Novel bicyclic substituted sulfonylurea compounds as inhibitors of interleukin-1 activity

Abstract

The present application relates to novel bicyclic substituted sulfonylurea compounds of formula (I), their preparation, pharmaceutical compositions containing said compounds and their use as medicaments for treating diseases associated with the modulation of cytokines such as IL-10 and IL-18, diseases associated with the modulation of NLRP3 or diseases associated with the inhibition of activation of NLRP3 or of related components of inflammatory processes. TIFF2025508790000121.tif37128

Description

[Technical field]

[0001] Field The present application relates to novel bicyclic substituted sulfonylurea compounds and analogs, the preparation of said compounds and analogs, pharmaceutical compositions comprising said compounds and analogs, and their use as medicaments for treating diseases associated with the regulation of cytokines such as IL-1β and IL-18, diseases associated with the regulation of NLRP3, or diseases associated with the inhibition of activation of NLRP3 or of 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 expressed primarily in macrophages and in 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)]. Inflammasome activation is also associated with pyroptosis, a rapid and proinflammatory 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 diseases characterized by IL-1β-mediated systemic inflammation, such as cryopyrin-associated periodic syndrome (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). In recent years, 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, where treatment with canakinumab (a monoclonal antibody against IL-1β) resulted in a significantly lower rate 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, blocks ATP hydrolysis, and inhibits 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), cancer, among other relevant human diseases.

[0007] There is a need to provide compounds that have improved pharmaceutical properties and / or 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 The present 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 obtaining therapeutic efficacy while minimizing undesirable properties.

[0010] In one aspect, the present technology provides a compound represented by formula (II) to (IV): TIFF2025508790000002.tif81152, or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof, During the ceremony, Each occurrence of ring Q is independently TIFF2025508790000003.tif21128, Q 1Each occurrence of is independently N or CH, provided that at least one Q 1 is N, Q 2 Each occurrence is independently O, S, S(=O2), CH2, or NR 12 and X 1 and X 5 are each independently N or C; X 2 , X 3 , and X 4 are each independently N or CR 7 and the dashed circle indicates a bond forming a 5-membered aromatic ring, with the proviso 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 , N, NR 8 or CH, and Y 3 , N, NR 8 or CH, TIFF2025508790000004.tif10128 is TIFF2025508790000005.tif11128, Z 1 is N or CH, Z 2 is 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, oxo (=O), 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 or two R at geminal positions 2 The group is spiro C 3~5 Cycloalkyl may be optionally formed, 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 with alkyl; R 11 Each occurrence of is independently hydrogen, C 1~4 Alkyl, haloC 1~4Alkyl, 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 12 Each occurrence of is independently hydrogen, C 1~4 Alkyl, haloC 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~4 Alkyl-C 3~7 Cycloalkyl, C 1~4 Alkyl-NR a R b , C(=O)R a , C(=O)NR a R b , or C 1~4 Alkyl, haloC 1~4 Alkyl, C 3~7 Cycloalkyl, halogen, CN, OH, C 1~4 Alkoxy, C 3~7 Cycloalkoxy or NR a R b is a 4- to 6-membered heterocyclyl optionally substituted by 1 to 3 groups selected from 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 form together with the nitrogen atom to which they are attached 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 C 1~4may be substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; and Each occurrence of n is independently 0, 1, or 2.

[0011] The present technology also relates to pharmaceutical compositions comprising the compounds of formulae (I)-(IV), their manufacture and 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 the inhibition of activation of related components of the inflammatory process. Thus, the compounds of formulae (I)-(IV) 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 (gouty flares and osteoarthritis), cancer, among other related human diseases. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description In one aspect, the present technology provides compounds and pharma- ceutically 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 of treating and / or managing various diseases and disorders, comprising administering to a patient a therapeutically effective amount of a compound provided herein or a pharma- ceutically acceptable form thereof (e.g., salts, hydrates, solvates, isomers, sterioisomers, enantiomers, prodrugs, and isotopically labeled derivatives). 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 compositions include a compound provided herein, or a pharma- ceutically 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 the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0018] As used herein, "agent", "biologically active agent", or "second active agent" refers to a biological, pharmaceutical, or chemical compound or another 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 a variety of 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 includes delivery of a compound as described herein, or a prodrug or other pharma- ceutically 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 separate 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 set forth below. In some embodiments, the amount is effective for detectable inhibition of NLRP3, which can be determined, for example, by biological assays described herein. Therapeutically effective amounts can vary depending on the intended use (in vitro or in vivo), or the subject and disease state to be 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. The term also applies to a dose that will induce a response in target cells, such as reduced cell migration. A particular dose will vary depending, for example, on the compound selected, the species of the subject 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 to 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 obtain beneficial or desired results, including but not limited to therapeutic benefit and / or preventative 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 of the physiological symptoms associated with the underlying disease such that an improvement is observed in the patient, even though the patient may still suffer from the underlying disease. For preventative benefit, the pharmaceutical compounds and / or compositions may be administered to patients at risk of developing the disease or to patients who report one or more of the physiological symptoms of the 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. It is understood in the medical field 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, for example, 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 that is 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 salts" refers to those salts that are suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and 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 by using other methods used in the art, such as ion exchange. For example, pharma- ceutically 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-hydroxy-ethanesulfonate, and the like. Examples of the salts include phonate, 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 may 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] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as 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 Examples of pharmaceutically acceptable salts include salts of sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. In addition, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate. 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, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts can be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0031] As used herein, the term "solvate" refers to a compound further comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate may consist of the disclosed compound, or a pharma- ceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that may contain, 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 include compounds and solvates of compounds, as well as mixtures thereof.

[0032] In some embodiments, the pharma- ceutically acceptable form is a prodrug. As used herein, the term "prodrug" refers to a compound that is transformed in vivo to produce a pharma- ceutically 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 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 a compound when administered to a subject (e.g., by allowing enhanced absorption into the blood after oral administration) or enhance delivery to a biological compartment of interest (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). Reviews of prodrugs are provided in Higuchi, T., et al., “Pro-drugs 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 digestive tract or enhance drug stability for long-term storage.

[0034] The term "prodrug" is also meant to include any covalently bonded carrier that releases an active compound in vivo when such a 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 in 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 a 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 in active compounds, or acetamide, formamide, and benzamide derivatives of amine functional groups. Other examples of prodrugs include compounds that contain -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] For example, if a disclosed compound, or a pharma- ceutically acceptable form of the compound, contains a carboxylic acid functional group, the prodrug may be a compound that is a combination of a hydrogen atom of the acid group and (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 other groups may be substituted to form pharma- ceutically acceptable esters.

[0036] Similarly, when the disclosed compounds contain an alcohol functional group, the prodrug may be a compound that is 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 each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, -P(O)(OH), -P(O)(O(C 1~6) alkyl) 2, or glycosyl (the radical resulting from removal of the hydroxyl group of a carbohydrate in the hemiacetal form), such as α-aminoacyl or α-aminoacyl-α-aminoacyl.

[0037] When the disclosed compounds incorporate an amine functional group, the prodrug can be a prodrug that is a combination of a hydrogen atom in the amine group and a cyclic alkyl group in which R and R′ are each independently: 1~10 ) alkyl, (C 3~7 ) R-carbonyl, RO-carbonyl, NRR′-carbonyl, Y selected from cycloalkyl, benzyl, natural α-aminoacyl or natural α-aminoacyl-natural α-aminoacyl 1 But, H, (C 1~6 ) alkyl, or benzyl, -C(OH)C(O)OY 1 ;Y 2 However, (C 1~4 ) alkyl, and Y 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, —C(OY 2 )Y 3 ; and Y 4 is H or methyl, and Y 5 However, mono-N- or di-N-(C 1 6 ) alkylamino, morpholino, piperidin-1-yl, or pyrrolidin-1-yl; 4 )Y 5 The substituents may be formed by replacement with groups such as:

[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, "isomers" include 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 fall within the scope of the present disclosure.

