.4% yield) as a colorless oil. LC / MS (ESI) m / z: 179 (M+H). + .

[0241] Step 2: 3-(benzyloxy)cyclobutyl 4-methylbenzene-1-sulfonate To a mixture of 3-(benzyloxy)cyclobutan-1-ol (360 mg, 2.0 mmol) and TEA (410 mg, 4.0 mmol) in DCM (10 mL) was added dropwise a solution of TosCl (580 mg, 3.0 mmol) in DCM (2 mL) at 0 °C under a N atmosphere. The mixture was stirred at room temperature for 3 h under a N atmosphere. The reaction mixture was quenched with ice water (20 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (490 mg, 72.8% yield) as a colorless oil. LC / MS (ESI) m / z: 333 (M+H). + .

[0242] Step 3: 1-[3-(benzyloxy)cyclobutyl]-N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-3-sulfonamide To a mixture of 3-(benzyloxy)cyclobutyl 4-methylbenzene-1-sulfonate (200 mg, 0.6 mmol) and N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-3-sulfonamide (200 mg, 0.5 mmol) in DMF (10 mL) was added KCO (145 mg, 1.0 mmol) at room temperature, and the mixture was stirred at 60 °C under a N atmosphere for 2 days. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc in PE) to give the title compound (185 mg, 65.4% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 8.03(d,J=2.3Hz,1H),7.43-7.24(m,5H),7.03(d,J=8.6Hz,4H),6.81(d,J=8.6Hz,4H),6.72(d,J=2.3Hz,1H),5.19- 4.98(m,1H),4.43(s,2H),4.37-4.29(m,1H),4.21(s,4H),3.71(s,6H),2.66-2.53(m,4H).LC / MS(ESI)m / z:548(M+H) + .

[0243] Step 4: 1-[3-(benzyloxy)cyclobutyl]-1H-pyrazole-3-sulfonamide To a solution of 1-[3-(benzyloxy)cyclobutyl]-N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-3-sulfonamide (180 mg, 0.329 mmol) in DCM (5 mL) was added TFA (5 mL) dropwise at 0 °C under a N atmosphere, and the mixture was stirred at room temperature under a N atmosphere for 3 h. The reaction mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to give the title compound (90 mg, 89.1% yield) as a colorless oil. LC / MS (ESI) m / z: 308 (M+H). + .

[0244] Step 5: 1-(3-hydroxycyclobutyl)-1H-pyrazole-3-sulfonamide To a solution of 1-[3-(benzyloxy)cyclobutyl]-1H-pyrazole-3-sulfonamide (90 mg, 0.293 mmol) in EtOH (5 mL) was added Pd / C (20 mg, 10 wt%) at room temperature under a N atmosphere, and the mixture was stirred at room temperature under a H balloon for 3 h. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% MeOH in DCM) to afford the title compound (45 mg, 70.7% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.95(d,J=2.2Hz,1H),7.40(s,2H),6.59(d,J=2.2Hz,1H),5.28(d,J=1.7Hz,1H),5.10-4.95 (m,1H),4.52-4.40(m,1H),2.68-2.58(m,2H),2.41-2.31(m,2H).LC / MS(ESI)m / z:218(M+H) + .

[0245] Intermediate A34: 1-cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide TIFF2024538602000077.tif70128 Step 1: 1-Cyclopropyl-5-formyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide To a solution of 1-cyclopropyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (1.0 g, 2.34 mmol) in THF (15 mL) was added n-BuLi (1.2 mL, 2.34 mmol, 2.5 M in hexane) dropwise at −70° C. under a N atmosphere, and the mixture was stirred at −70° C. for 1 h. A solution of DMF (0.2 mL, 2.57 mmol) in THF (5 mL) was added dropwise to the above mixture, maintaining the internal temperature below −65° C. The reaction mixture was stirred for an additional 1 h at −70° C. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (400 mg, 37.5% yield) as a yellow oil. LC / MS (ESI) (m / z): 456 (M+H). + .

[0246] Step 2: 1-Cyclopropyl-5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide To a solution of 1-cyclopropyl-5-formyl-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (400 mg, 0.88 mmol) in THF (5 mL) was added dimethylamine hydrochloride (144 mg, 1.76 mmol), TEA (0.2 mL, 1.76 mmol), and four molecular sieves at room temperature under a N atmosphere. After stirring the mixture at room temperature for 1 h, NaBH(OAc) (280 mg, 1.32 mmol) was added at 0 °C, and the resulting mixture was stirred at room temperature for an additional 3 h. The mixture was filtered through a pad of Celite, and the filtrate was diluted with water (15 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (160 mg, 37.6% yield) as a yellow oil. LC / MS (ESI) (m / z): 485 (M+H). + .

[0247] Step 3: 1-Cyclopropyl-5-((dimethylamino)methyl)-1H-pyrazole-3-sulfonamide To a solution of 1-cyclopropyl-5-((dimethylamino)methyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (160 mg, 0.33 mmol) in DCM (2 mL) was added TFA (4 mL) at 0 °C, and the mixture was stirred at 25 °C for 3 h. The mixture was quenched with saturated aqueous NaHCO and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% MeOH in DCM) to afford the title compound (30 mg, 37.2% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 6.52(s,1H),3.73-3.65(m,1H),3.54(s,2H),2.27(s,6H),1.08-0.99(m,2H),0.90-0.83(m,2H).LC / MS(ESI)(m / z):245(M+H) +.

[0248] Intermediate B2: 5-(imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-amine TIFF2024538602000078.tif49128 Step 1: N-(2,3-dihydro-1H-inden-4-yl)acetamide To a mixture of 2,3-dihydro-1H-inden-4-amine (1.0 g, 7.52 mmol) and TEA (1.25 mL, 9.02 mmol) in DCM (15 mL) was added AcO (767 mg, 7.52 mmol) dropwise at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (1.1 g, 91.8% yield) as a white solid. LC / MS (ESI) m / z: 176 (M+H). + .

[0249] Step 2: N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide A mixture of N-(2,3-dihydro-1H-inden-4-yl)acetamide (780 mg, 4.50 mmol), PTSA (460 mg, 2.44 mmol), and Pd(OAc) (38 mg, 0.17 mmol) in toluene (10 mL) was stirred at room temperature in air for 0.5 h. NBS (670 mg, 3.77 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (700 mg, 61.9% yield) as a white solid. LC / MS (ESI) m / z: 255 (M+H). + .

[0250] Step 3: 5-Bromo-2,3-dihydro-1H-inden-4-amine A mixture of N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide (650 mg, 2.56 mmol) in EtOH (10 mL) and concentrated HCl (15 mL, 36 wt % in water) was stirred at 80 °C for 16 h. The mixture was concentrated to dryness. The mixture was diluted with water and basified with saturated aqueous NaHCO to pH 8. The mixture was extracted with EtOAc (3 × 10 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-16% EtOAc in PE) to give the title compound (300 mg, 55.3% yield) as a gray solid. LC / MS (ESI) m / z: 212 (M+H). + .

[0251] Step 4: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-amine To a mixture of 5-bromo-2,3-dihydro-1H-inden-4-amine (500 mg, 2.36 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (780 mg, 3.07 mmol) in 1,4-dioxane (8 mL) was added KOAc (463 mg, 4.72 mmol) and Pd(dppf)Cl (173 mg, 0.24 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 100 °C for 3 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH Cl and brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% EtOAc in PE) to give the title compound (200 mg, 32.7% yield) as a yellow solid. LC / MS (ESI) (m / z): 260 (M+H). + .

[0252] Step 5: 5-(imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-amine To a mixture of 6-bromoimidazo[1,2-a]pyridine (190 mg, 0.96 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-amine (250 mg, 0.96 mmol) in 1,4-dioxane (5 mL) and HO (1 mL) was added KCO (333 mg, 2.41 mmol) followed by Pd(dppf)Cl (71 mg, 0.09 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 100 °C for 2 h. The mixture was diluted with EtOAc (20 mL), washed with water and brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give the title compound (150 mg, 62.4% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.20(s,1H),7.75-7.54(m,4H),6.98(d,J=7.4Hz,1H),6.77(d,J=7.2Hz,1H),2.97(t ,J=7.4Hz,2H),2.78(t,J=7.2Hz,2H),2.25-2.12(m,2H).LC / MS(ESI)(m / z):250(M+H) + .

[0253] Intermediate B6: 5-(imidazo[1,5-a]pyridin-7-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine TIFF2024538602000079.tif74128 Step 1: N-(2,3-dihydro-1H-inden-5-yl)acetamide To a mixture of 2,3-dihydro-1H-inden-5-amine (5 g, 37.5 mmol) and pyridine (4.86 mL, 60.1 mmol) in DCM (50 mL) was added acetic anhydride (3.88 mL, 41.3 mmol) dropwise at 0 °C, and the mixture was stirred at 0 °C for 1 h. The mixture was quenched with water and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (5.9 g, 89.7% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.44(s,1H),7.14(s,2H),2.91-2.84(m,4H),2.16(s,3H),2.10-2.02(m,2H).LC / MS(ESI)(m / z):176(M+H) + .

[0254] Step 2: N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide To a solution of N-(2,3-dihydro-1H-inden-5-yl)acetamide (5.9 g, 33.7 mmol) in AcOH (90 mL) was added Br (2.08 mL, 40.4 mmol) dropwise over 1 h at 10 °C. After stirring for an additional 10 min at 10 °C, the mixture was poured into ice water and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine, saturated aqueous NaHCO and saturated aqueous NaHSO, dried over NaSO, filtered, and concentrated to dryness to give the title compound (7 g, 81.8% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.44(s,1H),7.14(s,2H),2.91-2.84(m,4H),2.16(s,3H),2.10-2.02(m,2H).LC / MS(ESI)(m / z):254(M+H) + .

[0255] Step 3: N-(6-bromo-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide To a stirred solution of N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide (7 g, 27.6 mmol) in AcOH (40 mL) and sulfuric acid (20 mL), a precooled mixture of sulfuric acid (20 mL) and nitric acid (24.8 mL, 275.5 mmol) was added dropwise at less than 20° C. for 1 h, and the resulting mixture was stirred at room temperature for an additional 1 h. The mixture was poured into ice water and stirred at 0° C. for 2 h. The mixture was filtered, and the filter cake was washed with water, dried over NaSO, filtered, and concentrated to dryness to give the title compound (7.3 g, 88.6% yield) as a brown solid. 1 H NMR(400MHz,CDCl3)δ 7.65(s,1H),7.34(s,1H),3.11-3.07(t,J=7.5Hz,2H),3.01-2.97(t,J=7.6Hz,2H),2.20(s,3H),2.19-2.11(m,2H).LC / MS(ESI)(m / z):299(M+H) + .

[0256] Step 4: N-(6-methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide To a mixture of N-(6-bromo-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (7 g, 23.4 mmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (11.7 mL, 46.8 mmol), and KCO (34.7 g, 251 mmol) in 1,4-dioxane (70 mL) and HO (15 mL) was added Pd(dppf)Cl (1.71 g, 2.34 mmol) under N atmosphere, and the mixture was degassed three times under N atmosphere and stirred at 100 °C for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (0-20% EtOAc in PE) to give the title compound (2.9 g, 52.9% yield) as a yellow solid. 1H NMR(400MHz,CDCl3)δ 7.74(s,1H),7.31(s,1H),3.11-3.07(t,J=7.5Hz,2H),2.96-2.93(t,J=7.5Hz, 2H),2.27(s,3H),2.19(s,3H),2.16-2.08(m,2H).LC / MS(ESI)(m / z):235(M+H) + .

[0257] Step 5: 6-Methyl-4-nitro-2,3-dihydro-1H-inden-5-amine To a solution of N-(6-methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (2.9 g, 12.4 mmol) in EtOH (60 mL) was added concentrated HCl (60 mL), and the mixture was stirred at 80 °C overnight. The mixture was concentrated to dryness, and the residue was neutralized with 2 M aqueous NaOH. The mixture was extracted with DCM (2 × 20 mL), and the combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (2.1 g, 88.3% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.15(s,1H),5.81(s,2H),3.32-3.28(t,J=7.5Hz,2H),2.84-2.81(t,J=7.6Hz,2H),2.20(s,3H),2.09-2.01(m,2H).LC / MS(ESI)(m / z):193(M+H) + .

[0258] Step 6: 5-Bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene A mixture of 6-methyl-4-nitro-2,3-dihydro-1H-inden-5-amine (2.1 g, 10.9 mmol) and isopentyl nitrite (1.41 g, 12.0 mmol) in CHCN (30 mL) was heated to 55 °C, CuBr (2.44 g, 10.9 mmol) was added under a N atmosphere, and the mixture was stirred at 70 °C for 1 h. The reaction mixture was cooled to room temperature, and 1 M aqueous HCl (20 mL) was added. The reaction mixture was extracted with DCM (3 × 20 mL), and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (1.7 g, 60.8% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 7.49(s,1H),2.93-2.87(m,4H),2.40(s,3H),2.12-2.05(m,2H).LC / MS(ESI)(m / z):256(M+H) + .

[0259] Step 7: 5-Bromo-6-methyl-2,3-dihydro-1H-inden-4-amine To a solution of 5-bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene (1.7 g, 6.64 mmol) in EtOH (20 mL) was added saturated aqueous NH4Cl (4 mL) and Fe (3.7 g, 66.4 mmol), and the mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction was diluted with EtOAc (30 mL) and filtered through a pad of Celite. The filtrate was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (1.4 g, 93.3% yield) as a pink solid. 1H NMR(400MHz,DMSO-d6)δ 6.47(s,1H),4.94(s,2H),2.75-2.71(t,J=7.5Hz,2H),2.70-2.66(t,J=7.3Hz,2H),2.23(s,3H),2.02-1.93(m,2H).LC / MS(ESI)(m / z):226(M+H) + .

[0260] Step 8: 5-(imidazo[1,5-a]pyridin-7-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine To a mixture of imidazo[1,5-a]pyridin-7-ylboronic acid (100 mg, 0.6 mmol) and 5-bromo-6-methyl-2,3-dihydro-1H-inden-4-amine (150 mg, 0.6 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added KCO (260 mg, 1.9 mmol) followed by Pd(dppf)Cl (50 mg, 0.07 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 90 °C for 16 h. After cooling, the reaction mixture was diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (110 mg, 67.7% yield) as a white solid. LC / MS (ESI) m / z: 264 (M+H) + .

[0261] Intermediate B13: 5-(2-methoxypyridin-4-yl)benzo[d][1,3]dioxol-4-amine TIFF2024538602000080.tif54128Step 1: 5-Bromobenzo[d][1,3]dioxole-4-carboxylic acid To a solution of 5-bromo-2H-1,3-benzodioxole (5 g, 24.9 mmol) in THF (60 mL) was added LDA (25 mL, 1 M in THF) dropwise at −70° C., and the mixture was stirred at −70° C. for 30 min. CO was then bubbled into the mixture at −70° C. for 30 min, and the resulting mixture was stirred at room temperature for an additional 1 h. The mixture was quenched with ice water. The solvent was evaporated, and the mixture was acidified with 2N aqueous HCl to pH 3. The slurry was filtered, and the filter cake was washed with water and dried under vacuum to give the title compound (5.6 g, 91.9% yield) as a white solid. LC / MS (ESI) (m / z): 243 (MH). - .

[0262] Step 2: tert-butyl (5-bromobenzo[d][1,3]dioxol-4-yl)carbamate To a solution of 5-bromobenzo[d][1,3]dioxole-4-carboxylic acid (2 g, 8.16 mmol) in t-BuOH (20 L) were added DPPA (2.47 g, 8.98 mmol) and TEA (1.24 g, 12.24 mmol) at 0 °C, and the mixture was stirred at 100 °C for 1 h. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc in PE) to give the title compound (1.8 g, 69.8% yield) as a white solid. LC / MS (ESI) (m / z): 317 (M+H). + .

[0263] Step 3: 5-Bromobenzo[d][1,3]dioxol-4-amine To a solution of tert-butyl (5-bromobenzo[d][1,3]dioxol-4-yl)carbamate (1.8 g, 5.69 mol) in DCM (8 mL) was added TFA (4 mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness. The residue was neutralized with 1 N aqueous NaHCO3 and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc in PE) to give the title compound (1.2 g, 97.6% yield) as a white solid. LC / MS (ESI) (m / z): 217 (M+H) + .

[0264] Step 4: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d][1,3]dioxol-4-amine To a solution of 5-bromobenzo[d][1,3]dioxol-4-amine (500 mg, 2.31 mmol) and AcOK (681 mg, 6.94 mmol) in anhydrous 1,4-dioxane (10 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (881 mg, 3.47 mmol) and Pd(dppf)Cl (169 mg, 0.23 mol) under a N atmosphere. The reaction mixture was degassed three times under a N atmosphere and stirred at 90 °C for 3 h under a N atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc in PE) to give the title compound (195 mg, 32.0% yield) as a white solid. LC / MS (ESI) m / z: 264 (M+H) + .

[0265] Step 5: 5-(imidazo[1,2-a]pyridin-7-yl)benzo[d][1,3]dioxol-4-amine To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d][1,3]dioxol-4-amine (190 mg, 0.72 mmol) and 7-bromoimidazo[1,2-a]pyridine (171 mg, 0.87 mmol) in 1,4-dioxane (5 mL) and HO (1 mL) was added KCO (249 mg, 1.81 mmol) and Pd(dppf)Cl (52.8 mg, 0.072 mol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred overnight at 80 °C under a N atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give the title compound (42 mg, 77.6% yield) as a yellow solid. LC / MS (ESI) m / z: 254 (M+H) + .

[0266] Intermediate B14: 5-(imidazo[1,2-a]pyridin-7-yl)benzo[d][1,3]dioxol-4-amine To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d][1,3]dioxol-4-amine (200 mg, 0.76 mmol) and 6-bromoimidazo[1,2-a]pyridine (165 mg, 0.84 mmol) in 1,4-dioxane (5 mL) and HO (1 mL) was added KCO (263 mg, 1.9 mmol) and Pd(dppf)Cl (56 mg, 0.076 mol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 90 °C for 3 h under a N atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give the title compound (160 mg, 83.1% yield) as a yellow solid. LC / MS (ESI) m / z: 254 (M+H) + .

[0267] Intermediate B16: 6-chloro-5-(imidazo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-amine TIFF2024538602000082.tif77137 Step 1: 5-Chloro-6-nitro-2,3-dihydro-1H-inden-1-one A solution of 5-chloro-2,3-dihydro-1H-inden-1-one (5 g, 30 mmol) in nitric acid fumes was stirred at −10° C. for 2 hours. The mixture was poured into ice water and stirred at this temperature for 1 hour. The slurry was filtered, and the filter cake was washed twice with water and dried under vacuum to give the title compound (3 g, 47.2% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ 8.19 (s, 1H), 7.70 (s, 1H), 3.34-3.13 (m, 2H), 2.92-2.71 (m, 2H).

[0268] Step 2: 5-chloro-6-nitro-2,3-dihydro-1H-inden-1-ol To a solution of 5-chloro-6-nitro-2,3-dihydro-1H-inden-1-one (3 g, 14.2 mmol) in MeOH (30 mL) was added NaBH (720 mg, 21.3 mmol) in portions at 0 °C, and the mixture was stirred at 0 °C for 1 h. The mixture was quenched with saturated aqueous NH Cl at 0 °C and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (2.6 g, 85.9% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.91(s,1H),7.41(s,1H),5.28(t,J=6.5Hz,1H),3.16-3.03(m,1H),2.95-2.82(m,1H),2.67-2.51(m,1H),2.09-1.99(m,1H).

[0269] Step 3: 5-chloro-6-nitro-2,3-dihydro-1H-indene To a solution of 5-chloro-6-nitro-2,3-dihydro-1H-inden-1-ol (2.5 g, 11.7 mmol) in TFA (30 mL) was added TES (3.8 mL, 23.4 mmol) dropwise at 0 °C, and the mixture was stirred at 30 °C for 16 h. The mixture was poured into ice water and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (1.6 g, 69.2% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 7.72 (s, 1H), 7.36 (s, 1H), 2.96 (td, J = 7.5, 4.7Hz, 4H), 2.17 (p, J = 7.6Hz, 2H).

[0270] Step 4: 6-Chloro-2,3-dihydro-1H-inden-5-amine To a solution of 5-chloro-6-nitro-2,3-dihydro-1H-indene (1.40 g, 7.1 mmol) in EtOH (10 mL) and HO (10 mL) was added Fe powder (1.98 g, 35.4 mmol), followed by NHCl (1.89 g, 35.4 mmol), and the mixture was stirred at 100 °C for 2 h. The mixture was filtered, and the filter cake was washed with EtOAc (2 × 20 mL). The filtrate was washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (1.1 g, 92.6% yield) as a yellow oil. LC / MS (ESI) m / z: 168 (M+H). + .

[0271] Step 5: N-(6-chloro-2,3-dihydro-1H-inden-5-yl)acetamide To a solution of 6-chloro-2,3-dihydro-1H-inden-5-amine (1.1 g, 6.6 mmol) in DCM (15 mL) was added pyridine (1.59 mL, 19.7 mmol) followed by acetic anhydride (1.00 g, 9.84 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was washed with 1 N aqueous HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (1.12 g, 87.2% yield) as a white solid. LC / MS (ESI) m / z: 210 (M+H). + .

[0272] Step 6: N-(6-chloro-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide Nitric acid (5 mL) was slowly added to sulfuric acid (5 mL) in an ice-water bath, maintaining the temperature below 20° C. The mixture was stirred for 10 minutes and then added dropwise to a stirred solution of N-(6-chloro-2,3-dihydro-1H-inden-5-yl)acetamide (1.2 g, 5.7 mmol) in AcOH (10 mL) and sulfuric acid (5 mL), maintaining the temperature below 30° C. The mixture was stirred at room temperature for 4 hours and poured into ice water. The mixture was filtered, and the filter cake was washed twice with water and dried under vacuum to give the title compound (1.1 g, 75.5% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.48(s,1H),7.45(s,1H),3.11(t,J=7.5Hz,2H),2.98(t,J=7.5Hz,2H),2.20(s,3H),2.16(dd,J=15.2,7.7Hz,2H).LC / MS(ESI)m / z:255(M+H) + .

[0273] Step 7: 6-Chloro-4-nitro-2,3-dihydro-1H-inden-5-amine To a solution of N-(6-chloro-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (1.0 g, 3.9 mmol) in EtOH (10 mL) was added 6N aqueous HCl (5 mL) at 0° C., and the mixture was stirred at 100° C. for 16 h. The mixture was concentrated to dryness, and the residue was neutralized with 1N aqueous NaOH. The mixture was extracted with DCM (2×20 mL), and the combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (750 mg, 89.8% yield) as a brown solid. LC / MS (ESI) m / z: 213 (M+H) + .

[0274] Step 8: 5-Bromo-6-chloro-4-nitro-2,3-dihydro-1H-indene To a mixture of 6-chloro-4-nitro-2,3-dihydro-1H-inden-5-amine (600 mg, 2.82 mmol) and isopentyl nitrite (0.44 mL, 3.67 mmol) in MeCN (10 mL) was added CuBr (940 mg, 4.23 mmol) in portions at 55 °C under a N atmosphere, and the mixture was stirred at 70 °C for 1 h. The mixture was allowed to cool to room temperature, and 1 N aqueous HCl was added. The mixture was extracted with DCM (2 × 10 mL), and the combined organic phases were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (650 mg, 83.3% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 7.46 (s, 1H), 2.97 (dd, J=14.2, 7.0Hz, 4H), 2.23-2.12 (m, 2H).

[0275] Step 9: 5-Bromo-6-chloro-2,3-dihydro-1H-inden-4-amine To a solution of 5-bromo-6-chloro-4-nitro-2,3-dihydro-1H-indene (650 mg, 2.35 mmol) in EtOH (6 mL) and HO (7 mL) was added NH4Cl (628 mg, 11.7 mmol), followed by Fe powder (628 mg, 11.7 mmol), and the mixture was stirred at 90 °C for 2 h. The mixture was filtered through a Celite pad, and the filter cake was washed with EtOAc (2 × 10 mL). The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (0.45 g, 77.7% yield) as a yellow solid. LC / MS (ESI) m / z: 246 (M+H). + .

[0276] Step 10: 6-chloro-5-(imidazo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-amine To a solution of 7-bromoimidazo[1,5-a]pyridine (500 mg, 2.54 mmol) in 1,4-dioxane (10 mL) was added KOAc (498 mg, 5.08 mmol), followed by 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (644 mg, 2.54 mmol), and Pd(dppf)Cl (185 mg, 0.25 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 100 °C for 3 h. After cooling to room temperature, a solution of 5-bromo-6-chloro-2,3-dihydro-1H-inden-4-amine (350 mg, 1.42 mmol) in 1,4-dioxane (10 mL) was added, followed by a solution of KCO (392 mg, 2.8 mmol) and Pd(dppf)Cl (104 mg, 0.14 mmol) in water (5 mL). The resulting mixture was degassed three times under N and stirred at 100 °C for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (250 mg, 62.1% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.38(d,J=7.1Hz,2H),7.36(s,2H),6.64(s,1H),4.69(s,2H),2.81(t,J=7.3 Hz,2H),2.66(t,J=7.1Hz,2H),2.07-1.91(m,2H).LC / MS(ESI)m / z:284(M+H) + .

[0277] Intermediate B20: 6-cyano-5-(imidazo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-indene-4-carboxylic acid TIFF2024538602000083.tif83137 Step 1: 6-Bromo-2,3-dihydro-1H-inden-5-ol To a solution of 2,3-dihydro-1H-inden-5-ol (5.4 g, 40.2 mmol) in CHCl (100 mL) was added dropwise a solution of Br (2.5 mL, 48.7 mmol) in CHCl (30 mL) under a N atmosphere at 0 °C, and the mixture was stirred at room temperature for 3 h. The mixture was washed with saturated aqueous NaSO and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (7.9 g, 92.1% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.27(s,1H),6.88(s,1H),5.33(s,1H),2.82(t,J=7.4Hz,4H),2.11-2.02(m,2H).LC / MS(ESI)m / z:214(M+H) + .

[0278] Step 2: 6-Bromo-5-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde To a mixture of 6-bromo-2,3-dihydro-1H-inden-5-ol (6.4 g, 30.0 mmol) and MgCl (8.2 g, 90.1 mmol) in THF (100 mL) was added paraformaldehyde (3.6 g, 120 mmol) under a N atmosphere, and the mixture was stirred at 80 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL) and filtered through a pad of Celite. The filtrate was washed with 1 N HCl and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (5.9 g, 81.5% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 11.82(s,1H),10.07(s,1H),7.62(s,1H),3.17(t,J=7.5Hz,2H),2.87(t,J=7.4Hz,2H),2.19(p,J=7.5Hz,2H).LC / MS(ESI)m / z:242(M+H) + .

[0279] Step 3: 5-[(benzyloxy)methoxy]-6-bromo-2,3-dihydro-1H-indene-4-carbaldehyde To a mixture of 6-bromo-5-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (5.0 g, 20.7 mmol) and DIPEA (6.9 mL, 41.8 mmol) in DCM (100 mL), BOMCl (3.5 mL, 25.3 mmol) was added dropwise at 0 °C under a N atmosphere, and the mixture was stirred at room temperature for 3 h. The mixture was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (6.6 g, 88.1% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 11.82(s,1H),10.50(s,1H),7.64(s,1H),7.35(ddd,J=9.2,4.6,1.7Hz,5H),5.28(s,2H),4.85(s,2H) ,3.21(t,J=7.5Hz,2H),2.86(dd,J=9.7,5.5Hz,3H),2.11(p,J=7.6Hz,2H).LC / MS(ESI)m / z:361(M+H) + .