[0039] Geometric isomers are represented by symbols representing bonds which may be single, double, or triple bonds as described herein. TIFF2025508790000006.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 in 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 as "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 as "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. Mixtures of compounds in which substituents are located both on the same and opposite sides of the plane of the ring are designated as "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 ratio may be known as a "racemic" mixture. The term "(±)" is used to designate a racemic mixture when necessary. "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 by either R or S. A resolved compound 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, for example, using 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," as 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 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 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 by resolution of racemic mixtures according to conventional processes, for example, by formation of diastereoisomeric salts, by treatment with optically active acids or bases. Examples of suitable acids include, but are not limited to, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Separation of the diastereoisomeric mixtures by crystallization, followed by liberation of the optically active bases from these salts, results in separation of the isomers. Another method involves the synthesis of covalent diastereoisomeric molecules by reacting the disclosed compounds with optically pure acids in activated form or 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 pharma- ceutically acceptable form is a tautomer. As used herein, the term "tautomer" is a type of isomer that includes 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 proton transfer tautomerism, which is considered a subset of acid-base chemistry. "Prototropic tautomerism" or "proton transfer 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 a solution), a chemical equilibrium of the tautomers may be reached. Tautomerism (i.e., the reaction that provides the tautomeric pair) may be catalyzed by an acid or base, or may 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 pharma- ceutically acceptable forms that are "isotopically labeled derivatives," which are the same compounds as 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 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, and chlorine, such as Cl. 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 dose requirements) due to greater metabolic stability. Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent with a non-isotopically labeled reagent. In some embodiments, compounds are provided herein that can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. All isotopic variations of compounds as disclosed herein, whether radioactive or not, are encompassed within the scope of the 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] "Pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. Pharmaceutically acceptable carriers or excipients do not destroy the pharmacological activity of the disclosed compounds and are non-toxic when administered in a dosage 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 pharma- ceutically 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 wax; 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; non-toxic compatible lubricants, such as sodium lauryl sulfate and stearyl alcohol; Examples of suitable surfactants include magnesium phosphate; colorants; release agents; coating agents; sweetening, flavoring and fragrance agents; 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 hydroxyalkylcyclodextrins, 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. Additionally, 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 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" is 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 consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 10 carbon atoms (e.g., C 1~10 Whenever it appears herein, a numerical range such as "1-10" refers to each integer in the given range, for example, "1-10 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 1-10, 1-8, 1-6, or 1-3 carbon atoms. Representative saturated straight chain 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, and the like. The alkyl is attached to the parent molecule by a single bond. Unless otherwise stated herein, the alkyl group may be 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, cyclopropylmethyl, cyclobutoxymethyl, 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 Alkenyl includes alkyl, aryl, and aryl groups. Alkenyl is attached to the parent molecular structure by a single bond, such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). 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 alkenyls 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 up to 10 carbon atoms, such as 2 carbon atoms, 3 carbon atoms, etc. 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 is attached to the parent molecular structure by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, 3-methyl-4-pentynyl, hexynyl, and the like. Unless stated otherwise herein, an alkynyl group may be optionally substituted with one or more of the substituents disclosed herein.

[0054] "Alkoxy" refers to the group -O-alkyl containing from 1 to 10 carbon atoms of a straight chain, 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 from 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 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 It is an aryl group. For example, a divalent radical formed from a substituted benzene derivative and having a free valence at a ring atom is named a substituted phenylene radical. In other embodiments, a divalent radical derived from a monovalent polycyclic hydrocarbon radical, the name of which ends in "-yl", by removing one hydrogen atom from the carbon atom having a 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 "6-14 aryl" refers to each integer in the given range, for example, "6-14 ring atoms" means that the aryl group can consist of 14 or fewer 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 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 may 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. Cycloalkyl groups are groups having 3 to 13 ring atoms (i.e., C 3~13Whenever 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 cycloalkyl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" refers to any of the groups listed below, including 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: C 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 above-mentioned 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 above-mentioned C 3~8Examples of cycloalkenyl groups include carbocyclyl groups, and octahydro-1H indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless otherwise stated herein, cycloalkyl groups may be substituted with one or more of the substituents disclosed herein. The terms "cycloalkenyl" and "cycloalkynyl" mirror 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 further substituted as defined herein.

[0058] "Heteroaryl", or alternatively "heteroaromatic", refers to a radical of an aromatic ring system having one or more ring carbon atoms and one to six ring heteroatoms provided in a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring system (e.g., having 6, 10 or 14 pi electrons shared in a cyclic arrangement), each heteroatom being independently selected from nitrogen, oxygen, phosphorus and sulfur ("5-18 membered heteroaryl"). A heteroaryl polycyclic ring system may contain one or more heteroatoms in one or both rings. Whenever it appears herein, a numerical range such as "5-18" refers to each integer in the given range, for example, "5-18 ring atoms" means that the heteroaryl group may consist of up to 18 ring atoms, such as 5 ring atoms, 6 ring atoms, etc. In some cases, a heteroaryl may have 5-14 ring atoms. In some embodiments, heteroaryls have divalent radicals derived from monovalent heteroaryl radicals ending 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 having two points of attachment is a 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. Heteroaryl is attached to the parent molecular structure through any atom of the ring(s).

[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 at either the aryl or heteroaryl ring, or 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 at 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 at either ring, i.e., either the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl group is a 5-10 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 ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having one or more ring carbon atoms and one to four ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having one or more ring carbon atoms and one to four ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has one to three ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl has one to two ring heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl has one 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. Lazanyl, 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, 3-d]pyrimidinyl, 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, e.g., "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 heteroatom(s) 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 ring(s).

[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 5-14 membered non-aromatic ring system having one or more ring carbon atoms and one to four ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-14 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 3-10 membered non-aromatic ring system having one or more ring carbon atoms and one to four ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("3-10 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 one to four ring heteroatoms, each of which is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("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 one to four ring heteroatoms, each of which is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has one to three ring heteroatoms, each of which is independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has one to two ring heteroatoms, each of which is independently selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has one ring heteroatom, each of which is 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 are accessible by removing a hydrogen atom from the corresponding corepsonding 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 particular site. Suitable non-limiting examples of such groups, unless otherwise specified, include halogen atoms, mesyloxy, p-nitrobenzenesulfonyloxy, trifluoromethyloxy, and tosyloxy groups.

[0070] "Protecting group" has the meaning traditionally associated with it in organic synthesis, namely, 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 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 to generate 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 "substitution" 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 replacement with 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 specified, 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) is optionally substituted with one or more substituents (up to six, valences allowed) independently selected from OH, NH2, oxo, halo, nitro, COOH, C(O)NH2, or cyano. For example, a cycloalkyl substituent can have a halide substituted at 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(Ra )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 and the like. Examples of the alkyl group include, but are not limited to, aryl, aryl, and 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 pathology. Thus, for example, a phenyl ring substituted with a "p" substituent (where "p" ranges from 0 to 5) may 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 easily determined. Substituted groups include only those combinations of substituents and variables that result in a stable or chemically feasible compound. A stable or chemically feasible compound is one that has sufficient stability to permit its preparation and detection, among other factors. In some embodiments, the disclosed compounds are sufficiently stable that 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, they remain substantially unchanged 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, combining" refer to the act of adding at least one chemical to another chemical(s), either sequentially or simultaneously. In some embodiments, bringing these chemicals together can result in the conversion of the first chemical to one or more different chemicals. This conversion can occur through one or more chemical reactions, such as, for example, covalent bonds being formed, broken, rearranged, etc. 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 the generation of charged chemicals and charged chemicals, such as, but not limited to, N-oxide formation, acid addition salt formation, base addition salt formation, etc. These terms include the generation and / or conversion of radical chemicals and isotopically labeled chemicals.

[0075] The terms "convert, converting, to convert, convert" refer to a subset of "combining" 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(s). For example, converting includes, but is not limited to, converting a nitro functional group on a chemical to an amine using a reducing agent. Converting also includes alterations of charged chemicals, radical chemicals, and isotopically labeled chemicals. However, the term "convert" does not include alterations of conserved bonds in the disclosed genera and compounds.

[0076] compound In one aspect, the present technology provides a compound of formula (I): TIFF2025508790000007.tif30128 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof, During the ceremony, Ring A is a fused 6,5-bicyclic aryl or heteroaryl ring system, the heteroaryl ring system containing 1, 2, 3, or 4 nitrogen atoms as ring members, and Ring A is R 5 and R 6 Possessing a substituent and R 7 Or R 9 and / or R 8 and R 10 and having one or two substituents on the ring nitrogen selected from Ring Q is a fused 6,5-bicyclic heteroaryl or a fused 6,6-bicyclic heteroaryl ring system, which contains 1, 2, or 3 nitrogen atoms as ring members and optionally contains 1 or 2 ring members selected from O, S, or S(=O2), and Ring Q is R as shown in formula (I). 1 and R 2 Possessing a substituent and one or two R 12 optionally bearing substituents, 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, oxo (=O), 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 1~4 Alkyl, haloC 1~4 Alkyl, C 3~7 Cycloalkyl, halogen, CN, OH, C 1~4 Alkoxy, NRa 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 or two R at geminal positions 2 The group is spiro C 3~5 Cycloalkyl may be optionally formed, R 3 and R 4 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 with alkyl; R 11 Each occurrence of is independently 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; R12 Each occurrence of is independently hydrogen, C 1~4 Alkyl, haloC 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~4 Alkyl-C 3~7 Cycloalkyl, C 1~4 Alkyl-NR a R b , C(=O)R a , C(=O)NR a R b , or C 1~4 Alkyl, haloC 1~4 Alkyl, C 3~7 Cycloalkyl, halogen, CN, OH, C 1~4 Alkoxy, C 3~7 Cycloalkoxy or NR a R b is a 4- to 6-membered heterocyclyl optionally substituted by 1 to 3 groups selected from 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 form together with the nitrogen atom to which they are attached 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 C 1~4 may be substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; and Each occurrence of n is independently 0, 1, or 2.