[0280] Step 4: 6-Bromo-5-(methoxymethoxy)-2,3-dihydro-1H-indene-4-carboxylic acid To a mixture of 5-[(benzyloxy)methoxy]-6-bromo-2,3-dihydro-1H-indene-4-carbaldehyde (2 g, 5.54 mmol), NaClO (1.1 g, 14.78 mmol), and NaHPO (3.3 g, 27.50 mmol) in t-BuOH (30 mL) and HO (10 mL) was added 2-methylbut-2-ene (3.2 g, 45.6 mmol) at 0 °C, and the mixture was stirred at room temperature for 3 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (1.5 g, 71.8% yield) as a white solid. LC / MS (ESI) m / z: 378 (M+H). + .

[0281] Step 5: 6-Bromo-5-(methoxymethoxy)-2,3-dihydro-1H-indene-4-carboxylic acid To a solution of 6-bromo-5-(methoxymethoxy)-2,3-dihydro-1H-indene-4-carboxylic acid (1.5 g, 3.98 mmol) in MeOH (20 mL) was added SOCl (1.44 mL, 19.9 mmol) at 0 °C, and the mixture was stirred at 70 °C for 3 h. The mixture was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (1.0 g, 92.7% yield) as a white solid. LC / MS (ESI) m / z: 272 (M+H). + .

[0282] Step 6: 6-Cyano-5-hydroxy-2,3-dihydro-1H-indene-4-carboxylate To a mixture of methyl 6-bromo-5-hydroxy-2,3-dihydro-1H-indene-4-carboxylate (1 g, 3.69 mmol) and Zn(CN) (0.52 g, 4.43 mmol) in DMF (15 mL) was added Pd(PPh) (0.3 g, 0.25 mmol) under N. The mixture was degassed three times under N and stirred at 110 °C overnight. The mixture was diluted with EtOAc (20 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-25% EtOAc in PE) to give the title compound (450 mg, 81.1% yield) as a white solid. LC / MS (ESI) m / z: 218 (M+H). + .

[0283] Step 7: Methyl 6-cyano-5-(trifluoromethanesulfonyloxy)-2,3-dihydro-1H-indene-4-carboxylate To a solution of methyl 6-cyano-5-hydroxy-2,3-dihydro-1H-indene-4-carboxylate (400 mg, 1.8 mmol) in DCM (5 mL) was added pyridine (0.5 mL, 5.5 mmol) and TfO (779 mg, 2.7 mmol) at 0 °C, and the mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM (10 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (500 mg, 77.7% yield) as a yellow oil. LC / MS (ESI) m / z: 350 (M+H). + .

[0284] Step 8: Methyl 6-cyano-5-{imidazo[1,5-a]pyridin-7-yl}-2,3-dihydro-1H-indene-4-carboxylate To a mixture of 6-cyano-5-(trifluoromethanesulfinyloxy)-2,3-dihydro-1H-indene-4-carboxylate (500 mg, 1.50 mmol) and 7-(tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine (366 mg, 1.5 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added KCO (622 mg, 4.5 mmol) followed by Pd(dppf)Cl (42 mg, 0.06 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 80 °C for 16 h. The mixture was diluted with EtOAc (15 mL), washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% MeOH in DCM) to give the title compound (450 mg, 94.5% yield) as a white solid. LC / MS (ESI) m / z: 318 (M+H) + .

[0285] Step 9: 6-cyano-5-{imidazo[1,5-a]pyridin-7-yl}-2,3-dihydro-1H-indene-4-carboxylic acid To a solution of methyl 6-cyano-5-{imidazo[1,5-a]pyridin-7-yl}-2,3-dihydro-1H-indene-4-carboxylate (450 mg, 1.4 mmol) in THF (4 mL), water (1 mL), and MeOH (1 mL) was added LiOH (280 mg, 7.0 mmol), and the mixture was stirred at 50 °C for 3 h. The mixture was concentrated to approximately one-fifth volume, diluted with water, and washed with EtOAc (2 × 10 mL). The aqueous layer was acidified to pH 3 with 1 N aqueous HCl and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (430 mg, 93.0% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.35(s,1H),8.63(d,J=7.3Hz,1H),7.96(d,J=15.2Hz,2H),7.76(s,1H),6.97(dd,J=7.3 ,1.6Hz,1H),3.01(dd,J=13.7,6.1Hz,4H),2.14-2.08(m,2H).LC / MS(ESI)m / z:304(M+H) + .

[0286] Intermediate B36: 6-Fluoro-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine TIFF2024538602000084.tif82139 Step 1: 5-Fluoro-6-nitro-2,3-dihydro-1H-inden-1-one To fuming nitric acid (150 mL), 5-fluoro-2,3-dihydro-1H-inden-1-one (15 g, 99.9 mmol) was added portionwise at −10° C., and the reaction was stirred at 0° C. for 1 hour. The mixture was poured into ice water and filtered. The filter cake was washed with water and dried under vacuum to give the title compound (13 g, 66.7% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 8.40(d,J=7.1Hz,1H),7.41(d,J=10.1Hz,1H),3.28-3.25(m,2H),2.83-2.80(m,2H).

[0287] Step 2: 5-Fluoro-6-nitro-2,3-dihydro-1H-inden-1-ol To a solution of 5-fluoro-6-nitro-2,3-dihydro-1H-inden-1-one (13 g, 66.6 mmol) in MeOH (150 mL) was added NaBH (3.38 g, 99.9 mmol) in portions at 0 °C, and the reaction was stirred at 0 °C for 1 h. The reaction was quenched with saturated aqueous NH Cl at 0 °C and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na SO , filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (12.5 g, 95.1% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.08(d,J=7.0Hz,1H),7.14(d,J=10.7Hz,1H),5.30-5.27(m,1H),3.17-3.10(m,1H),2.94-2.86(m,1H),2.63-2.55(m,1H),2.10-2.01(m,1H).

[0288] Step 3: 5-Fluoro-6-nitro-2,3-dihydro-1H-indene To a solution of 5-fluoro-6-nitro-2,3-dihydro-1H-inden-1-ol (12.5 g, 63.4 mmol) in TFA (80 mL) was added TES (20.5 mL, 126.8 mmol) at 0 °C, and the reaction was stirred at 30 °C for 16 h. The mixture was poured into ice water and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (10 g, 87.1% yield) as a yellow solid. 1H NMR(400MHz, CDCl3)δ 7.88(d,J=7.0Hz,1H),7.10(d,J=10.9Hz,1H),3.00-2.97(m,2H),2.22-2.14(m,2H),0.93(t,J=7.9Hz,2H).

[0289] Step 4: 6-Fluoro-2,3-dihydro-1H-inden-5-amine To a solution of 5-fluoro-6-nitro-2,3-dihydro-1H-indene (10 g, 55.2 mmol) in EtOH (80 mL) and HO (80 mL) was added Fe powder (15.4 g, 276 mmol) followed by NH4Cl (14.8 g, 276 mmol), and the mixture was stirred at 100 °C for 30 min. The mixture was filtered, and the filtrate was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (8 g, 95.9% yield) as a yellow solid. LC / MS (ESI) m / z: 152 (M+H). + .

[0290] Step 5: N-(6-fluoro-2,3-dihydro-1H-inden-5-yl)acetamide To a solution of 6-fluoro-2,3-dihydro-1H-inden-5-amine (8 g, 52.9 mmol) in DCM (80 mL) was added pyridine (12.8 mL, 158.7 mmol) followed by acetic anhydride (8.1 g, 79.4 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 h. The mixture was washed with 1 N aqueous HCl and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (9 g, 88.0% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.05(d,J=7.4Hz,1H),7.32(s,1H),6.92(d,J=10.9Hz,1H),2.86(q,J=7.3Hz,5H),2.20(s,3H),2.11-2.04(m,2H).LC / MS(ESI)m / z:194(M+H)+ .

[0291] Step 6: N-(6-fluoro-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide Nitric acid (40 mL) was slowly added to sulfuric acid (40 mL) at 0° C. while maintaining the internal temperature below 20° C. The mixture was stirred for 10 minutes and then added dropwise to a stirred mixture of N-(6-fluoro-2,3-dihydro-1H-inden-5-yl)acetamide (9.0 g, 46.6 mmol) and sulfuric acid (40 mL) in AcOH (80 mL) while maintaining the internal temperature below 30° C. The mixture was stirred at room temperature for 1 hour and then poured into ice water. The mixture was filtered, and the filter cake was washed with water and dried under vacuum to give the title compound (7.0 g, 63.1% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.24(d,J=9.4Hz,1H),3.13(t,J=7.4Hz,2H),2.99(t,J=7.5Hz,2H),2.20-2.12(m,5H).LC / MS(ESI)m / z:255(M+H) + .

[0292] Step 7: 6-Fluoro-4-nitro-2,3-dihydro-1H-inden-5-amine To a solution of N-(6-fluoro-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide (7 g, 29.4 mmol) in EtOH (70 mL) was added 6 N aqueous HCl (20 mL) at 0 °C, and the mixture was stirred at 100 °C for 16 h. The mixture was concentrated to dryness, and the residue was basified to pH 10 with 2 M aqueous NaOH. The mixture was extracted with DCM (3 × 20 mL), and the combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (5.1 g, 88.5% yield) as a yellow solid. LC / MS (ESI) m / z: 197 (M+H). + .

[0293] Step 8: 5-Bromo-6-fluoro-4-nitro-2,3-dihydro-1H-indene To a mixture of CuBr (4.27 g, 19.12 mmol) in MeCN (30 mL) under a N atmosphere, t-BuONO (2.89 g, 28.04 mmol) was added, and the mixture was stirred at 60 °C for 10 min. Then, a solution of 6-fluoro-4-nitro-2,3-dihydro-1H-inden-5-amine (2.5 g, 12.7 mmol) in MeCN (20 mL) was added dropwise, and the resulting mixture was stirred at 60 °C for an additional 30 min. The reaction was quenched with 1 M aqueous HCl and extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–2% EtOAc in PE) to give the title compound (2.3 g, 69.4% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 7.15 (d, J=7.8Hz, 1H), 3.03-2.96 (m, 4H), 2.22-2.15 (m, 2H).

[0294] Step 9: 5-Bromo-6-fluoro-2,3-dihydro-1H-inden-4-amine To a solution of 5-bromo-6-fluoro-4-nitro-2,3-dihydro-1H-indene (2.3 g, 8.84 mmol) in EtOH (30 mL) and HO (30 mL) was added Fe powder (2.47 g, 44.2 mmol) followed by NH4Cl (2.37 g, 44.2 mmol), and the mixture was stirred at 100 °C for 30 min. The mixture was filtered. The filtrate was extracted three times with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (2.0 g, 98.3% yield) as a yellow solid. LC / MS (ESI) m / z: 230 (M+H). + .

[0295] Step 10: 6-Fluoro-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine To a mixture of 5-bromo-6-fluoro-2,3-dihydro-1H-inden-4-amine (500 mg, 2.17 mmol) and 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (690 mg, 2.82 mmol) in 1,4-dioxane (10 mL) and HO (1.5 mL) was added KCO (751 mg, 5.43 mmol) followed by Pd(dppf)Cl (80 mg, 0.11 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 100 °C for 1 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (530 mg, 91.2% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.54(d,J=7.1Hz,1H),7.98(d,J=2.1Hz,1H),7.58(s,1H),6.78(d,J=7.2Hz,1H),6.54(d,J=1.8Hz,1H),6.51(d,J=9 .5Hz,1H),3.73(s,2H),2.94(t,J=7.5Hz,2H),2.72(t,J=7.3Hz,2H),2.21-2.13(m,2H).LC / MS(ESI)(m / z):268(M+H) + .

[0296] Intermediate B37: 5-methyl-6-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydrobenzofuran-7-amine TIFF2024538602000085.tif104154 Step 1: 2-Bromo-6-fluoro-3-methylbenzaldehyde To a solution of 2-bromo-4-fluoro-1-methylbenzene (13.2 mL, 106 mmol) in THF (200 mL) was added LDA (63.5 mL, 127 mmol, 2 M in THF) dropwise at −70 °C under a N atmosphere, and the mixture was stirred at −70 °C for 30 min. DMF (18.0 mL, 233 mmol) was added dropwise to the mixture at −70 °C, and the resulting mixture was stirred at −70 °C for 0.5 h. The mixture was quenched with saturated aqueous NH4Cl at 0 °C and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–9% EtOAc in PE) to give the title compound (22 g, 95.8% yield) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ 10.39(s,1H),7.42(dd,J=8.2,5.9Hz,1H),7.05(t,J=9.2Hz,1H),2.44(s,3H).

[0297] Step 2: 2-Bromo-6-fluoro-3-methylbenzoic acid To a mixture of 2-bromo-6-fluoro-3-methylbenzaldehyde (22 g, 101 mmol) and 2-methyl-2-butene (59.6 mL, 710 mmol) in t-BuOH (440 mL) was added a mixture of NaClO (18.3 g, 203 mmol) and NaHPO (25.8 mL, 304 mmol) in HO (260 mL) dropwise at 0 °C, and the mixture was stirred at room temperature for 30 min. The mixture was acidified with 1 N aqueous HCl to pH 3 and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% MeOH in DCM) to give the title compound (18.6 g, 78.7% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.47(dd,J=8.3,6.4Hz,1H),7.28(t,J=8.7Hz,1H),2.35(s,3H).LC / MS(ESI)m / z:231 / 233(MH)- .

[0298] Step 3: Methyl 2-bromo-6-fluoro-3-methylbenzoate To a solution of 2-bromo-6-fluoro-3-methylbenzoic acid (18 g, 77.240 mmol) in DMF (180 mL) were added KCO (16.0 g, 116 mmol) and MeI (5.77 mL, 92.7 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-2% EtOAc in PE) to give the title compound (18.6 g, 97.5% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 7.27 (dd, J = 8.3, 6.2 Hz, 1H), 7.00 (t, J = 8.5 Hz, 1H), 3.97 (s, 3H), 2.39 (s, 3H).

[0299] Step 4: Methyl 2-bromo-6-methoxy-3-methylbenzoate To a solution of methyl 2-bromo-6-fluoro-3-methylbenzoate (16.5 g, 66.8 mmol) in DMF (160 mL) was added NaOMe (26.5 g, 147 mmol) at 0 °C under a N atmosphere, and the mixture was stirred at 50 °C for 2 h. The mixture was poured into ice-water (100 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–5% EtOAc in PE) to give the title compound (14.1 g, 81.5% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 7.21(d,J=8.5Hz,1H),6.80(d,J=8.5Hz,1H),3.94(s,3H),3.80(s,3H),2.34(s,3H).

[0300] Step 5: Methyl 2-bromo-6-hydroxy-3-methylbenzoate To a solution of methyl 2-bromo-6-methoxy-3-methylbenzoate (14 g, 54.0 mmol) in DCM (260 mL) was added AlCl (14.4 g, 108 mmol) under a N atmosphere at 0 °C, and the mixture was stirred at 45 °C for 20 min. The mixture was poured into ice-water (100 mL) and extracted with DCM (4 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (13 g, 98.2% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 10.06(s,1H),7.26(d,J=8.5Hz,1H),6.87(d,J=8.5Hz,1H),3.99(s,3H),2.36(s,3H).LC / MS(ESI)m / z:245 / 247(M+H) + .

[0301] Step 6: Methyl 2-bromo-6-(2-(tert-butoxy)-2-oxoethoxy)-3-methylbenzoate To a mixture of methyl 2-bromo-6-hydroxy-3-methylbenzoate (11 g, 44.9 mmol) in DMF (110 mL) was added tert-butyl 2-bromoacetate (9.81 mL, 67.3 mmol) and K2CO3 (12.4 g, 89.8 mmol), and the mixture was stirred at 65 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc in PE) to give the title compound (16 g, 99.2% yield) as a yellow oil. LC / MS (ESI) m / z: 359 / 361 (M+H). + .

[0302] Step 7: 2-(3-bromo-2-(methoxycarbonyl)-4-methylphenoxy)acetic acid To a solution of methyl 2-bromo-6-[2-(tert-butoxy)-2-oxoethoxy]-3-methylbenzoate (17 g, 47.3 mmol) in DCM (200 mL) was added TFA (100 mL) at 0° C., and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness and coevaporated twice with DCM to give the title compound (14 g, 97.6% yield) as a yellow oil, which was used directly in the next reaction without purification. LC / MS (ESI) m / z: 301 / 303 (M−H). - .

[0303] Step 8: Methyl 6-bromo-5-methyl-3-oxo-2,3-dihydrobenzofuran-7-carboxylate To a solution of 2-[3-bromo-2-(methoxycarbonyl)-4-methylphenoxy]acetic acid (16.9 g, 55.7 mmol) in DCM (200 mL) was added DMF (4.30 mL, 55.7 mmol), followed by dropwise addition of oxalyl chloride (9.4 mL, 111 mmol) under a N atmosphere at 0 °C, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness, and the residue was dissolved in DCE (200 mL). AlCl (14.8 g, 111 mmol) was added under a N atmosphere at 0 °C, and the resulting mixture was stirred at 50 °C for 3 h. The mixture was poured into ice water (200 mL) and extracted with DCM (4 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc in PE) to give the title compound (2.2 g, 13.8% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.58(s,1H),4.67(s,2H),4.00(s,3H),2.45(s,3H).LC / MS(ESI)m / z:285 / 287(M+H) + .

[0304] Step 9: Methyl 6-bromo-5-methyl-1-benzofuran-7-carboxylate To a solution of methyl 6-bromo-5-methyl-3-oxo-2,3-dihydro-1-benzofuran-7-carboxylate (3.2 g, 11.2 mmol) in TFA (32 mL) was added EtSiH (18.1 mL, 112 mmol) at 0 °C, and the mixture was stirred at 70 °C for 16 h. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (1.9 g, 62.9% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.62(d,J=2.0Hz,1H),7.54(s,1H),6.71(d,J=2.4Hz,1H),4.04(s,3H),2.51(s,3H).LC / MS(ESI)m / z:269 / 271(M+H) + .

[0305] Step 10: Methyl 6-bromo-5-methyl-2,3-dihydro-1-benzofuran-7-carboxylate To a solution of methyl 6-bromo-5-methyl-1-benzofuran-7-carboxylate (1.9 g, 7.06 mmol) in EtOH (20 mL) was added Rh / C (0.19 g, 5 wt%) at room temperature under a N atmosphere, and the mixture was stirred at 30 °C under a H balloon for 3 h. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (1.7 g, 88.8% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 7.11(s,1H),4.63(t,J=8.7Hz,2H),3.94(s,3H),3.15(t,J=8.7Hz,2H),2.33(s,3H).LC / MS(ESI)m / z:271 / 273(M+H) + .

[0306] Step 11: 6-Bromo-5-methyl-2,3-dihydro-1-benzofuran-7-carboxylic acid To a solution of methyl 6-bromo-5-methyl-2,3-dihydro-1-benzofuran-7-carboxylate (1.7 g, 6.27 mmol) in MeOH (20 mL) and water (7 mL) was added NaOH (0.75 g, 18.81 mmol) at 0 °C, and the mixture was stirred at 80 °C for 12 h. The mixture was concentrated to dryness, and the residue was dissolved in water (20 mL). The mixture was acidified to pH 3 with 1 N aqueous HCl and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness to give the title compound (1.3 g, 80.6% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 7.25(s,1H),4.57(t,J=8.8Hz,2H),3.14(t,J=8.4Hz,2H),2.27(s,3H).LC / MS(ESI)m / z:255 / 257(MH) - .

[0307] Step 12: tert-butyl N-(6-bromo-5-methyl-2,3-dihydro-1-benzofuran-7-yl)carbamate To a solution of 6-bromo-5-methyl-2,3-dihydro-1-benzofuran-7-carboxylic acid (1.3 g, 5.06 mmol) in t-BuOH (10 mL) and toluene (10 mL), DPPA (1.20 mL, 5.56 mmol) and DIPEA (1.09 mL, 6.57 mmol) were added under a N atmosphere, and the mixture was stirred at 100 °C for 3 h. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (1 g, 60.3% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 8.41(s,1H),7.10(s,1H),4.53(t,J=8.8Hz,2H),3.15(t,J=8.8Hz,2H),2.27(s,3H),1.40(s,9H).LC / MS(ESI)m / z:328 / 330(M+H) + .

[0308] Step 13: 6-Bromo-5-methyl-2,3-dihydro-1-benzofuran-7-amine To a solution of tert-butyl N-(6-bromo-5-methyl-2,3-dihydro-1-benzofuran-7-yl)carbamate (1.1 g, 3.35 mmol) in EtOAc (4 mL) was added HCl / 1,4-dioxane (4 mL, 4 M) at 0 °C, and the reaction was stirred at 30 °C for 3 h. The mixture was concentrated to dryness under reduced pressure, and the residue was neutralized with saturated aqueous NaHCO. The mixture was extracted with DCM (3 × 10 mL), and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to dryness to give the title compound (660 mg, 86.4% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 6.51(s,1H),4.51(t,J=8.8Hz,3H),3.08(t,J=8.6Hz,2H),2.21(s,3H).LC / MS(ESI)m / z:228 / 230(M+H) + .

[0309] Step 14: 5-methyl-6-{pyrazolo[1,5-a]pyridin-5-yl}-2,3-dihydro-1-benzofuran-7-amine To a mixture of 6-bromo-5-fluoro-2,3-dihydro-1-benzofuran-7-amine (500 mg, 2.16 mmol), 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (107 mg, 0.44 mmol), and KCO (182 mg, 1.32 mmol) in 1,4-dioxane (8 mL) and HO (2 mL) was added Pd(dppf)Cl (32.1 mg, 0.04 mmol) under N atmosphere, and the mixture was degassed three times under N atmosphere and stirred at 100 °C for 1 h under N atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (126 mg, 22.3% yield) as a grey solid. 1H NMR(400MHz,CDCl3)δ 8.55(d,J=7.1Hz,1H),7.98(d,J=1.9Hz,1H),7.43(s,1H),6.65(d,J=7.1Hz,1H),6.61(s,1H),6.53(s, 1H),4.61(t,J=8.7Hz,2H),3.45(s,2H),3.23(t,J=8.7Hz,2H),2.03(s,3H).LC / MS(ESI)m / z:266(M+H) + .

[0310] Intermediate B38: 5-Fluoro-6-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydrobenzofuran-7-amine TIFF2024538602000086.tif92137Step 1: 3-Bromo-4-fluoro-2-nitrophenol To a suspension of 3-bromo-4-fluorophenol (16 g, 84 mmol) and ammonium nickel(II) sulfate (12 g, 42 mmol) in DCM (100 mL) was added concentrated HNO (5.74 mL, 89 mmol) over 10 min while maintaining the internal temperature below 25 °C with an ice bath. The resulting mixture was stirred for 20 min and poured into ice water. The layers were separated, and the aqueous layer was extracted with DCM (3 × 30 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to afford the title compound (7 g, 35.3% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 9.09 (s, 1H), 7.30 (dd, J=9.2, 7.6Hz, 1H), 7.12 (dd, J=9.3, 4.6Hz, 1H).

[0311] Step 2: 2-Bromo-1-fluoro-3-nitro-4-(prop-2-en-1-yloxy)benzene To a solution of 3-bromo-4-fluoro-2-nitrophenol (20 g, 84.8 mmol) in acetonitrile (110 mL) were added KCO (35.1 g, 254 mmol) and 3-bromoprop-1-ene (14.75 mL, 169.5 mmol) at room temperature, and the mixture was stirred at 90 °C for 3 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel, 0-5% EtOAc in PE) to give the title compound (23 g, 98.3% yield) as a pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 7.63(t,J=9.2Hz,1H),7.43(dd,J=9.2,4.0Hz,1H),56.00-5.91(m,1H),5.31(m,2H),5.37-5.26(d,J=4.8Hz,2H).LC / MS(ESI)m / z:276 / 278(M+H) + .

[0312] Step 3: 3-Bromo-4-fluoro-2-nitro-6-(prop-2-en-1-yl)phenol A solution of 2-bromo-1-fluoro-3-nitro-4-(prop-2-en-1-yloxy)benzene (13.8 g, 50.0 mmol) in NMP (65 mL) was stirred at 190 °C for 3 h. The mixture was cooled to room temperature and poured into ice water (100 mL). The mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (4.9 g, 35.5% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 9.29(s,1H),7.22(d,J=8.5Hz,1H),5.97(d,J=2.7Hz,1H),5.37-5.29(m,1H),3.44(d,J=6.6Hz,2H).LC / MS(ESI)m / z:276 / 278(M+H) + .

[0313] Step 4: 2-(4-bromo-5-fluoro-2-hydroxy-3-nitrophenyl)acetaldehyde To a solution of 3-bromo-4-fluoro-2-nitro-6-(prop-2-en-1-yl)phenol (4.9 g, 17.8 mmol) in DCM (10 mL) was bubbled O3 for 20 min at −55 °C, followed by the addition of Me2S (1 mL, 13.52 mmol) and stirring the mixture for 20 min at 25 °C. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0–5% EtOAc in PE) to give the title compound (4.5 g, 91.2% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 9.87(t,J=7.6Hz,1H),7.05(d,J=5.8Hz,1H),3.64(d,J=1.3Hz,2H).LC / MS(ESI)m / z:278 / 280(M+H) + .

[0314] Step 5: 3-Bromo-4-fluoro-6-(2-hydroxyethyl)-2-nitrophenol To a solution of 2-(4-bromo-5-fluoro-2-hydroxy-3-nitrophenyl)acetaldehyde (4.5 g, 16.2 mmol) in MeOH (5 mL) was added NaBH (733 mg, 19.4 mmol) in portions at 0 °C, and the mixture was stirred at 25 °C for 30 min. The mixture was quenched with saturated aqueous NH Cl (50 mL), acidified to pH 5 with 1 N aqueous HCl, and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na SO , filtered, and concentrated to dryness to give the title compound (4.3 g, 94.9% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.09(d,J=5.2Hz,1H),2.94(t,J=5.3Hz,2H),2.84(t,J=5.2Hz,2H).LC / MS(ESI)m / z:280 / 282(M+H) + .

[0315] Step 6: 6-Bromo-5-fluoro-7-nitro-2,3-dihydro-1-benzofuran To a mixture of 3-bromo-4-fluoro-6-(2-hydroxyethyl)-2-nitrophenol (4.3 g, 15.4 mmol) and PPh3 (8.05 g, 30.7 mmol) in THF (3 mL) was added dropwise DIAD (4.57 mL, 23.03 mmol) under N2 atmosphere at 0 °C, and the mixture was stirred at 25 °C for 3 h. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0-10% EtOAc in PE) to give the title compound (3.9 g, 96.9% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.14(d,J=7.2Hz,1H),4.79(t,J=8.8Hz,2H),3.29(t,J=8.7Hz,2H).LC / MS(ESI)m / z:262 / 264(M+H) + .

[0316] Step 7: 6-Bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine To a solution of 6-bromo-5-fluoro-7-nitro-2,3-dihydrobenzofuran (1 g, 3.82 mmol) in EtOH (10 mL) and HO (3 mL) was added Fe powder (0.85 g, 15.3 mmol) followed by NH4Cl (1.63 g, 30.53 mmol) at room temperature under a N2 atmosphere, and the reaction was stirred at 50 °C for 1 h. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (850 mg, 95.9% yield) as a yellow solid. LC / MS (ESI) m / z: 232 / 234 (M+H). + .

[0317] Step 8: 5-Fluoro-6-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydrobenzofuran-7-amine To a mixture of 6-bromo-5-fluoro-2,3-dihydrobenzofuran-7-amine (250 mg, 1.08 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (263 mg, 1.08 mmol) in 1,4-dioxane (6 mL) and HO (2 mL) was added KCO (372.3 mg, 2.69 mmol) followed by Pd(dppf)Cl (78.8 mg, 0.11 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 100 °C for 1 h under a N atmosphere. The mixture was diluted with water and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (140 mg, 48.3% yield) as a yellow solid. LC / MS (ESI) (m / z): 270 (M+H). + .