[0077] In some embodiments, the present technology provides a compound represented by formula (II)-(IV): 20. The present invention relates to a compound of formula (I) having the structure: During the ceremony, Each occurrence of ring Q is independently TIFF2025508790000009.tif20128, Q 1 Each occurrence of is independently N or CH, provided that at least one Q 1 is N, Q 2 Each occurrence is independently O, S, S(=O2), CH2, or NR 12 However, there are two Q 2 are adjacent in a ring, at least one Q 2 is CH, X 1 and X 5 are each independently N or C; X 2 , X 3 , and X 4 are each independently N or CR 7 and the dashed circle indicates a bond forming a 5-membered aromatic ring, with the proviso 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 , N, NR 8 or CH, and Y 3 , N, NR 8 or CH, TIFF2025508790000010.tif10128 is TIFF2025508790000011.tif11128, Z 1 is N or CH, Z 2 is 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, C3~7 Cycloalkoxy, oxo (=O), 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 or two R at geminal positions 2 The group is spiro C 3~5 Cycloalkyl may be optionally formed, 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, C3~7 Cycloalkyl, or C 1~4 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)R a or 4- to 6-membered heterocyclyl; R 12 Each occurrence of is independently hydrogen, C 1~4 Alkyl, haloC 1~4 Alkyl, C 3~7 Cycloalkyl, C 1~4 Alkyl-C 3~7 Cycloalkyl, C 1~4 Alkyl-NR a R b , C(=O)R a , C(=O)NR a R b , or C 1~4 Alkyl, haloC 1~4 Alkyl, C 3~7 Cycloalkyl, halogen, CN, OH, C 1~4 Alkoxy, C 3~7 Cycloalkoxy or NR a R b is a 4- to 6-membered heterocyclyl optionally substituted by 1 to 3 groups selected from R a and R b Each occurrence of is independently hydrogen, C 1~4 Alkyl, C 3~5 cycloalkyl or R a and R bform together with the nitrogen atom to which they are attached 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 C 1~4 may be substituted with 1 to 3 groups, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; and Each occurrence of n is independently 0, 1, or 2.

[0078] In some embodiments, the present technology provides a compound of formula (II): or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof, wherein Q, Q 1 , Q 2 , 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 12 , R a , R b , and n can each be as defined above or have any of the values ​​disclosed herein.

[0079] In any embodiment of the compound of formula (II), TIFF2025508790000013.tif20128 is TIFF2025508790000014.tif65142, where R 5 and R 6 Each of may be as defined above or may have any of the values ​​disclosed herein.

[0080] In some embodiments, the present technology provides a compound of formula (III): or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof, wherein Q, Q 1 , Q 2 , Y 1 , Y 2 , Y 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 11 , R 12 , R a , R b , and n can each be as defined above or have any of the values ​​disclosed herein.

[0081] In any embodiment of the compound of formula (III), TIFF2025508790000016.tif19128 is TIFF2025508790000017.tif24128, where R 5 , R 6 , and R 8 Each of may be as defined above or may have any of the values ​​disclosed herein.

[0082] In some embodiments, the present technology provides a compound of formula (IV): or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof, wherein Q, Q 1 , Q 2 , 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 12 , R a , Rb , and n can each be as defined above or have any of the values ​​disclosed herein.

[0083] In any embodiment of the compound of formula (IV), TIFF2025508790000019.tif17128 is TIFF2025508790000020.tif20128, where R 5 , R 6 , R 9 and R 8 Each of may be as defined above or may have any of the values ​​disclosed herein.

[0084] In any embodiment of the present compounds (including, but not limited to, compounds of Formula I, II, III, and IV), Q, in each occurrence, is independently In some embodiments, Q is independently, at each occurrence, In some embodiments, Q is independently, at each occurrence, In some embodiments, Q is independently, at each occurrence, In some embodiments, Q is, independently at each occurrence, In some embodiments, Q is independently, at each occurrence, In some embodiments, Q is independently, at each occurrence, In some embodiments, Q is independently, at each occurrence, The file is TIFF2025508790000028.tif19128.

[0085] In some embodiments, R 1 and R 2 and each occurrence of Q is independently TIFF2025508790000029.tif18128. In some embodiments, R 1 and R 2 and each occurrence of Q is independently TIFF2025508790000030.tif19128. In some embodiments, R 1 and R 2 and each occurrence of Q is independently TIFF2025508790000031.tif20128. In some embodiments, R 1 and R 2 and each occurrence of Q is independently TIFF2025508790000032.tif20128. In some embodiments, R 1 and R 2 and each occurrence of Q is independently TIFF2025508790000033.tif23128. In some embodiments, R 1 and R 2 and each occurrence of Q is independently TIFF2025508790000034.tif21128. In some embodiments, R 1 and R 2 and each occurrence of Q is independently The file is TIFF2025508790000035.tif24128.

[0086] In any embodiment of the compound, Q 1 Each occurrence of is independently N or CH, with the exception that there is only one Q per ring. 1 is N. In some embodiments, Q 2 Each occurrence is independently O, CH, or NR12 where there are two adjacent Q 2 When there is at least one Q 2 is CH.

[0087] In any embodiment of the compound, R 1 may, in each occurrence, independently be 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 may, in each occurrence, independently be 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; 3~5 Cycloalkoxy is cyclopropyloxy or cyclobutyloxy. In some embodiments, R 1 may, in each occurrence, independently be 1~4 In some embodiments, R 1 may, in each occurrence, independently be 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 1is, independently at each occurrence, methoxy. In some embodiments, R 1 is, independently at each occurrence, cyclopropyl. In some embodiments, R 1 is independently, at 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, independently at each occurrence, oxetane. In some embodiments, R 1 is, independently in each occurrence, an oxetane, which is represented by one R 11 In some embodiments, R 1 may, in each occurrence, independently: TIFF2025508790000036.tif13128. In some embodiments, R 1 may, in each occurrence, independently: TIFF2025508790000037.tif17128. In some embodiments, R 1 may, in each occurrence, independently: The file is TIFF2025508790000038.tif17128.

[0088] In any embodiment of the compound, R 2 is, in each occurrence, 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 In some embodiments, two R at geminal positions may be substituted. 2 The group is spiro C3~5 In some embodiments, two R at geminal positions may be optionally formed to form a cycloalkyl. 2 The group may optionally form a spirocyclobutyl. In some embodiments, R 3 is independently at each occurrence 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 independently at each occurrence 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 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, the 4- to 6-membered heterocyclyl containing 1-2 heteroatoms selected from N, O, and S. In some embodiments, R 11 is, independently at each occurrence, cyclopropyl. In some embodiments, R 11 is, independently at each occurrence, cyclobutyl. In some embodiments, R11 is, independently at each occurrence, oxetane. In some embodiments, R 12 is, in each occurrence, independently, hydrogen, C 1~4 Alkyl, haloC 1~4 Alkyl, C 3~5 Cycloalkyl, C 1~4 Alkyl-C 3~5 Cycloalkyl, C 1~4 Alkyl-NR a R b , C(=O)R a , C(=O)NR a R b , or C 1~4 Alkyl, haloC 1~4 Alkyl, C 3~5 Cycloalkyl, halogen, CN, OH, C 1~4 Alkoxy, C 3~5 Cycloalkoxy or NR a R b and the 4- to 6-membered heterocyclyl contains 1 to 2 heteroatoms selected from N, O, and S. In some embodiments, R 12 may, in each occurrence, independently be 1~4 In some embodiments, R 12 is, independently at each occurrence, methyl. In some embodiments, R 12 may, in each occurrence, independently be 3~5 In some embodiments, R 12 is, independently at each occurrence, cyclopropyl.

[0089] In any embodiment of the compound, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0090] In any embodiment, the compound is Selected from TIFF2025508790000039.tif60128.

[0091] In any embodiment, the compound is Selected from TIFF2025508790000040.tif59158.

[0092] In some embodiments, the present technology relates to compounds of formulas (I), (II), (III), and (IV), 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).

[0093] In another aspect, the present technology relates to a pharmaceutical composition comprising a compound disclosed herein (including, but not limited to, compounds of formula (I), (II), (III), and (IV)) and a pharma- ceutically acceptable carrier.

[0094] 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), (III), and (IV)).

[0095] In yet another aspect, the technology relates to a method 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), (III), and (IV)), 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.

[0096] In yet another aspect, the present technology relates to processes for making compounds of formulas (I), (II), (III), and (IV), including each of the exemplary compounds and intermediates described herein. EXAMPLES

[0097] 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, those exemplary schemes and working examples described below.All substituents are as defined hereinabove, unless otherwise indicated.Reactions are carried out in a solvent or solvent mixture appropriate for the reagents and materials used and suitable for the proposed transformation.This may sometimes require judgment to modify the order of synthetic steps or to select a particular process scheme over another in order to obtain the desired compound of the present technology.

[0098] It will be recognized that another major consideration in the planning of 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 to the trained practitioner is 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 reflect the actual chemical names of those compounds.

[0099] TIFF2025508790000041.tif55167 Scheme 1 describes a general synthetic route to compounds of formula (II). Compounds 1 and 2 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)Cl2) and a base (e.g., K2CO3) to give compound 3. Compound 3 is treated with triphosgene in the presence of a base (e.g., TEA, DIPEA) in a suitable solvent (e.g., DCM, THF) to give 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, CH3CN) to give the desired compound of formula (II).

[0100] TIFF2025508790000042.tif54166 Scheme 2 describes a general synthetic route to compounds of formula (III). 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)Cl2) and a base (e.g., K2CO3) to give compound 6. Compound 6 is treated with triphosgene in the presence of a base (e.g., TEA, DIPEA) in a suitable solvent (e.g., DCM, THF) to give 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, CH3CN) to give compounds of formula (III).

[0101] TIFF2025508790000043.tif52166 Scheme 3 describes a general synthetic route to compounds of formula (IV). 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)Cl2) and a base (e.g., K2CO3) to give compound 8. Compound 8 is treated with triphosgene in the presence of a base (e.g., TEA, DIPEA) in a suitable solvent (e.g., DCM, THF) to give 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, CH3CN) to give compounds of formula (IV).

[0102] Pharmaceutical Compositions and Methods The compounds used in the methods described herein may be formulated into a pharma- ceutically acceptable composition with a pharma- ceutically acceptable carrier or adjuvant prior to administration to a subject. In another embodiment, such a pharma- ceutically acceptable composition further comprises an effective amount of an additional therapeutic agent to achieve modulation of a disease or disease symptoms, including those described herein.

[0103] 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 is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the compound.

[0104] Pharmaceutically acceptable carriers, adjuvants and vehicles that may 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 polymeric 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 the compounds of the formulae described herein.

[0105] The pharmaceutical composition 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 composition of the present technology can contain any conventional non-toxic pharma- ceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation can be adjusted with a pharma- ceutically 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.

[0106] The pharmaceutical composition 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, for example, 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. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any smooth fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharma-ceutically 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 preparation of pharma- ceutically 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 pharma- ceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0107] The pharmaceutical composition of the present technology may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. For tablets for oral use, 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. When aqueous suspensions and / or emulsions are orally administered, the active ingredient may 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 colorings may be added.

[0108] 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 suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature, and therefore melt in the rectum to release active components.Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0109] 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 components 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 may 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 may 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.

[0110] The pharmaceutical compositions of the present technology may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulations and may 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.

[0111] When the composition of the present technology includes a combination of a compound of the formula described herein and 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.

[0112] The compounds described herein may be administered, for example, by injection, intravenous, intraarterial, subdermal, intraperitoneal, intramuscular, or subcutaneous, or in oral, buccal, nasal, mucosal, topical, 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 the compound or compound composition to achieve the desired or described effect. Typically, the 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 may be used as a chronic or acute therapy. The amount of active ingredient which 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 from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound.

[0113] 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, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition or symptom, disposition of the subject to the disease, condition or symptom, and the judgment of the treating physician.

[0114] When the condition of the subject is improved, a maintenance dose of the compound, composition or combination of the present technology can be administered as necessary.Then, the dosage or frequency of administration, or both, can be reduced as a function of symptoms, to a level at which the improved condition is maintained when symptoms are alleviated to a desired level.However, the subject may require intermittent treatment on a long-term basis based on any recurrence of disease symptoms.

[0115] 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.

[0116] 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 the preferred aspects of the present technology. The examples should not be construed in any way as limiting the scope of the present technology, which is defined by the appended claims. The examples may include or incorporate any of the variations, aspects, or aspects of the present technology described above. The variations, aspects, or aspects described above may also each further include or incorporate any or all other variations, aspects, or aspects of the present technology.

[0117] Working Example The abbreviations used herein are as follows: TIFF2025508790000044.tif120167TIFF2025508790000045.tif154167

[0118] 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, dichloromethane was continuously refluxed and freshly distilled from CaH2 under nitrogen.

[0119] Flash chromatography was performed on an Ez Purifier III via a column with 200-300 mesh silica gel particles. Analytical and preparative thin layer chromatography plates (TLC) were HSGF254 (0.15-0.2 mm thickness, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were recorded using a Brucker AMX-300 or AMX-400 NMR (Brucker, Switzerland) at approximately 20-30 °C unless otherwise specified. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublets; dt, doublet of triplets; 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 or reverse phase HPLC or flash columns, or Prep-TLC plates, under acidic, neutral, or basic conditions as appropriate.

[0120] Preparative HPLC: Unless otherwise stated, compounds were purified using a WATERS Fractionlynx system equipped with a YMC Pack Pro d8 column (5 μm, 120A, 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, but generally all elution gradients of HO and MeCN were run over a 7 minute run time with a flow rate of 35 mL / min. An autoblend method was used to ensure a concentration of 0.1% TFA throughout each run. The specific elution gradients were based on retention times obtained by analytical LC-MS, but generally all elution gradients of HO and MeCN were run over a 8 minute run time with a flow rate of 50 mL / min.

[0121] 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 μιη) at a column temperature of 45 °C 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, at a flow rate of 0.6 mL / min over a run time of 1.5 min.

[0122] Preparative Chiral SFC Separations: Stereoisomeric mixtures were separated using a Berger Minigram SFC instrument on one of the following columns: ChiralPak AS-H (10×250 mm), ChiralPak IA (10×250 mm), ChiralPak AD-H (21×250 mm), Phenomenex Lux-2 (21.2×250 mm), or ChiralPak IC (10×250 mm), eluting with either 0.1% diethylamine in MeOH / CO2, or 0.1% diethylamine in EtOH / CO2, or 0.1% diethylamine in isopropanol / CO2, using a flow rate of 2.5 mL / min and a column temperature of 35° C.

[0123] 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 (4.6×250 mm), ChiralPak IA (4.6×250 mm), ChiralPak AD-H (4.6×250 mm), Phenomenex Lux-2 (4.6×250 mm), or ChiralPak IC (4.6×250 mm), eluting with either 0.1% diethylamine in MeOH / CO2, or 0.1% diethylamine in EtOH / CO2, or 0.1% diethylamine in isopropanol / CO2, using a flow rate of 6.0 mL / min and a column temperature of 35° C.

[0124] Preparation of intermediates Intermediates A1 and A2: (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide and (S)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000046.tif60133 Step 1: 3-Iodo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole To a stirred solution of 3-iodo-1H-pyrazole (3 g, 15 mmol) in MeCN (30 mL) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (3.8 g, 18 mmol) and Cs2CO3 (15 g, 46 mmol) at room temperature. After stirring at room temperature for 3 h, the mixture was filtered. The filtrate was poured into water and extracted with EtOAc (2 x 10 mL). The combined organic phases 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 (2 g, 40% yield) as a colorless oil. LC / MS (ESI) m / z: 323 (M+H) + .

[0125] Step 2: Cyclopropyl(3-iodo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-5-yl)methanol To a stirred solution of 3-iodo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole (2 g, 6.2 mmol) in THF (30 mL) was added LDA (3.5 mL, 7 mmol, 2 M in THF) dropwise at −75° C. After stirring at −75° C. for 30 min, cyclopropanecarbaldehyde (0.5 mL, 6.2 mmol) was added to the mixture and the resulting mixture was stirred at −75° C. for 1 h. The mixture was poured into ice water and extracted with EtOAc (2×10 mL). The combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (1.4 g, 57% yield) as a colorless oil. LC / MS(ESI) m / z:309(M+H) + .

[0126] Step 3: 4-Cyclopropyl-2-iodo-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine To a stirred solution of 2-(5-(cyclopropyl(hydroxy)methyl)-3-iodo-1H-pyrazol-1-yl)ethan-1-ol (1.4 g, 3.6 mmol) in DCE (20 mL) was added PTSA (0.31 g, 1.8 mmol) and the mixture was stirred at 95 °C for 3 h. The mixture was poured into ice water and extracted with DCM (2 x 20 mL). The combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (400 mg, 38% yield) as a white solid. LC / MS (ESI) m / z: 291 (M+H) + .

[0127] Step 4: 2-(Benzylsulfanyl)-4-cyclopropyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine To a stirred solution of 4-cyclopropyl-2-iodo-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine (400 mg, 1.36 mmol) in 1,4-dioxane (15 mL) was added phenylmethanethiol (0.2 mL, 1.8 mmol), Pd2(dba)3 (140 mg, 0.16 mmol), Xant-Phos (180 mg, 0.32 mmol), and DIPEA (1 mL, 6 mmol) under N2 atmosphere. The mixture was degassed three times under N2 atmosphere and stirred at 95 °C for 3 h under N2 atmosphere. 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, 0-50% EtOAc in PE) to give the title compound (360 mg, 91% yield) as a yellow solid. LC / MS (ESI) m / z: 287 (M+H). + .

[0128] Step 5: 4-Cyclopropyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-2-sulfonyl chloride To a stirred solution of 2-(benzylsulfanyl)-4-cyclopropyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine (360 mg, 1.26 mmol) in AcOH (8 mL) / HO (2 mL) was added NCS (738 mg, 5.5 mmol) at 0° C. and the mixture was stirred at room temperature for 3 h. The mixture was poured into ice water and extracted with EtOAc (2×10 mL). The combined organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness to give the title compound (300 mg, 90% yield) as a yellow oil, which was used directly in the next reaction without purification.