[0318] Intermediate B41: (7-amino-6-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-5-yl)methanol TIFF2024538602000087.tif89139 Step 1: Methyl 6-acetamido-2,3-dihydro-1H-indene-5-carboxylate To a solution of N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide (7 g, 27.5 mmol) in MeOH (80 mL) and TEA (20 mL) was added Pd(dppf)Cl (2.02 g, 2.75 mmol) at room temperature under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 80 °C under a CO atmosphere for 16 h. The mixture was cooled to room temperature and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (3.6 g, 56.0% yield) as a yellow solid. LC / MS (ESI) m / z: 234 (M+H). + .

[0319] Step 2: Methyl 6-acetamido-7-nitro-2,3-dihydro-1H-indene-5-carboxylate HNO3 (10 mL, 42 wt%) was slowly added to H2SO4 (8 mL) at 0 °C, keeping the internal temperature below 20 °C. The mixture was stirred at 0 °C for 10 min. Then, a mixture of methyl 6-acetamido-2,3-dihydro-1H-indene-5-carboxylate (1.9 g, 8.15 mmol) in AcOH (10 mL) and H2SO4 (5 mL) was added at 0 °C. The resulting mixture was stirred at room temperature for 10 min and poured into ice water. The mixture was basified to pH 8 with 2 M aqueous NaOH and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (1.5 g, 66.2% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 10.19(s,1H),8.01(s,1H),3.95(s,3H),3.20(t,J=7.5Hz,2H),3.02-2.98(m,2H),2.21(s,3H),2.18-2.13(m,2H).LC / MS(ESI)m / z:279(M+H) + .

[0320] Step 3: Methyl 6-amino-7-nitro-2,3-dihydro-1H-indene-5-carboxylate To a solution of methyl 6-acetamido-7-nitro-2,3-dihydro-1H-indene-5-carboxylate (1.5 g, 5.39 mmol) in EtOH (20 mL) was added aqueous HCl (10 mL, 6 M) at room temperature, and the mixture was stirred at 100 °C for 8 h. The mixture was concentrated to dryness under reduced pressure, and the residue was basified by dropwise addition of 2 M aqueous NaOH. The aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (0–20% EtOAc in PE) to give the title compound (0.92 g, 72.3% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.18(s,2H),8.03(s,1H),3.89(s,3H),3.35(t,J=7.5Hz,2H),2.86(t,J=7.5Hz,2H),2.12-2.04(m,2H).LC / MS(ESI)m / z:237(M+H) + .

[0321] Step 4: Methyl 6-bromo-7-nitro-2,3-dihydro-1H-indene-5-carboxylate To a solution of methyl 6-amino-7-nitro-2,3-dihydro-1H-indene-5-carboxylate (0.9 g, 3.81 mmol) in MeCN (8 mL) was added 3-methylbutyl nitrite (0.56 mL, 4.19 mmol), and the mixture was stirred at 55 °C for 10 min. CuBr (0.94 g, 4.19 mmol) was then added, and the resulting mixture was stirred at 70 °C for 20 min. The mixture was cooled to room temperature, and 1 N aqueous HCl (20 mL) was added. The mixture was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (0–30% EtOAc in PE) to give the title compound (0.7 g, 61.2% yield) as a yellow solid. 1H NMR (400MHz, CDCl3) δ 7.71 (s, 1H), 3.95 (s, 3H), 3.04-2.98 (m, 4H), 2.25-2.17 (m, 2H).

[0322] Step 5: Methyl 6-bromo-7-nitro-2,3-dihydro-1H-indene-5-carboxylate To a solution of methyl 6-bromo-7-nitro-2,3-dihydro-1H-indene-5-carboxylate (700 mg, 2.33 mmol) in EtOH (10 mL) and HO (5 mL) was added Fe (521 mg, 9.33 mmol) and NH₄Cl (998 mg, 18.7 mmol) at room temperature, and the mixture was stirred at 90 °C for 20 min. The mixture was filtered, and the filtrate was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (500 mg, 79.4% yield) as a yellow solid. LC / MS (ESI) m / z: 270 / 272 (M+H). + .

[0323] Step 6: Methyl 7-amino-6-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-indene-5-carboxylate To a mixture of methyl 6-bromo-7-nitro-2,3-dihydro-1H-indene-5-carboxylate (100 mg, 0.37 mmol) and 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (108 mg, 0.44 mmol) in 1,4-dioxane (4 mL) and HO (1 mL) was added KCO (128 mg, 0.93 mmol) followed by Pd(dppf)Cl (27 mg, 0.04 mmol) under a N atmosphere. The mixture was degassed three times under a N atmosphere and stirred at 100 °C for 2 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (60 mg, 52.7% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.54(d,J=7.2Hz,1H),7.97(s,1H),7.40(s,1H),7.29(s,1H),6.67(d,J=7.2Hz,1H),6.51(s,1H),3.5 9(s,3H),3.00(t,J=7.4Hz,2H),2.78(t,J=7.4Hz,2H),2.23-2.16(m,2H).LC / MS(ESI)(m / z):308(M+H) + .

[0324] Step 7: (7-amino-6-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-5-yl)methanol To a solution of methyl 7-amino-6-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-indene-5-carboxylate (60 mg, 0.20 mmol) in THF (3 mL) was added LiAlH (14.8 mg, 0.39 mmol) at 0 °C under a N atmosphere, and the mixture was stirred at room temperature for 2 h. The mixture was quenched with sodium sulfate decahydrate at 0 °C and filtered. The filtrate was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0-70% EtOAc in PE) to give the title compound (30 mg, 55.0% yield) as a yellow solid.1 H NMR(400MHz,CDCl3)δ 8.56(d,J=7.0Hz,1H),8.00(d,J=2.0Hz,1H),7.51(s,1H),6.91(s,1H),6.72-6.70(m,1H),6.55(s,1H),4.43-4.3 6(m,2H),3.50(s,2H),2.99(t,J=7.5Hz,2H),2.77(t,J=7.3Hz,2H),2.22-2.14(m,2H).LC / MS(ESI)m / z:280(M+H) + .

[0325] The intermediates in Table 1 below were prepared by using methods similar to those used to prepare the intermediates described herein.

[0326] [Table 1] TIFF2024538602000089.tif217167TIFF2024538602000090.tif243167TIFF2024538602000091.tif237167TIFF2024538602 000092.tif249167TIFF2024538602000093.tif236167TIFF2024538602000094.tif243167TIFF2024538602000095.tif90167

[0327] Example 1: 1-Cyclopropyl-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide To a mixture of 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (60 mg, 0.23 mmol) and EtN (0.06 mL, 0.46 mmol) in THF (4 mL), triphosgene (36 mg, 0.11 mmol) was added under a N atmosphere at 0° C., and the mixture was stirred at 0° C. for 0.5 h. The mixture was filtered, and the filtrate was added to a mixture of 1-cyclopropyl-1H-pyrazole-3-sulfonamide (43 mg, 0.23 mmol) and NaH (23 mg, 0.57 mmol, 60% dispersion in mineral oil) in THF (5 mL) at 0° C. The resulting mixture was stirred at room temperature for 15 min and poured into ice water. The mixture was washed twice with EtOAc, and the aqueous layer was acidified with 1N aqueous HCl to approximately pH 5. The mixture was extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (18.0 mg, 16.6% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.26(d,J=28.8Hz,2H),7.93(d,J=9.2Hz,1H),7.77(s,1H),7.62(s,1H),7.38 (d,J=7.6Hz,1H),7.28(d,J=9.4Hz,1H),7.19(d,J=8.0Hz,1H),3.94(d,J=7.3 Hz,2H),2.93(d,J=7.5Hz,2H),2.02-1.98(m,2H),1.26-1.22(m,2H),0.88-0. 83(m,1H),0.54-0.48(m,2H),0.38-0.31(m,2H).LC / MS(ESI)(m / z):477(M+H) + .

[0328] Example 2: N-((6-cyano-5-(imidazo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide TIFF2024538602000097.tif27128 Step 1: 6-(imidazo[1,5-a]pyridin-7-yl)-7-isocyanato-2,3-dihydro-1H-indene-5-carbonitrile To a solution of 6-cyano-5-{imidazo[1,5-a]pyridin-7-yl}-2,3-dihydro-1H-indene-4-carboxylic acid (100 mg, 0.30 mmol) in THF (5 mL) was added oxalyl chloride (42 mg, 0.30 mmol) followed by DMF (0.05 mL) at 0 °C, and the mixture was stirred at room temperature for 1.5 h. The mixture was concentrated to dryness. The residue was dissolved in THF (5 mL), and NaN3 (50 mg, 1.5 mmol) was added at 0 °C. The resulting mixture was stirred at 70 °C for 1 h and used directly in the next reaction without workup. LC / MS (ESI) m / z: 301 (M+H). + .

[0329] Step 2: N-((6-cyano-5-(imidazo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide To a solution of 5-(2-hydroxypropan-2-yl)thiophene-3-sulfonamide (60 mg, 0.27 mmol) in THF (3 mL) was added NaH (19 mg, 0.71 mmol, 60% dispersion in mineral oil) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, 6-{imidazo[1,5-a]pyridin-7-yl}-7-isocyanato-2,3-dihydro-1H-indene-5-carbonitrile (80 mg, 0.27 mmol) in THF (5 mL) was added, and the mixture was stirred at 0 °C for 1 h. The mixture was poured into ice water and neutralized to pH 5 with 1N aqueous HCl. The mixture was extracted with DCM (2 × 10 mL), and the combined organic layers were washed with water and brine, dried over Na SO , filtered, and concentrated to dryness. The residue was purified by preparative HPLC (C 18 , 10-80% acetonitrile in H2O containing 0.1% ammonium bicarbonate) to afford the title compound (16 mg, 11.5% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.43(s,1H),8.28(d,J=7.2Hz,1H),7.63-7.52(m,2H),7.47(s,1H),7.41(s,1H),6.98(s,1H),6.41(d,J=7.3Hz,1H ),5.14(s,1H),2.95(t,J=7.4Hz,2H),2.80-2.74(m,2H),2.03-1.95(m,2H),1.41(s,6H).LC / MS(ESI)m / z:522(M+H) + .

[0330] Example 3: 3-Cyclopropoxy-N-((6-methyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)cyclobutane-1-sulfonamide TIFF2024538602000098.tif25128 Step 1: tert-Butyl 4-(4-(3-((3-cyclopropoxycyclobutyl)sulfonyl)ureido)-6-methyl-2,3-dihydro-1H-inden-5-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate The title compound was prepared from 3-cyclopropoxycyclobutane-1-sulfonamide (Intermediate A25) and tert-butyl 4-(4-amino-6-methyl-2,3-dihydro-1H-inden-5-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate B27-2) as described for Example 1. LC / MS (ESI) m / z: 581 (M+H) + .

[0331] Step 2: 3-Cyclopropoxy-N-((6-methyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)cyclobutane-1-sulfonamide (Example 53) To a solution of tert-butyl 4-[4-({[(3-cyclopropoxycyclobutyl)sulfonyl]carbamoyl}amino)-6-methyl-2,3-dihydro-1-hinden-5-yl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (63 mg, 0.11 mmol) in DCM (9 mL) was added TFA (2.20 mL, 30.3 mmol) at 0 °C, and the mixture was stirred at room temperature for 1 h. The mixture was neutralized with saturated aqueous NaHCO and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (3 mg, 4.03% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.73(d,J=8.4Hz,1H),8.27(dd,J=6.5,4.9Hz,1H),7.54-7.42(m,1H),7.24(s,1 H),7.14(s,1H),6.80(t,J=5.1Hz,1H),5.96(s,1H),4.14-3.93(m,1H),3.70-3.3 9(m,1H),3.25-3.19(m,1H),2.97-2.88(m,2H),2.84-2.66(m,2H),2.42-2.21(m, 3H),2.08-1.92(m,3H),1.92(s,3H),0.50-0.42(m,4H).LC / MS(ESI)m / z:481(M+H) + .

[0332] Example 4: 1-(cyclopropylmethyl)-N-((5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A3) and 5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B22) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.18(d,J=4.9Hz,1H),8.02(s,1H),7.58(s,1H),7.33(d,J=3.5Hz,1H),7.13(d,J=3 .1Hz,2H),6.91(d,J=4.9Hz,1H),6.17(d,J=3.5Hz,1H),3.99(d,J=7.2Hz,2H),3.84 (s,3H),2.93(t,J=7.4Hz,2H),2.76(t,J=7.4Hz,2H),2.02-1.94(m,2H),1.29-1.17 (m,1H),0.52(dt,J=8.0,2.9Hz,2H),0.40-0.34(m,2H).LC / MS(ESI)(m / z):491(M+H) + .

[0333] Example 5: N-((5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide TIFF2024538602000100.tif34128 The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A3) and 5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B27) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.65(s,1H),8.22(s,1H),8.15(d,J=1.1Hz,1H),7.71(s,1H),7.40(s,1H),7.24- 7.23(m,1H),7.21-7.15(m,2H),6.83(d,J=4.9Hz,1H),6.10-6.09(m,1H),4.04(d, J=7.2Hz,2H),2.94(t,J=7.4Hz,2H),2.73(t,J=7.3Hz,2H),2.04-1.97(m,2H),1.2 9-1.21(m,1H),0.56-0.51(m,2H),0.41-0.37(m,2H).LC / MS(ESI)(m / z):477(M+H) + .

[0334] Example 6: 1-(cyclopropylmethyl)-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A3) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.52(d,J=7.1Hz,1H),8.07(s,1H),8.00(d,J=2.2Hz,1H),7.60(s,1H),7.34(s,1H) ),7.03(s,1H),6.52(d,J=1.6Hz,1H),6.48(dd,J=7.2,1.7Hz,1H),3.99(d,J=7.2H z,2H),2.87(t,J=7.3Hz,2H),2.72-2.61(m,2H),2.04(s,3H),2.00-1.90(m,2H),1 .30-1.17(m,1H),0.55-0.51(m,2H),0.39-0.35(m,2H).LC / MS(ESI)m / z:491(M+H) + .

[0335] Example 7: 1-(cyclopropylmethyl)-N-((5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide TIFF2024538602000102.tif35128 The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A3) and 5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid.1 H NMR(400MHz,DMSO-d6)δ 8.51(d,J=7.2Hz,1H),8.30(s,1H),8.00(d,J=2.2Hz,1H),7.79(s,1H),7.50(s,1H) ,7.20(dd,J=17.9,7.7Hz,2H),6.65(dd,J=7.2,1.7Hz,1H),6.55(d,J=1.8Hz,1H),4. 01(d,J=7.2Hz,2H),2.93(t,J=7.4Hz,2H),2.69(t,J=7.3Hz,2H),2.04-1.95(m,2H) ,1.30-1.19(m,1H),0.55-0.49(m,2H),0.40-0.35(m,2H).LC / MS(ESI)m / z:477(M+H) + .

[0336] Example 8: 1-(cyclopropylmethyl)-N-((6-methyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A3) and 6-methyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B27-2) as described for Example 3. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.61(s,1H),8.10(d,J=4.7Hz,2H),7.58(s,1H),7.23-7.18(m,1H),7.02(s ,1H),6.63(d,J=4.6Hz,1H),5.84(s,1H),3.98(d,J=7.3Hz,2H),2.87-2.82(m ,2H),2.62(t,J=7.8Hz,2H),1.90(d,J=8.1Hz,2H),1.84(s,3H),1.11(t,J=7. 2Hz,1H),0.51-0.46(m,2H),0.34(q,J=4.7Hz,2H).LC / MS(ESI)m / z:491(M+H) + .

[0337] Example 9: 1-(cyclopropylmethyl)-N-((5-(imidazo[1,5-a]pyridin-7-yl)-6-methyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A3) and 5-(imidazo[1,5-a]pyridin-7-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate B6) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.38(s,1H),8.24(d,J=7.4Hz,2H),7.68(s,1H),7.28(s,1H),7.19(s,1H) ,7.05(s,1H),6.22(d,J=7.6Hz,1H),4.01(d,J=7.4Hz,2H),2.86(t,J=7.4H z,2H),2.33-2.34(m,1H),2.06(s,3H),1.93(d,J=18.2Hz,2H),1.23-1.24( m,2H),0.52(d,J=6.5Hz,2H),0.35-0.37(m,2H).LC / MS(ESI)m / z:491(M+H) + .

[0338] Example 10: 1-(cyclopropylmethyl)-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate A1) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid.1 H NMR (400 MHz, DMSO-d6) δ 8.62(d,J=7.0Hz,1H),8.04(d,J=1.9Hz,1H),7.86(s,1H),7.54(s,1H),7.40(s, 1H),7.10(s,1H),6.60(s,1H),6.55-6.47(m,2H),4.03(d,J=7.2Hz,2H),2.88(t ,J=7.3Hz,2H),2.60(d,J=7.3Hz,2H),2.04(s,3H),1.98-1.91(m,2H),1.24-1.2 5(m,1H),0.56(d,J=6.7Hz,2H),0.40(d,J=4.2Hz,2H).LC / MS(ESI)m / z:491(M+H) + .

[0339] Example 11: 1-(cyclobutylmethyl)-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide The title compound was prepared from 1-(cyclobutylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate A4) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.62(d,J=7.1Hz,1H),8.04(d,J=2.0Hz,1H),7.86-7.74(m,1H),7.39(s,1H),7.08(s,1H),6.60(s,1H),6.53-6.45(m,2H),4.18(d,J= 7.1Hz,2H),2.88(t,J=7.2Hz,2H),2.04(s,3H),1.98-1.92(m,4H),1.88-1.71(m,5H),1.24-1.25(m,2H).LC / MS(ESI)(m / z):505(M+H) + .

[0340] Example 12: 1-Cyclobutyl-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide The title compound was prepared from 1-cyclobutyl-1H-pyrazole-4-sulfonamide (Intermediate A5) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.51(d,J=7.1Hz,1H),8.14(s,1H),8.01(d,J=1.9Hz,1H),7.66(s,1H),7.34(s,1H), 7.04(s,1H),6.51(s,1H),6.47(d,J=5.7Hz,1H),4.95-4.81(m,1H),2.88(t,J=7.3Hz, 2H),2.66(dd,J=16.9,1.4Hz,2H),2.47(d,J=10.6Hz,2H),2.39(d,J=7.9Hz,2H),2.04 (s,3H),1.98-1.91(m,2H),1.81(dd,J=14.4,8.1Hz,2H).LC / MS(ESI)(m / z):491(M+H) + .

[0341] Example 13: N-((6-cyano-5-(imidazo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A3) and 6-cyano-5-(imidazo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-indene-4-carboxylic acid (Intermediate B20) as described for Example 2. The residue was purified by preparative HPLC to afford the title compound as a white solid.1 H NMR(400MHz,DMSO-d6)δ 8.45(s,1H),8.31-8.26(m,1H),7.77-7.70(m,1H),7.67(s,1H),7.46(s, 1H),7.41(s,1H),7.24-6.96(m,1H),6.57-6.30(m,1H),4.01(d,J=7.1Hz ,2H),2.97(s,2H),2.78-2.68(m,2H),2.08-1.96(m,2H),1.28-1.22(m,1 H),0.52-0.53(m,2H),0.37(d,J=5.4Hz,2H).LC / MS(ESI)(m / z):502(M+H) + .

[0342] Example 14: 1-Cyclopropyl-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide The title compound was prepared from 1-cyclopropyl-1H-pyrazole-4-sulfonamide (Intermediate A6) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ8.54(d,J=7.2Hz,1H),8.23(s,1H),8.01(d,J=2.0Hz,1 H),7.68(d,J=3.2Hz,1H),7.34(s,1H),7.08(s,1H),6.53(s,1H),6.45(d,J=7. 6Hz,1H),3.86(s,1H),2.88(t,J=7.2Hz,2H),2.67(s,1H),2.04(s,3H),2.01-1 .90(m,3H),1.11-1.06(m,2H),1.04-0.99(m,2H).LC / MS(ESI)(m / z):477(M+H) + .

[0343] Example 15: 5-(cyclopropyl(methoxy)methyl)-1-methyl-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide The title compound was prepared from 5-(cyclopropyl(methoxy)methyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate A7) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.58(s,1H),8.00(s,1H),7.41(d,J=12.8Hz,2H),7.01(s,1H),6.59-6.52(m,2H), 3.84(d,J=17.8Hz,4H),3.25(s,3H),2.90-2.83(m,2H),2.54-2.53(s,2H),2.32-2 .31(m,1H),2.03-2.01(m,2H),1.93-1.92(m,2H),1.23-1.22(m,1H),0.68(d,J=7. 6Hz,1H),0.48(d,J=6.3Hz,2H),0.20(d,J=5.5Hz,1H).LC / MS(ESI)(m / z):535(M+H) + .

[0344] Example 16: 5-(cyclopropyl(hydroxy)methyl)-1-methyl-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide The title compound was prepared as described for Example 1 from (1-methyl-3-sulfamoyl-1H-pyrazol-5-yl)methyl acetate (Intermediate A8) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1 to give Example 16-1. The intermediate was treated with K2CO3 in MeOH at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC to give the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.58(d,J=7.2Hz,1H),7.99(s,1H),7.39(s,1H),7.31(s,1H),7.12(s,1H),6.99(s,1H),6.5 7(s,1H),6.54(d,J=6.4Hz,1H),6.39(s,1H),5.44(s,1H),4.07(t,J=6.5Hz,1H),3.80(s,3H) ),2.85(t,J=7.3Hz,2H),2.69(d,J=17.8Hz,2H),2.03(s,3H),1.93(m,2H),1.23-1.19(m,1H ),0.53-0.51(m,1H),0.47-0.41(m,2H),0.27(d,J=4.2Hz,1H).LC / MS(ESI)(m / z):521(M+H) + .

[0345] Example 17: 5-(cyclopropylmethyl)-1-methyl-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide The title compound was prepared from 5-(cyclopropylmethyl)-1-methyl-1H-pyrazole-3-sulfonamide (Intermediate A9) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.59(d,J=7.3Hz,1H),8.01(s,1H),7.39(s,1H),7.04(s,1H),6.57(s,1H), 6.52(d,J=6.8Hz,1H),6.38(s,1H),3.74(s,3H),2.86(t,J=7.1Hz,2H),2.69 -2.62(m,2H),2.55(s,2H),2.04(s,3H),1.98-1.91(m,2H),1.03-0.93(m,1H ),0.52(d,J=6.8Hz,2H),0.19(d,J=4.5Hz,2H).LC / MS(ESI)(m / z):505(M+H) + .

[0346] Example 18: 1-(cyclopropylmethyl)-N-((5-(imidazo[1,2-a]pyridin-7-yl)-6-methyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A3) and 5-(imidazo[1,2-a]pyridin-7-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate B1-1) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.48(d,J=6.9Hz,1H),8.35(s,1H),8.00(s,1H),7.76(s,1H),7.62(s,1H),7.24(s ,1H),7.11(s,1H),6.47(d,J=6.0Hz,1H),4.07(d,J=7.1Hz,2H),2.89(t,J=7.3Hz,2 H),2.58(dd,J=15.4,9.1Hz,2H),2.06(s,3H),1.96(d,J=7.8Hz,2H),1.26(d,J=12. 0Hz,1H),0.54(d,J=6.8Hz,2H),0.40(d,J=4.1Hz,2H).LC / MS(ESI)(m / z):491(M+H) + .

[0347] Example 19: 1-(cyclopropylmethyl)-N-((5-(imidazo[1,2-a]pyridin-6-yl)-6-methyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide TIFF2024538602000114.tif35128 The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A3) and 5-(imidazo[1,2-a]pyridin-6-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate B3) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.32(s,1H),8.28(s,1H),7.85(s,1H),7.76(s,1H),7.60(s,1H),7.53(s,1H),7.44 (d,J=9.2Hz,1H),7.11(s,1H),6.75(d,J=9.2Hz,1H),4.05(d,J=7.2Hz,2H),2.88(t, J=7.2Hz,2H),2.70-2.55(m,2H),2.05(s,3H),1.94(dd,J=15.6,7.2Hz,2H),1.31-1. 21(m,1H),0.53(d,J=7.2Hz,2H),0.39(d,J=4.4Hz,2H).LC / MS(ESI)(m / z):491(M+H) + .

[0348] Example 20: 1-(cyclopropylmethyl)-N-((5-(imidazo[1,5-a]pyridin-6-yl)-6-methyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A3) and 5-(imidazo[1,5-a]pyridin-6-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate B15-1) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.24(s,1H),8.15(s,1H),8.04(s,1H),7.65(s,1H),7.43(d,J=9.3Hz,1H), 7.36(s,2H),7.04(s,1H),6.35(d,J=9.0Hz,1H),4.00(d,J=7.1Hz,2H),2.87 (t,J=7.5Hz,2H),2.69-2.64(m,2H),2.06(s,3H),1.99-1.91(m,2H),1.27-1 .20(m,1H),0.55-0.48(m,2H),0.41-0.32(m,2H).LC / MS(ESI)m / z:491(M+H) + .

[0349] Example 21: 1-(cyclopropylmethyl)-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A3) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-3) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.41(s,1H),8.29(s,1H),8.02(d,J=2.1Hz,1H),7.72(s,1H),7.60(d,J=9 .0Hz,1H),7.11(s,1H),6.77(d,J=8.9Hz,1H),6.65(d,J=1.3Hz,1H),4.05 (d,J=7.2Hz,2H),2.89(t,J=7.4Hz,2H),2.72-2.56(m,2H),2.06(s,3H),2 .03-1.89(m,2H),1.33-1.22(m,1H),0.54(d,J=6.6Hz,2H),0.39(d,J=4.2 Hz,2H).LC / MS(ESI)m / z:491(M+H) + .

[0350] Example 22 (for comparison): 1-(cyclopropylmethyl)-N-((5-(pyrazolo[1,5-a]pyrimidin-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A3) and 5-(pyrazolo[1,5-a]pyrimidin-6-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B12) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.94(d,J=1.4Hz,1H),8.39(d,J=2.0Hz,1H),8.23(d,J=2.3Hz,1H),8.20(s,1H ),7.68(s,1H),7.25(d,J=3.7Hz,2H),6.74(d,J=2.2Hz,1H),3.99(d,J=7.1Hz,2 H),2.94(t,J=7.5Hz,2H),2.69(t,J=7.2Hz,2H),2.03-1.96(m,2H),1.26-1.22 (m,l1H),0.55-0.50(m,2H),0.37(t,J=5.2Hz,2H).LC / MS(ESI)(m / z):478(M+H) + .

[0351] Example 23: 1-Cyclobutyl-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide The title compound was prepared from 1-cyclobutyl-1H-pyrazole-3-sulfonamide (Intermediate A10) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.59(s,1H),8.03(s,1H),7.86(s,1H),7.41(s,1H),7.07(s,1H),6.59(s,1H),6.52(d,J=32.6Hz,2H),4.96-4.83(m,1H),3.7 3(s,1H),2.88(d,J=6.9Hz,2H),2.44-2.37(m,4H),2.04(s,3H),1.94(s,2H),1.86-1.76(m,3H).LC / MS(ESI)(m / z):491(M+H) + .