[0129] Step 6: (R)-4-Cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide and (S)-4-Cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide A mixture of 4-cyclopropyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-2-sulfonyl chloride (300 mg, 1.14 mmol) in NH3 / THF (20 mL, 1 M) 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 phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give 4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (180 mg, 64.8% yield) as an off-white solid, which was repurified by chiral SFC to give the arbitrarily assigned (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A1, 80 mg, 28.8% yield) and (S)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A2, 85 mg, 30.6% yield) as white solids.

[0130] Intermediate A1 (peak 1, retention time: 5.728 min), 1 H NMR(400MHz,DMSO-d6) δ 7.42(s,1H),6.51(s,1H),4.29-4.25(m,1H),4.16-4.13(m,2H),4.05-4.03(d,J=8.8Hz,1H),3 .94-3.90(m,1H),1.16-1.14(m,1H),0.69-0.67(m,1H),0.59-0.51(m,2H),0.47-0.45(m,2H). LC / MS(ESI) m / z:244(M+H) + . Intermediate A2 (peak 2, retention time: 6.700 min), 1H NMR(400MHz,DMSO-d6) δ 7.42(s,1H),6.52(s,1H),4.29-4.25(m,1H),4.16-4.13(m,2H),4.05-4.03(d,J=8.8Hz,1H),3 .94-3.89(m,1H),1.17-1.12(m,1H),0.69-0.67(m,1H),0.58-0.52(m,2H),0.47-0.45(m,2H). LC / MS(ESI) m / z:244(M+H) + . SFC conditions: Column: ChiralPak IC-H, 250 x 21.2 mm i.d., 5 μm, Mobile phase: A in CO2 and B in methanol (0.1% NH4OH), Gradient: B 25%, Flow rate: 50 mL / min.

[0131] Intermediate A3: 6',7'-dihydrospiro[cyclobutane-1,4'-pyrazolo[5,1-c][1,4]oxazine]-2'-sulfonamide TIFF2025508790000047.tif55149 Step 1: N,N-bis(4-methoxybenzyl)-1-(2-(tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole-3-sulfonamide To a solution of N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (2 g, 5.16 mmol) in MeCN (25 mL) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.0 mL, 6.71 mmol) and Cs2CO3 (3.4 g, 10.3 mmol) and the reaction mixture was stirred at 65 °C under N2 atmosphere for 16 h. The reaction mixture was poured into water and extracted with EtOAc (3 x 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, 94.3% yield) as a yellow solid. LC / MS (ESI) (m / z): 516 (M+H) + .

[0132] Step 2: 5-(1-hydroxycyclobutyl)-N,N-bis(4-methoxybenzyl)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole-3-sulfonamide To a solution of N,N-bis(4-methoxybenzyl)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole-3-sulfonamide (700 mg, 1.62 mmol) in THF (8 mL) was added LDA (1.1 mL, 2.2 mmol, 2M in THF) dropwise at -70 °C and the mixture was stirred at this temperature for 1 h. A solution of cyclobutanone (0.13 mL, 1.78 mmol) in THF (4 mL) was added dropwise at -70 °C and the resulting mixture was stirred at -70 °C to room temperature for 2 h. The reaction mixture was quenched with ice-cold saturated aqueous NH4Cl solution and extracted with EtOAc (2 x 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, 0-30% EtOAc in PE) to give the title compound (200 mg, 24.6% yield) as a yellow solid. LC / MS (ESI) (m / z): 586 (M+H). + .

[0133] Step 3: 5-(1-hydroxycyclobutyl)-1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide To a solution of 5-(1-hydroxycyclobutyl)-N,N-bis(4-methoxybenzyl)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole-3-sulfonamide (100 mg, 0.17 mmol) in MeOH (5 mL) was added PPTS (43 mg, 0.17 mmol) and the reaction mixture was stirred at 50° C. for 1 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, 0-50% EtOAc in PE) to give the title compound (40 mg, 46.6% yield) as a yellow oil. LC / MS (ESI) (m / z): 502 (M+H) + .

[0134] Step 4: 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-(1-hydroxycyclobutyl)-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate To a solution of 5-(1-hydroxycyclobutyl)-1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide (100 mg, 0.20 mmol) in DCM (5 mL) was added TosCl (38 mg, 0.20 mmol), DIPEA (77 mg, 0.60 mmol), and DMAP (24 mg, 0.20 mmol) and the mixture was stirred at room temperature for 30 min. The mixture was diluted with DCM, washed with water and brine, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (105 mg, 80% yield) as a yellow solid. LC / MS (ESI) (m / z): 656 (M+H) + .

[0135] Step 5: N,N-Bis(4-methoxybenzyl)-6',7'-dihydrospiro[cyclobutane-1,4'-pyrazolo[5,1-c][1,4]oxazine]-2'-sulfonamide To a solution of 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-(1-hydroxycyclobutyl)-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate (80 mg, 0.12 mmol) in THF (3 mL) was added NaH (10 mg, 0.24 mmol, 60% dispersion in mineral oil) at 0° C. and the reaction mixture was stirred at room temperature for 30 min. The reaction was quenched with ice water 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, 0-30% EtOAc in PE) to give the title compound (40 mg, 67.8% yield) as a yellow solid. LC / MS (ESI) (m / z): 484 (M+H) + .

[0136] Step 6: 6',7'-Dihydrospiro[cyclobutane-1,4'-pyrazolo[5,1-c][1,4]oxazine]-2'-sulfonamide A solution of N,N-bis(4-methoxybenzyl)-6',7'-dihydrospiro[cyclobutane-1,4'-pyrazolo[5,1-c][1,4]oxazine]-2'-sulfonamide (40 mg, 0.08 mmol) in TFA (3 mL) was stirred at room temperature for 2 h. The mixture was concentrated to dryness and the residue was dissolved in EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness to give the title compound (15 mg, 74.6% yield) as a yellow solid. LC / MS (ESI) (m / z): 244 (M+H). + .

[0137] Intermediate A4: 8-Cyclopropyl-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000048.tif56128Step 1: 4-Iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-imidazole To a mixture of 4-iodo-1H-imidazole (2.0 g, 10.3 mmol) and 2-(2-bromoethoxy)oxane (2.6 g, 12.4 mmol) in CH3CN (30 mL) was added Cs2CO3 (5.0 g, 15.5 mmol) and the mixture was stirred at 60 °C for 3 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 (1.7 g, 51% yield) as a pale yellow oil. LC / MS (ESI) m / z: 323 (M+H) + .

[0138] Step 2: Cyclopropyl({4-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-imidazol-2-yl})methanol To a solution of 4-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-imidazole and 5-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-imidazole (1.7 g, 5.3 mmol) in THF (30 mL) was added LDA (4 mL, 2 M in hexane) dropwise at -70 °C. After stirring at this temperature for 30 min, cyclopropanecarbaldehyde (440 mg, 6.3 mmol) was added and the resulting mixture was stirred at -70 °C to room temperature for 2 h. The reaction was poured into ice water and extracted with EtOAc (2 x 20 mL). The organic layer was 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 (1.2 g, 58% yield) as a colorless oil. LC / MS(ESI) m / z:393(M+H) + .

[0139] Step 3: 8-Cyclopropyl-2-iodo-5H,6H,8H-imidazo[2,1-c][1,4]oxazine To a solution of cyclopropyl({4-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-imidazol-2-yl})methanol (1.0 g, 2.5 mmol) in DCE (15 mL) was added PTSA (220 mg, 1.3 mmol) and the mixture was stirred at reflux for 2 h. The mixture was diluted with DCM (10 mL), washed with water and 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 (240 mg, 32% yield) as a white solid. LC / MS (ESI) m / z: 291 (M+H) + .

[0140] Step 4: 2-(benzylsulfanyl)-8-cyclopropyl-5H,6H,8H-imidazo[2,1-c][1,4]oxazine To a solution of 8-cyclopropyl-2-iodo-5H,6H,8H-imidazo[2,1-c][1,4]oxazine (240 mg, 0.8 mmol), phenylmethanethiol (133 mg, 1.0 mmol), and DIPEA (320 mg, 2.5 mmol) in toluene (8 mL) was added Pd2(dba)3 (151 mg, 0.16 mmol), Xant-Phos (96 mg, 0.16 mmol) under N2 atmosphere. The mixture was degassed three times under N2 atmosphere and stirred at 100 °C for 3 h under N2 atmosphere. The mixture was concentrated to dryness and the residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (230 mg, 97% yield) as a yellow oil. LC / MS (ESI) m / z: 286 (M+H) + .

[0141] Step 5: 8-Cyclopropyl-5H,6H,8H-imidazo[2,1-c][1,4]oxazine-2-sulfonamide To a stirred solution of 2-(benzylsulfanyl)-8-cyclopropyl-5H,6H,8H-imidazo[2,1-c][1,4]oxazine (100 mg, 0.35 mmol) in AcOH (4 mL) and HO (1 mL) was added 1,3-dichloro-5,5-dimethylhydantoin (206 mg, 1.0 mmol) in portions at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was dissolved in THF (1 mL), and NH3 / THF (2 mL, 1 M) was added dropwise at 0° C. After stirring at room temperature for 1 h, the mixture was 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% yield) as a white solid. LC / MS(ESI) m / z:244(M+H) + .

[0142] Intermediate A5: 4,4-Dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000049.tif62128 Step 1: 3-Iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-pyrazole To a stirred solution of 3-iodo-1H-pyrazole (5 g, 26 mmol) in MeCN (100 mL) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (4.7 mL, 31 mmol) and Cs2CO3 (17 g, 51 mmol) and the mixture was stirred at 40 °C for 2 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 (8 g, 96% yield) as a colorless oil. LC / MS (ESI) m / z: 323 (M+H) + .

[0143] Step 2: 2-{3-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-pyrazol-5-yl}propan-2-ol To a stirred solution of 3-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-pyrazole (2 g, 6.2 mmol) in THF (30 mL) was added LDA (3.8 mL, 7.1 mmol, 2M in THF) dropwise at -75 °C. After stirring at -75 °C for 30 min, acetone (1 mL, 18 mmol) was added dropwise to the mixture and the resulting mixture was stirred at -75 °C for 1 h. The mixture was poured into ice water and extracted with EtOAc (2 x 15 mL). The combined organic phase was 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 (1.1 g, 46% yield) as a pale yellow oil. LC / MS (ESI) m / z: 381 (M+H) + .

[0144] Step 3: 2-Iodo-4,4-dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine To a stirred solution of 2-{3-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-pyrazol-5-yl}propan-2-ol (1.1 g, 2.9 mmol) in DCE (20 mL) was added PTSA (0.3 g, 1.8 mmol) and the mixture was stirred at 95 °C for 3 h. The mixture was poured into ice water and extracted with DCM (2 x 20 mL). The combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-80% EtOAc in PE) to give the title compound (500 mg, 62% yield) as a yellow oil. LC / MS (ESI) m / z: 279 (M+H) + .

[0145] Step 4: 2-(benzylsulfanyl)-4,4-dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine To a stirred solution of 2-iodo-4,4-dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine (500 mg, 1.8 mmol) in 1,4-dioxane (15 mL) was added phenylmethanethiol (0.2 mL, 1.9 mmol), Pd2(dba)3 (140 mg, 0.16 mmol), Xant-Phos (190 mg, 0.33 mmol), and DIPEA (1 mL, 6 mmol) under N2 atmosphere, and the mixture was degassed under N2 atmosphere three times and stirred at 95 °C under N2 atmosphere for 3 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, 0-50% EtOAc in PE) to give the title compound (400 mg, 81% yield) as a yellow solid. LC / MS(ESI) m / z:275(M+H) + .

[0146] Step 5: 4,4-Dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-2-sulfonyl chloride To a stirred solution of 2-(benzylsulfanyl)-4,4-dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine (200 mg, 0.72 mmol) in AcOH (8 mL) / HO (2 mL) was added NCS (738 mg, 5.5 mmol) in portions at 0° C., and the mixture was stirred at room temperature for 1 h. The mixture was poured into 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 to give the title compound (120 mg, 66% yield) as a colorless oil, which was used directly in the next reaction without purification.

[0147] Step 6: 4,4-Dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-2-sulfonamide. A mixture of 4,4-dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-2-sulfonyl chloride (120 mg, 0.48 mmol) in NH3 / THF (20 mL, 2M) 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 phases were washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (40 mg, 36% yield) as a white solid. LC / MS (ESI) m / z: 232 (M+H) + .

[0148] Intermediate A6: 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000050.tif95149Step 1: 3-Iodo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole-5-carbaldehyde To a solution of 3-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-pyrazole (2 g, 6.2 mmol) in THF (10 mL) was added LDA (3.7 mL, 7.4 mmol, 2 M in THF) at -70 °C, and the mixture was stirred at -70 °C for 0.5 h. A solution of DMF (0.9 mL, 12.4 mmol) in THF (5 mL) was added dropwise to the mixture at -70 °C, and the resulting mixture was stirred at -70 °C to room temperature for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl solution and extracted with EtOAc (2 x 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, 0-20% EtOAc in PE) to give the title compound (1.1 g, 50.6% yield) as a pale yellow oil. LC / MS(ESI)(m / z):351(M+H) + .

[0149] Step 2: (3-iodo-1-(2-(tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-5-yl)methanol To a solution of 3-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-pyrazole-5-carbaldehyde (1.1 g, 3.1 mmol) in THF (15 mL) was added NaBH4 (178 mg, 4.7 mmol) in portions at 0 °C, and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was poured into ice water and extracted with EtOAc (2 x 10 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, 0-20% EtOAc in PE) to give the title compound (950 mg, 85.8% yield) as a colorless oil. LC / MS (ESI) (m / z): 353 (M+H) + .

[0150] Step 3: 2-(5-(hydroxymethyl)-3-iodo-1H-pyrazol-1-yl)ethan-1-ol A solution of 5-[(R)-cyclopropyl(methoxy)methyl]-1-methyl-1H-pyrazole-3-sulfonyl chloride (1 g, 0.3 mmol) in HCl / 1,4-dioxane (5 mL, 4 M) was stirred at room temperature for 1 h. The mixture was filtered, and the filter cake was washed with PE and dried under vacuum to give the title compound (500 mg, 72.9% yield) as a white solid. LC / MS (ESI) (m / z): 269 (M+H). + .

[0151] Step 4: 2-(5-(hydroxymethyl)-3-iodo-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate To a solution of 2-[5-(hydroxymethyl)-3-iodo-1H-pyrazol-1-yl]ethan-1-ol (300 mg, 1.1 mmol) in DCM (2 mL) was added TEA (0.5 mL, 3.4 mmol) and TosCl (0.2 mL, 1.1 mmol) at 0° C., and the mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM, 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 (240 mg, 50.7% yield) as a colorless oil. LC / MS (ESI) (m / z): 423 (M+H) + .

[0152] Step 5: 2-Iodo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine To a solution of 2-[5-(hydroxymethyl)-3-iodo-1H-pyrazol-1-yl]ethyl 4-methylbenzene-1-sulfonate (240 mg, 0.57 mmol) in THF (2 mL) was added NaH (68 mg, 1.7 mmol, 60% dispersion in mineral oil) in portions at 0 °C, and the mixture was stirred at room temperature for 1 h. The mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc (2 x 10 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, 0-30% EtOAc in PE) to give the title compound (140 mg, 98.5% yield) as a pale yellow oil. LC / MS (ESI) (m / z): 251 (M+H) + .

[0153] Step 6: 2-(benzylthio)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine To a mixture of 2-iodo-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine (150 mg, 0.60 mmol), phenylmethanethiol (0.07 mL, 0.6 mmol), and DIPEA (0.3 mL, 1.8 mmol) in 1,4-dioxane (10 mL) was added Pd2(dba)3 (110 mg, 0.1 mmol), XantPhos (139 mg, 0.2 mmol) under N2 atmosphere. The mixture was degassed three times under N2 atmosphere and stirred at 100 °C for 2 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, 94.7% yield) as a yellow oil. LC / MS (ESI) (m / z): 247 (M+H) +

[0154] Step 7: 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonyl chloride To a solution of 2-(benzylsulfanyl)-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine (140 mg, 0.57 mmol) in HO (1 mL) and AcOH (5 mL) was added NCS (379 mg, 2.8 mmol) in portions at 0° C., and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with EtOAc (2×5 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 (90 mg, 70.9% yield) as a pale yellow oil. LC / MS (ESI) (m / z): 223 (M+H) +

[0155] Step 8: 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide To a solution of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonyl chloride (70 mg, 0.31 mmol) in THF (2 mL) was added NH3 / THF (2 mL, 1 M) at 0° C. and the mixture was stirred at room temperature for 1 h. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (55 mg, 86.2% yield) as a white solid. LC / MS (ESI) (m / z): 204 (M+H). + .

[0156] Intermediate A7: 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-sulfonamide TIFF2025508790000051.tif69146 Step 1: 5-(hydroxymethyl)-N,N-bis[(4-methoxyphenyl)methyl]-1-(oxan-2-yl)-1H-pyrazole-4-sulfonamide To a solution of N,N-bis[(4-methoxyphenyl)methyl]-1-(oxan-2-yl)-1H-pyrazole-4-sulfonamide (2.0 g, 4.2 mmol) in THF (40 mL) was added LDA (3.2 mL, 6.4 mmol, 2 M in THF) dropwise at -70 °C and the mixture was stirred at -70 °C for 30 min. Paraformaldehyde (380 mg, 12.7 mmol) was added and the mixture was stirred at -70 °C to room temperature for 2 h. The reaction was poured into ice water and extracted with EtOAc (2 x 10 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, 0-40% EtOAc in PE) to give the title compound (1.2 g, 56% yield) as a brown oil. LC / MS(ESI)(m / z):323(M+H) + .