[0352] Example 24: 1-(cyclopropylmethyl)-N-((6-fluoro-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide The title compound was prepared from 1-(cyclopropylmethyl)-1H-pyrazole-3-sulfonamide (Intermediate A1) and 6-fluoro-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B36) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.69(d,J=7.0Hz,1H),8.01-8.00(m,1H),7.88-7.87(m,1H),7.59(s,1H), 6.74(d,J=7.3Hz,1H),6.63-6.58(m,2H),6.40(d,J=9.8Hz,1H),4.73(s,2H) ),4.04(d,J=7.2Hz,2H),2.84(t,J=7.4Hz,2H),2.70-2.67(m,2H),2.08-1. 98(m,3H),0.59-0.54(m,2H),0.41-0.38(m,2H).LC / MS(ESI)m / z:495(M+H) + .

[0353] Example 25: 1-Cyclopropyl-N-((6-fluoro-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide The title compound was prepared from 1-cyclopropyl-1H-pyrazole-3-sulfonamide (Intermediate A2) and 6-fluoro-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B36) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.63-8.57(m,1H),8.04-7.98(m,1H),7.73-7.63(m,2H),7.53-7.49(m,1H),7.08-7.02(m,1H),6.67-6.56(m,2H),6.37-6.31(m ,1H),3.78-3.71(m,1H),2.94-2.86(m,2H),2.67-2.62(m,2H),2.02-1.98(m,2H),1.06-0.94(m,4H).LC / MS(ESI)m / z:481(M+H) + .

[0354] Example 26: (S)-1-(2-Methoxypropyl)-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide The title compound was prepared from (S)-1-(2-methoxypropyl)-1H-pyrazole-3-sulfonamide (Intermediate A11) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.59(d,J=7.2Hz,1H),8.02(d,J=1.9Hz,1H),7.64(s,1H),7.38(s,1H),7.03 (s,1H),6.58(s,1H),6.55-6.51(m,1H),6.36(s,1H),4.13(d,J=3.7Hz,2H), 3.68-3.64(m,1H),3.18(s,3H),2.90-2.82(m,2H),2.67-2.58(m,2H),2.03( s,3H),1.96-1.89(m,2H),1.04(d,J=6.2Hz,3H).LC / MS(ESI)(m / z):509(M+H) + .

[0355] Example 27: (R)-1-(2-Methoxypropyl)-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide The title compound was prepared from (R)-1-(2-methoxypropyl)-1H-pyrazole-3-sulfonamide (Intermediate A12) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.62(d,J=7.2Hz,1H),8.02(d,J=1.6Hz,1H),7.72(s,1H),7.44(s,1H),7.38(s,1H) ,7.07(s,1H),6.59(s,1H),6.50(d,J=6.8Hz,1H),6.46(s,1H),4.16(t,J=4.4Hz,2H) ,3.66(dd,J=11.6,6.0Hz,1H),3.17(s,3H),2.86(t,J=7.2Hz,2H),2.67-2.57(m,2H) ,2.03(s,3H),1.97-1.91(m,2H),1.04(d,J=6.4Hz,3H).LC / MS(ESI)(m / z):509(M+H) + .

[0356] Example 28: 1-(cyclobutylmethyl)-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-4-sulfonamide The title compound was prepared from 1-(cyclobutylmethyl)-1H-pyrazole-4-sulfonamide (Intermediate A29) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.55(d,J=7.1Hz,1H),8.21(s,1H),8.01(d,J=2.1Hz,1H),7.69(s,1H),7.33(s,1H),7.07(s,1H),6.54(s,1H),6.44(d,J=7.0Hz,1H),4.18( d,J=7.3Hz,2H),2.87(t,J=7.5Hz,2H),2.80-2.65(m,2H),2.03(s,3H),1.94(d,J=6.1Hz,5H),1.85-1.72(m,4H).LC / MS(ESI)m / z:505(M+H) + .

[0357] Example 29: 5-(cyclopropyl(methyl)amino)-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyridine-3-sulfonamide The title compound was prepared from 5-(cyclopropyl(methyl)amino)pyridine-3-sulfonamide (Intermediate A14) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.48(d,J=6.8Hz,1H),8.37(s,1H),8.22(s,1H),7.99(s,1H),7.54(s,1H) ,7.31(s,1H),7.00(s,1H),6.56(s,1H),6.44(s,1H),2.96(s,3H),2.86(d, J=7.4Hz,2H),2.68(s,2H),2.02(s,3H),1.93(d,J=5.8Hz,2H),1.24-1.23( m,1H),0.87(d,J=5.8Hz,2H),0.58-0.57(m,2H).LC / MS(ESI)m / z:517(M+H) + .

[0358] Example 30: 5-(cyclopropyl(methyl)amino)-N-((5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyridine-3-sulfonamide The title compound was prepared from 5-(cyclopropyl(methyl)amino)pyridine-3-sulfonamide (Intermediate A14) and 5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.43(d,J=7.2Hz,1H),8.37(s,1H),8.29(s,1H),7.98(d,J=2.1Hz,1H),7.59(s,1 H),7.49(s,1H),7.11(d,J=8.0Hz,2H),6.68(d,J=7.3Hz,1H),6.55(d,J=1.6Hz,1H ),2.96(s,3H),2.90(t,J=7.5Hz,2H),2.70(t,J=7.2Hz,2H),2.47(s,1H),2.04-1. 88(m,2H),0.86(d,J=5.0Hz,2H),0.58(d,J=2.6Hz,2H).LC / MS(ESI)m / z:503(M+H) + .

[0359] Example 31: 5-(cyclopropylamino)-N-((5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyridine-3-sulfonamide The title compound was prepared from 5-(cyclopropylamino)pyridine-3-sulfonamide (Intermediate A15) and 5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.48(d,J=7.2Hz,1H),8.18(d,J=13.8Hz,2H),7.99(d,J=2.1Hz,1H),7.49(s, 1H),7.43(s,1H),7.15(d,J=5.3Hz,2H),6.64(d,J=6.3Hz,1H),6.58(d,J=1.7H z,1H),2.90(d,J=4.4Hz,2H),2.69(d,J=7.6Hz,2H),2.38(s,1H),2.01-1.95( m,2H),0.73(m,J=6.2Hz,2H),0.42(d,J=2.7Hz,2H).LC / MS(ESI)m / z:489(M+H) + .

[0360] Example 32: N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2-morpholinopyridine-4-sulfonamide The title compound was prepared from 2-morpholinopyridine-4-sulfonamide (Intermediate A16) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.56(d,J=7.1Hz,1H),8.27(d,J=5.1Hz,1H),8.03(d,J=2.2Hz,1H),7.36 (s,1H),7.09(d,J=4.9Hz,2H),6.83(d,J=5.1Hz,1H),6.55(d,J=1.6Hz,1H ),6.45(d,J=6.6Hz,1H),3.73-3.70(m,4H),3.51-3.48(m,6H),2.88(t,J =7.4Hz,2H),2.04(s,3H),1.99-1.93(m,2H).LC / MS(ESI)(m / z):533(M+H) + .

[0361] Example 33: 2-Cyclopropoxy-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyridine-4-sulfonamide The title compound was prepared from 2-cyclopropoxypyridine-4-sulfonamide (Intermediate A17) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.55(d,J=7.2Hz,1H),8.32(d,J=4.4Hz,1H),8.02(d,J=2.0Hz,1H),7.33(s,1H),7 .19(d,J=4.4Hz,1H),7.07(d,J=13.2Hz,2H),6.54(d,J=2.0Hz,1H),6.46(d,J=6.8 Hz,1H),4.26(s,1H),2.86(t,J=7.2Hz,2H),2.61(d,J=6.0Hz,2H),2.03(s,3H),1. 98-1.93(m,2H),0.82-0.78(m,2H),0.73-0.70(m,2H).LC / MS(ESI)(m / z):504(M+H) + .

[0362] Example 34: 5-Cyclopropoxy-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyridine-3-sulfonamide The title compound was prepared from 5-cyclopropoxypyridine-3-sulfonamide (Intermediate A18) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO)δ 8.52(d,J=5.3Hz,2H),8.01(d,J=1.9Hz,1H),7.77(s,1H),7.30(s,1H),7.05(s,1H),6.56(s,1H),6.44(d,J=7.2Hz,1H), 4.01(s,1H),2.87(t,J=7.1Hz,2H),2.59(s,2H),2.03(s,3H),1.94(t,J=7.2Hz,2H),0.85(d,J=6.2Hz,2H),0.73(m,2H).

[0363] Example 35: 5-Cyclobutoxy-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyridine-3-sulfonamide The title compound was prepared from 5-cyclobutoxypyridine-3-sulfonamide (Intermediate A19) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.52(d,J=7.1Hz,1H),8.49(d,J=1.6Hz,1H),8.43(d,J=2.6Hz,1H),8.01(d,J=2.2Hz,1H),7.56-7 .53(m,1H),7.30(s,1H),7.07(s,1H),6.55(d,J=1.7Hz,1H),6.43(d,J=6.8Hz,1H),4.86-4.74(m, 1H),2.87(t,J=7.4Hz,2H),2.56(d,J=3.6Hz,2H),2.48-2.42(m,2H),2.12-2.06(m,2H),2.03(s,3 H),1.94(t,J=7.4Hz,2H),1.82(d,J=10.2Hz,1H),1.73-1.61(m,1H).LC / MS(ESI)(m / z):518(M+H) + .

[0364] Example 36: 5-(cyclobutyl(methyl)amino)-N-(((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyridine-3-sulfonamide The title compound was prepared from 5-(cyclobutyl(methyl)amino)pyridine-3-sulfonamide (Intermediate A20) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.50(d,J=7.1Hz,1H),8.28(d,J=2.3Hz,1H),8.18(d,J=1.6Hz,1H),8.00(d,J=2.2Hz,1H),7 .38-7.36(m,1H),7.31(s,1H),7.05(s,1H),6.56(d,J=1.8Hz,1H),6.43(d,J=6.2Hz,1H),4. 11(t,J=8.2Hz,1H),2.89-2.83(m,5H),2.57(d,J=6.8Hz,2H),2.27-2.19(m,2H),2.13-2.06 (m,2H),2.03(s,3H),1.93(t,J=7.4Hz,2H),1.71-1.64(m,2H).LC / MS(ESI)(m / z):531(M+H) + .

[0365] Example 37: 5-(cyclopropylamino)-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyridine-3-sulfonamide The title compound was prepared from 5-(cyclopropylamino)pyridine-3-sulfonamide (Intermediate A15) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.54(d,J=7.1Hz,1H),8.24(s,1H),8.14(s,1H),8.02(d,J=2.0Hz,1H),7. 40(s,1H),7.32(s,1H),7.08(s,1H),6.59(s,1H),6.41(d,J=7.2Hz,1H),2 .89-2.84(m,2H),2.61-2.54(m,2H),2.39(s,1H),2.03(s,3H),1.98-1.91 (m,2H),0.78-0.73(m,2H),0.45-0.40(m,2H).LC / MS(ESI)(m / z):504(M+H) + .

[0366] Example 38: 2-Cyclobutyl-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)pyridine-4-sulfonamide The title compound was prepared from 2-cyclobutylpyridine-4-sulfonamide (Intermediate A21) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.65(s,1H),8.53(d,J=7.1Hz,1H),8.01(d,J=2.2Hz,1H),7.63-7.59(m ,1H),7.51-7.49(m,1H),7.04-7.34(m,2H),7.21-7.05(m,2H),6.53-6.5 1(m,1H),6.47-6.45(m,1H),2.68-2.66(m,1H),2.34-2.27(m,4H),2.07 -2.04(m,1H),2.03(s,3H),2.01-1.82(m,7H).LC / MS(ESI)m / z:502(M+H) + .

[0367] Example 39: 1-(cyclopropylmethyl)-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide The title compound was prepared from 1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (Intermediate A22) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B7-2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.58(d,J=6.8Hz,1H),8.26(d,J=2.4Hz,1H),8.00(d,J=2.4Hz,1H),7.54(dd,J=9.6,2. 8Hz,1H),7.35(s,1H),7.06(s,1H),6.52(d,J=3.6Hz,1H),6.51-6.40(m,2H),3.82(d,J= 7.2Hz,2H),2.87(t,J=7.2Hz,2H),2.72-2.57(m,3H),2.03(s,3H),1.96-1.91(m,2H),0 .90-0.78(m,1H),0.53-0.42(m,2H),0.36(d,J=4.0Hz,2H).LC / MS(ESI)(m / z):518(M+H) + .

[0368] Example 40: N-((5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide TIFF2024538602000135.tif35128 The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B21) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),8.15(d,J=4.8Hz,1H),7.53(dt,J=15.2,9.1Hz,2H),7.29(d,J=5.7Hz,1H),7.14(s,2H),6.89(s,1H),6.17(s,1H),5.32 -4.95(m,1H),2.94(t,J=7.4Hz,2H),2.75(dd,J=6.9,5.6Hz,2H),1.98(dd,J=14.5,7.2Hz,2H),1.42(s,6H).LC / MS(ESI)m / z:497(M+H) + .

[0369] Example 41: 4-(2-hydroxypropan-2-yl)-N-((5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)thiophene-2-sulfonamide The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B22) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. LC / MS (ESI) m / z: 511 (M+H). + .

[0370] Example 42: 4-(2-hydroxypropan-2-yl)-N-((5-(imidazo[1,2-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)thiophene-2-sulfonamide TIFF2024538602000137.tif35128 The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(imidazo[1,2-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B1) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.45(d,J=7.0Hz,1H),7.95(s,1H),7.87(s,1H),7.63(d,J=13.5Hz,2H),7.53(d,J=10.0Hz,1H),7.42(s,1H),7.18(q,J=7.7Hz,2 H),6.74(d,J=6.9Hz,1H),2.91(t,J=7.5Hz,2H),2.66(t,J=7.2Hz,2H),2.01-1.94(m,2H),1.41(s,6H).LC / MS(ESI)m / z:497(M+H) + .

[0371] Example 43: 4-(2-hydroxypropan-2-yl)-N-((5-(1-methyl-1H-benzo[d]imidazol-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)thiophene-2-sulfonamide TIFF2024538602000138.tif35128 The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(1-methyl-1H-benzo[d]imidazol-6-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B28) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ 10.81(s,1H),8.20(s,1H),7.73-7.63(m,2H),7.57(d,J=8.3Hz,1H),7.44(s,1H),7.21-7.14(m,2H),7.04(d,J=8.7Hz,1H),5 .24(s,1H),3.78(s,3H),2.92(t,J=7.4Hz,2H),2.70-2.65(m,2H),2.02-1.94(m,2H),1.42(s,6H).LC / MS(ESI)m / z:511(M+H) + .

[0372] Example 44: 4-(2-hydroxypropan-2-yl)-N-((5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)thiophene-2-sulfonamide The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B29) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.14(d,J=1.9Hz,1H),7.81(d,J=2.0Hz,1H),7.65-7.52(m,3H),7.20(d,J=7.6Hz,1H),7.12(d,J=7.6Hz,1H),6.43(d,J=3.4Hz,1H) ,5.25(s,1H),3.86(s,3H),2.92(t,J=7.4Hz,2H),2.67(t,J=7.1Hz,2H),2.03-1.93(m,2H),1.43(s,6H).LC / MS(ESI)m / z:511(M+H) + .

[0373] Example 45: N-((5-(1H-pyrrolo[2,3-c]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide TIFF2024538602000140.tif35128 The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(1H-pyrrolo[2,3-c]pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B30) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.83(s,1H),8.77(s,1H),7.92(s,1H),7.65(d,J=5.1Hz,2H),7.59(s,1H),7.47(s,1H),7.22(d,J=7.6Hz,1H),7.15(d,J=7. 6Hz,1H),6.17(s,1H),2.94(t,J=7.4Hz,2H),2.68(t,J=7.3Hz,2H),2.04-1.95(m,2H),1.42(s,3H).LC / MS(ESI)m / z:497(M+H) + .

[0374] Example 46: N-((5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide TIFF2024538602000141.tif39128 The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(1H-pyrrolo[2,3-b]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B31) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ 11.67(s,1H),10.80(s,1H),8.08(s,1H),7.78(s,1H),7.68(s,2H),7.51-7.48(m,1H),7.20(d,J=6.7Hz,1H),7.12(d,J=7.3Hz,1H),6.41( dd,J=3.4,1.8Hz,1H),5.26(s,1H),2.91(t,J=7.3Hz,2H),2.64(t,J=7.7Hz,2H),2.01-1.93(m,2H),1.42(s,6H).LC / MS(ESI)m / z:497(M+H) + .

[0375] Example 47: 4-(2-hydroxypropan-2-yl)-N-((5-(1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)thiophene-2-sulfonamide The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B32) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.87(s,1H),7.96(s,1H),7.66(s,2H),7.60-7.57(m,1H),7.43(d,J=2.8Hz,1H),7.23(d,J=7.6Hz,1H),7.14(d,J=7.6Hz,1H),6.13( d,J=2.3Hz,1H),3.95(s,3H),2.95(t,J=7.4Hz,2H),2.68(t,J=7.2Hz,2H),2.03-1.96(m,2H),1.45(s,6H).LC / MS(ESI)m / z:511(M+H) + .

[0376] Example 48: 4-(2-hydroxypropan-2-yl)-N-((5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)thiophene-2-sulfonamide TIFF2024538602000143.tif35128 The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B33) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.45(d,J=4.7Hz,1H),7.87(s,1H),7.55(s,1H),7.24(s,2H),7.03(d,J=4.3Hz,1H),5.21(s,1H),4.08(s,3 H),2.95(t,J=7.5Hz,2H),2.71(d,J=7.0Hz,2H),2.04-1.96(m,2H),1.42(s,6H).LC / MS(ESI)m / z:512(M+H) + .

[0377] Example 49: N-((5-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B23) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.17(d,J=4.9Hz,1H),7.33(d,J=1.6Hz,1H),7.27(d,J=3.6Hz,1H),7.20( d,J=1.6Hz,1H),7.08(s,2H),6.98(d,J=4.9Hz,1H),6.92(s,1H),6.19(d,J =3.6Hz,1H),5.08(s,1H),2.90(t,J=7.4Hz,2H),2.77(t,J=7.4Hz,2H),2. 02-1.91(m,3H),1.39(s,6H),1.05-1.00(m,4H).LC / MS(ESI)m / z:537(M+H) + .

[0378] Example 50: 1-Isopropyl-N-((5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-1H-pyrazole-3-sulfonamide The title compound was prepared from 1-isopropyl-1H-pyrazole-3-sulfonamide (Intermediate A24) and 5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B22) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.25(d,J=4.8Hz,1H),7.93(s,1H),7.46(d,J=3.4Hz,1H),7.21(s,1H),7.16(d,J=7.6Hz,1H),6.91(d,J=4.9Hz,1H),6.57(s,1H),6.18( s,1H),4.59(s,1H),3.86(s,3H),2.93(t,J=7.3Hz,2H),2.64(s,2H),2.04-1.95(m,2H),1.43(d,J=6.6Hz,6H).LC / MS(ESI)m / z:479(M+H) + .

[0379] Example 51: 4-(2-hydroxypropan-2-yl)-N-((5-(imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)thiophene-2-sulfonamide TIFF2024538602000146.tif35128 The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B2) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.45(s,1H),7.89(s,1H),7.71-7.57(m,3H),7.44(d,J=9.3Hz,1H),7.20(dd,J=15.5Hz,2H),7.03(d,J=10.6H) z,1H),2.93(t,J=7.4Hz,2H),2.68(t,J=7.4Hz,2H),2.02-1.96(m,2H),1.42(s,6H).LC / MS(ESI)m / z:497(M+H) + .

[0380] Example 52: N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B4) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.82(s,1H),8.51(s,1H),7.89(s,1H),7.71(d,J=9.1Hz,1H),7.56(s,1H) ,7.47(s,2H),7.21(s,2H),7.12-6.86(m,1H),5.20(s,1H),2.93(t,J=7.2 Hz,2H),2.76-2.65(m,2H),2.06-1.93(m,2H),1.41(s,6H).LC / MS(ESI)m / z:498(M+H) + .

[0381] Example 53: N-((5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B5) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.78(d,J=7.1Hz,1H),8.49(s,1H),7.69(d,J=0.8Hz,1H),7.50(s,1H),7.37(s,1H),7.22-7.18(m,2H),7.06(d,J=7.0Hz, 2H),5.19(s,1H),2.93(t,J=7.4Hz,2H),2.74(t,J=7.4Hz,2H),2.03-1.95(m,2H),1.41(s,6H).LC / MS(ESI)m / z:498(M+H) + .

[0382] Example 54: 4-(2-hydroxypropan-2-yl)-N-((5-(imidazo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)thiophene-2-sulfonamide TIFF2024538602000149.tif35128 The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(imidazo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B6) as described for Example 1. The residue was purified by preparative HPLC to afford the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.36(s,1H),8.49(s,1H),8.24-8.22(d,J=7.2Hz,1H),7.85(br,1H),7.69(d ,J=0.8Hz,1H),7.59(s,1H),7.38(s,1H),7.31(s,1H),7.20-7.13(m,2H),6.6 7-6.45(d,J=7.2Hz,1H),5.24(s,1H),2.93-2.89(t,J=7.4Hz,2H),2.68-2.6 4(t,J=7.4Hz,2H),1.99-1.96(m,2H),1.41(s,6H).LC / MS(ESI)m / z:497(M+H) + .

[0383] Example 55: 4-(2-hydroxypropan-2-yl)-N-((5-(1-(1-methylpiperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)thiophene-2-sulfonamide The title compound was prepared from 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (Intermediate A23) and 5-(1-(1-methylpiperidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-am...

Claims

1. Compounds of formulas (I) to (III): or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof, During the ceremony: A is CH ２ or O, Each occurrence of the Q ring is independently a 5-membered heteroaryl, a 6-membered heteroaryl, C ３－７ cycloalkyl, or 5- to 6-membered heterocyclyl; X １ and X ５ are each independently N or C, and X ２ , X ３ , and X ４ are each independently N or CR ７ and the dashed circle indicates the bond that forms the five-membered aromatic ring, provided that X １ , X ２ , X ３ , X ４ , and X ５ at least two but not more than three of Y １ is N or CH, and Y ２ But N, NR ８ or CH, and Y ３ But N, NR ８ or CH, and Y ４ is C or N, and in formula (II), but, indicates, Z １ is N or CH, and Z ２ But N or CR ９ and Z ３ is N or CH; R １ each occurrence of is independently hydrogen, C １－４ Alkyl, haloC １－４ Alkyl, C ３－７ Cycloalkyl, C １－４ Alkoxy, C ３－７ Cycloalkoxy, NR ａ R ｂ , C(=O)OR ａ , OC(=O)R ａ , C(═O)NR ａ R ｂ , N.R. ｂ C(=O)R ａ , C(=O)NHC(=O)R ａ or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R １１ may be substituted with R ２ each occurrence of is independently hydrogen, C １－４ Alkyl, haloC １－４ Alkyl, C ３－７ Cycloalkyl, halogen, CN, OH, C １－４ Alkoxy, NR ａ R ｂ , C(═O)NR ａ R ｂ or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 2 R １１ may be substituted with R ３ , R ４ , R ５ and R ６ are each independently hydrogen, halogen, CN, C １－４ Alkyl or haloC １－４ is alkyl, R ７ each occurrence of is independently hydrogen or C １－４ is alkyl, R ８ each occurrence of is independently hydrogen or C １－４ is alkyl, R ９ each occurrence of is independently hydrogen, C １－４ Alkyl or C １－４ is an alkoxy; R １０ each occurrence of is independently hydrogen, C １－４ Alkyl, C ３－７ cycloalkyl, or C １－４ 4- to 6-membered heterocyclyl optionally substituted by alkyl; R １１ each occurrence of is independently hydrogen, C １－４ Alkyl, haloC １－４ Alkyl, halogen, CN, OH, C ３－７ Cycloalkyl, C １－４ Alkoxy, C ３－７ Cycloalkoxy, NR ａ R ｂ , C(=O)OR ａ , OC(=O)R ａ , C(═O)NR ａ R ｂ , N.R. ｂ C(=O)R ａ , C(=O)NHC(=O)R ａ or 4- to 6-membered heterocyclyl; R ａ and R ｂ each occurrence of is independently hydrogen, C １－４ Alkyl, or C ３－５ cycloalkyl, or R ａ and R ｂ together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally C １－４ optionally substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; each occurrence of n is independently 0, 1, or 2; A compound, or a pharmaceutically acceptable salt, tautomer, and / or stereoisomer thereof.

2. Structure of Formula (I): and optionally having formula (I): but, 2. The compound of claim 1, wherein:

3. Structure of Formula (II): and optionally having formula (II): but, 2. The compound of claim 1, wherein:

4. Structure of formula (III): and optionally having formula (III): but, 2. The compound of claim 1, wherein:

5. Each occurrence of Q ring independently (a) 5-membered heteroaryl, optionally wherein each occurrence of the Q ring is independently thiophene, pyrazole, imidazole, thiazole, furan, oxazole, iso-oxazole, or triazole; (b) 6-membered heteroaryl, optionally wherein each occurrence of the Q ring is independently pyridine, pyridazine, pyrimidine, or pyrazine; (c) C 3-7 cycloalkyl, optionally with each occurrence of the Q ring independently being cyclobutyl; or (d) 5- to 6-membered heterocyclyl, optionally said 5- to 6-membered heterocyclyl containing 1 to 2 heteroatoms selected from N, O, and S; The compound of claim 1.

6. Each occurrence of Q ring independently 2. The compound of claim 1, wherein:

7. Each occurrence of the Q ring is independently R １ Along with, (a) Is it; (b) or (c) 2. The compound of claim 1, wherein:

8. The following:

10. The compound of claim 1 having a structure selected from:

9. R １ Each occurrence of １－４ Alkyl, haloC １－４ Alkyl, cyclopropyl, cyclobutyl, C １－４ Alkoxy, cyclopropyloxy, cyclobutyloxy, NR ａ R ｂ or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R １１ and optionally R １ is independently methyl, cyclopropyl, or cyclobutyl, each of which is independently selected from one R １１ The compound of claim 1, optionally substituted with

10. R ２ each occurrence of is independently hydrogen, C １－４ Alkyl, haloC １－４ Alkyl, C ３－５ Cycloalkyl, halogen, CN, OH, C １－４ Alkoxy, NR ａ R ｂ or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 2 R １１ The compound of claim 1, optionally substituted with

11. R ３ each occurrence of is hydrogen, methyl, F, or Cl, and optionally R ４ is hydrogen, methyl, or halogen; R ５ , R ６ , R ７ , R ８ is hydrogen or methyl; R ９ is hydrogen, methyl, or methoxy; The compound of claim 1.

12. R １０ each occurrence of is independently hydrogen, C １－４ Alkyl, C ３－５ cycloalkyl, or C １－４ The compound according to claim 1, which is a 4- to 6-membered heterocyclyl optionally substituted with alkyl, wherein the 4- to 6-membered heterocyclyl contains 1 to 2 heteroatoms selected from N, O and S.

13. R １１ each occurrence of is independently hydrogen, C １－４ Alkyl, C ３－５ Cycloalkyl, halogen, CN, OH, C １－４ Alkoxy, C ３－５ Cycloalkoxy, NR ａ R ｂ or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl contains 1 to 2 heteroatoms selected from N, O and S, and optionally R １１ 2. The compound of claim 1, wherein each occurrence of is independently cyclopropyl, cyclobutyl, or oxetane.

14. below:

2. The compound of claim 1 selected from:

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15 for treating or preventing a disease or condition responsive to inhibition of NLRP3, optionally wherein the disease or condition is a genetic disease, a neurodegenerative disorder, a metabolic disorder, an inflammatory syndrome, or cancer.

17. 17. The pharmaceutical composition of claim 16, wherein the genetic disease is cryopyrin-associated periodic syndrome, the neurodegenerative disorder is multiple sclerosis, Alzheimer's disease or Parkinson's disease, the metabolic disorder is atherosclerosis or type 2 diabetes, and the inflammatory syndrome is gout flare or osteoarthritis.

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