[0157] Step 2: N,N-bis[(4-methoxyphenyl)methyl]-1-(oxan-2-yl)-5-{[2-(oxan-2-yloxy)ethoxy]methyl}-1H-pyrazole-4-sulfonamide To a solution of 5-(hydroxymethyl)-N,N-bis[(4-methoxyphenyl)methyl]-1-(oxan-2-yl)-1H-pyrazole-4-sulfonamide (300 mg, 0.6 mmol) in DMF (6 mL) was added NaH (36 mg, 0.9 mmol, 60% dispersion in mineral oil) at 0 °C. After stirring at 0 °C for 30 min, 2-(2-bromoethoxy)oxane (150 mg, 0.72 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. The mixture was poured into ice water and extracted with EtOAc (2 × 10 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, 0-60% EtOAc in PE) to give the title compound (270 mg, 72% yield) as a colorless oil. LC / MS(ESI)(m / z):462(M-2THP+H) + .

[0158] Step 3: 5-[(2-hydroxyethoxy)methyl]-N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-4-sulfonamide To a solution of N,N-bis[(4-methoxyphenyl)methyl]-1-(oxan-2-yl)-5-{[2-(oxan-2-yloxy)ethoxy]methyl}-1H-pyrazole-4-sulfonamide (270 mg, 0.4 mmol) in EtOH (4 mL) and THF (4 mL) was added 1N aqueous HCl (3 mL) and the mixture was stirred at room temperature for 16 h. The mixture was diluted with ice water and extracted with EtOAc (2×10 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, 0-8% MeOH in DCM) to give the title compound (150 mg, 76% yield) as a colorless oil. LC / MS (ESI) (m / z): 462 (M+H) + .

[0159] Step 4: N,N-bis[(4-methoxyphenyl)methyl]-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-3-sulfonamide To a solution of 5-[(2-hydroxyethoxy)methyl]-N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-4-sulfonamide (150 mg, 0.3 mmol) in 1,4-dioxane (5 mL) was added cyanomethylenetributylphosphorane (157 mg, 0.6 mmol) under N2 atmosphere and the mixture was stirred at 120 °C for 2 h under a CEM microwave reactor. 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, 69% yield) as a pale yellow solid. LC / MS (ESI) (m / z): 444 (M+H) + .

[0160] Step 5: 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-sulfonamide A solution of N,N-bis[(4-methoxyphenyl)methyl]-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-3-sulfonamide (100 mg, 0.2 mmol) in TFA (3 mL) was stirred at 60° C. for 2 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 (35 mg, 86.1% yield) as a yellow solid. LC / MS (ESI) (m / z): 204 (M+H). + .

[0161] Intermediate A8: 7-Cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000052.tif54128Step 1: Ethyl 3-iodo-1H-pyrazole-5-carboxylate To a solution of ethyl 5-amino-1H-pyrazole-3-carboxylate (2 g, 12.9 mmol) in diiodomethane (30 mL) was added isoamyl nitrite (15.6 mL, 116 mmol) at −10° C. under N2 atmosphere over 20 min. The mixture was stirred at room temperature for 1 h and at 90° C. for an additional 1 h. The mixture was diluted with EtOAc (20 mL), washed successively with saturated aqueous Na2S2O3, 1N aqueous HCl, 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 (1.4 g, 40.8% yield) as a yellow solid. LC / MS (ESI) m / z: 266 (M+H) + .

[0162] Step 2: Ethyl 1-(1-cyclopropyl-2-ethoxy-2-oxoethyl)-3-iodo-1H-pyrazole-5-carboxylate To a mixture of ethyl 3-iodo-1H-pyrazole-5-carboxylate (1.27 g, 4.76 mmol) and ethyl 2-bromo-2-cyclopropyl acetate (920 mg, 4.76 mmol) in MeCN (10 mL) was added K2CO3 (1.97 g, 14.3 mmol) and the mixture was stirred at 80 °C for 3 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, 0-9% EtOAc in PE) to give the title compound (1.4 g, 75% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3) δ 7.00(s,1H),4.38(q,J=7.1Hz,2H),4.31(d,J=10.1Hz,1H),4.26-4.17(m,2H),2.02-1.95(m,1H),1.37(t, LC / MS(ESI) m / z:393(M+H) + .

[0163] Step 3: Ethyl 3-(benzylthio)-1-(1-cyclopropyl-2-ethoxy-2-oxoethyl)-1H-pyrazole-5-carboxylate To a mixture of ethyl 1-(1-cyclopropyl-2-ethoxy-2-oxoethyl)-3-iodo-1H-pyrazole-5-carboxylate (460 mg, 1.17 mmol), benzyl mercaptan (0.23 mL, 1.88 mmol), DIPEA (0.62 mL, 3.74 mmol), and XantPhos (216 mg, 0.37 mmol) in 1,4-dioxane (5 mL) was added Pd2(dba)3 (171 mg, 0.19 mmol) under N2 atmosphere. The mixture was degassed three times under N2 atmosphere and stirred at 90 °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, 0-25% EtOAc in PE) to give the title compound (400 mg, 88% yield) as a yellow oil. LC / MS (ESI) m / z: 389 (M+H). + .

[0164] Step 4: 2-(3-(benzylthio)-5-(hydroxymethyl)-1H-pyrazol-1-yl)-2-cyclopropylethan-1-ol To a solution of ethyl 1-(1-cyclopropyl-2-ethoxy-2-oxoethyl)-3-iodo-1H-pyrazole-5-carboxylate (400 mg, 1.03 mmol) in THF (10 mL) was added LiAlH4 (118 mg, 3.09 mmol) in portions at 0° C. under N2 atmosphere and the mixture was stirred at room temperature for 1 h. The reaction was quenched with Na2SO4.10H2O at 0° C. and filtered. The filtrate was concentrated to dryness to give the title compound (200 mg, 63.9% yield) as a yellow solid. LC / MS (ESI) m / z: 305 (M+H) + .

[0165] Step 5: 2-(benzylthio)-7-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine To a solution of 2-(3-(benzylthio)-5-(hydroxymethyl)-1H-pyrazol-1-yl)-2-cyclopropylethan-1-ol (120 mg, 0.39 mmol) in THF (2 mL) was added NaH (38.6 mmol, 0.97 mmol, 60% dispersion in mineral oil) at 0 °C under N2 atmosphere and the mixture was stirred at room temperature for 0.5 h. The mixture was cooled to 0 °C and 1-(p-toluenesulfonyl)imidazole (88 mg, 0.39 mmol) was added. After stirring at room temperature for 1 h, the mixture was quenched with ice water and extracted with EtOAc (2 x 10 mL). The combined organic layers were 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 (70 mg, 62% yield) as a yellow oil. LC / MS(ESI) m / z:287(M+H) + .

[0166] Step 6: 7-Cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide To a solution of 7-cyclopropyl-2-(phenylthio)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (80 mg, 0.28 mmol) in AcOH (5 mL) and HO (2 mL) was added NCS (135 mg, 1.0 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 h. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, and filtered. The filtrate was added to NH3 / THF solution (10 mL, 1 M) at 0 °C, and the resulting mixture was stirred at 0 °C for 0.5 h. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (45 mg, 66.3% yield) as a colorless oil. LC / MS (ESI) m / z: 244 (M+H) + .

[0167] Intermediate A9: 1-Cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonamide TIFF2025508790000053.tif72128 Step 1: Methyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)acetate To a solution of 5-bromo-2-chloro-3-nitropyridine (10 g, 40.00 mmol) and methyl 2-hydroxyacetate (3.4 mL, 44.40 mmol) in anhydrous THF (100 mL) was added NaH (1.76 g, 44.4 mmol, 60% dispersion in mineral oil) in portions at 0° C., and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water and extracted with EtOAc (2×50 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, 0-30% EtOAc in PE) to give the title compound (10 g, 90.3% yield) as a pale yellow solid. LC / MS (ESI) (m / z): 291 / 293 (M+H). + .

[0168] Step 2: 7-Bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one To a solution of methyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)acetate (10 g, 34.8 mmol) in AcOH (100 mL) was added Fe (9.75 g, 174.1 mmol) and the mixture was stirred at 80 °C for 1 h. The mixture was filtered through diatomaceous earth and the filtrate was poured into water and extracted with EtOAc (3 x 50 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, 0-25% EtOAc in PE) to give the title compound (4.7 g, 52.3% yield) as a red solid. LC / MS (ESI) (m / z): 229 / 231 (M+H) + .

[0169] Step 3: 7-Bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine To a solution of 7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (4 g, 17.5 mmol) in THF (40 mL) was added BH3-THF complex (90 mL, 90 mmol, 1 M in THF) and the mixture was stirred at 70 °C for 1 h. The reaction was quenched with MeOH at 0 °C and the mixture was concentrated to dryness. The residue was dissolved in EtOH (20 mL) and 6N aqueous HCl (5 mL) and the mixture was stirred at 80 °C for 2 h. The mixture was basified with 1N aqueous NaOH and extracted with EtOAc (3 x 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, 0-50% EtOAc in PE) to give the title compound (1.4 g, 32.2% yield) as a yellow solid. LC / MS(ESI)(m / z):215 / 217(M+H) + .

[0170] Step 4: 7-Bromo-1-cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine To a mixture of 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (1.4 g, 5.76 mmol) and cyclopropylboronic acid (1.4 g, 11.52 mmol) in DCE (20 mL) was added Cu(OAc)2 (1.12 g, 5.76 mmol), 2,2'-bipyridine (1.92 g, 11.5 mmol), and Na2CO3 (1.30 g, 11.5 mmol), and the mixture was stirred at 70 °C under O2 atmosphere for 16 h. The mixture was filtered, and the filtrate was diluted with DCM, washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-18% EtOAc in PE) to give the title compound (1.2 g, 52.3% yield) as a white solid. LC / MS(ESI)(m / z):255(M+H) + .

[0171] Step 5: 7-(benzylthio)-1-cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine To a mixture of 7-bromo-1-cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (500 mg, 1.96 mmol) and phenylmethanethiol (0.25 mL, 2.16 mmol) in 1,4-dioxane (5 mL) was added DIPEA (556 mg, 2.20 mmol), Xant-Phos (56 mg, 0.098 mol), and Pd2(dba)3 (45 mg, 0.049 mol) under N2 atmosphere, and the mixture was degassed three times under N2 atmosphere and stirred at 120° C. for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by chromatography (silica gel, 0-17% EtOAc in PE) to give the title compound (580 mg, 93.2% yield) as a yellow solid. LC / MS (ESI) (m / z): 299 (M+H). + .

[0172] Step 6: 1-Cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonamide To a solution of 1-cyclopropyl-7-(phenylthio)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (80 mg, 0.27 mmol) in AcOH (6 mL) and water (1.5 mL) was added NCS (107 mg, 0.8 mmol) and 1.0 N aqueous HCl (2.0 mL) at 0° C., 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 Na2SO4, and filtered. The filtrate was added to a NH3 / THF solution (5 mL, 1 M) at −50° C., and the resulting mixture was stirred at −50° C. for 30 min. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (35 mg, 50.7% yield) as a white solid. 1H NMR(400MHz,DMSO-d6) δ 7.88(d,J=2.0Hz,1H),7.65(d,J=2.0Hz,1H),4.39-4.34(m,2H),3.03-2.97(m,1H),2.38-2.34 (m,1H),2.28-2.24(m,1H),0.70-0.68(m,2H),0.63-0.57(m,2H).LC / MS(ESI)(m / z):256(M+H) + .

[0173] Intermediate A10: (S)-6-Methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide TIFF2025508790000054.tif75137 Step 1: 1-Acetyl-1,2-dihydro-pyrazol-3-one To a solution of 1,2-dihydro-pyrazol-3-one (5.0 g, 60 mmol) in pyridine (30 mL) was added acetic anhydride (6.12 g, 60 mmol) dropwise at 95° C. and the mixture was stirred at 95° C. for 1 h. The mixture was concentrated to dryness and the residue was triturated with MeOH at 0° C. The slurry was filtered and the filter cake was dried under vacuum to give the title compound (5.4 g, 71% yield) as a white solid. LC / MS (ESI) (m / z): 127 (M+H). + .

[0174] Step 2: 1-(3-{[(2S)-oxiran-2-yl]methoxy}-1H-pyrazol-1-yl)ethan-1-one To a mixture of 1-acetyl-2,3-dihydro-1H-pyrazol-3-one (5 g, 39.6 mmol) and PPh3 (15.6 g, 59.4 mmol) in THF (400 mL), DIAD (11.8 mL, 59.4 mmol) was added dropwise at 0 °C under N2 atmosphere, and the mixture was stirred at 0 °C for 1 h. [(2R)-oxiran-2-yl]methanol (3.16 mL, 47.6 mmol) was added dropwise to the mixture at 0 °C, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (3.1 g, 42.9% yield) as a white solid. LC / MS (ESI) (m / z): 183 (M+H) + .

[0175] Step 3: 1-{3-[(2R)-3-chloro-2-hydroxypropoxy]-1H-pyrazol-1-yl}ethan-1-one To a solution of 1-(3-{[(2S)-oxiran-2-yl]methoxy}-1H-pyrazol-1-yl)ethan-1-one (5 g, 27.4 mmol) in THF (100 mL) was added AcOH (4.71 mL, 82.3 mmol) and LiCl (3.49 mg, 82 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the title compound (6 g, 99% yield) as a yellow oil, which was used directly in the next reaction without purification. LC / MS (ESI) (m / z): 219 (M+H). + .

[0176] Step 4: (6S)-5H,6H,7H-Pyrazolo[3,2-b][1,3]oxazin-6-ol To a solution of 1-{3-[(2R)-3-chloro-2-hydroxypropoxy]-1H-pyrazol-1-yl}ethan-1-one (6 g, 27.4 mmol) in DMF (3 mL) was added K2CO3 (11.4 g, 82.3 mmol) and the mixture was stirred at 100 °C for 3 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, 0-10% DCM in MeOH) to give the title compound (3 g, 78% yield) as a white solid. LC / MS (ESI) (m / z): 141 (M+H) + .

[0177] Step 5: (6S)-6-Methoxy-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine To a solution of (6S)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazin-6-ol (3 g, 21.4 mmol) in DMF (30 mL) was added NaH (1.28 g, 32.1 mmol, 60% dispersion in mineral oil) in portions at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. MeI (1.99 mL, 32.1 mmol) was added, and the resulting mixture was stirred at 25 °C for 4 h. The mixture was quenched with ice water and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-5% DCM in MeOH) to give the title compound (2.9 g, 87.9% yield) as a white solid. LC / MS(ESI)(m / z):155(M+H) + .

[0178] Step 6: (6S)-6-Methoxy-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-sulfonic acid To a solution of (6S)-6-methoxy-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine (2 g, 12.9 mmol) in DCM (20 mL) was added chlorosulfonic acid (2.59 mL, 38.9 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to dryness to give the title compound (3 g, 98% yield) as a yellow oil, which was used directly in the next reaction without purification. LC / MS (ESI) (m / z): 235 (M+H). + .

[0179] Step 7: (6S)-6-Methoxy-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-sulfonyl chloride To a solution of (6S)-6-methoxy-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-sulfonic acid (3 g, 12.8 mmol) in DCM (30 mL) was added PCl5 (8.0 g, 38.4 mmol) and the mixture was stirred at room temperature for 4 h. The mixture was poured into ice water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3 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 (3 g, 92% yield) as a white solid. LC / MS (ESI) (m / z): 253 (M+H) + .

[0180] Step 8: (6S)-6-Methoxy-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-sulfonamide To a solution of (6S)-6-methoxy-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-sulfonyl chloride (1 g, 3.95 mmol) in DCM (16 mL) was added NH3 / THF (10 mL, 1 M) dropwise at 0 °C and the mixture was stirred at room temperature for 1 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 (560 mg, 60.8% yield) as a yellow solid.1 H NMR(400MHz,DMSO-d6) δ 7.49(s,1H),4.59(d,J=11.9Hz,1H),4.32(d,J=11.9Hz,1H),4.28-4.22(m,1H), 4.20-4.16(m,1H),4.06-4.01(m,1H),3.35(s,3H).LC / MS(ESI)(m / z):234(M+H) + .

[0181] Intermediate B1: 5-(imidazo[1,2-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-amine TIFF2025508790000055.tif65132 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 Ac2O (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 Na2SO4, 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) + .

[0182] 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)2 (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 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 (700 mg, 61.9% yield) as a white solid. LC / MS (ESI) m / z: 255 (M+H) + .

[0183] 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 to pH ∼8 with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (3×10 mL) and the combined organic layers were dried over Na2SO4, 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 grey solid. LC / MS (ESI) m / z: 212 (M+H) + .

[0184] 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)Cl2 (173 mg, 0.24 mmol) under N2 atmosphere. The mixture was degassed three times under N2 atmosphere and stirred at 100 °C for 3 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl and brine, dried over anhydrous Na2SO4, 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). + .

[0185] Step 5: 5-(imidazo[1,2-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-amine To a mixture of 7-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 N atmosphere. The mixture was degassed three times under 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. 1H NMR(400MHz,CDCl3) δ 8.16(d,J=6.9Hz,1H),7.71(s,1H),7.65(s,1H),7.59(s,1H),7.02(d,J=7.6Hz,1H),6.95(d,J=6.6Hz,1H),6.7 7(d,J=7.6Hz,1H),2.96(t,J=7.5Hz,2H),2.77(t,J=7.3Hz,2H),2.23-2.11(m,2H).LC / MS(ESI)(m / z):250(M+H) + .

[0186] Intermediate B7: 6-Methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine TIFF2025508790000056.tif94145 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 Na2SO4, 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) + .

[0187] 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 Br2 (2.08 mL, 40.4 mmol) dropwise over a period of 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 x 50 mL). The combined organic layers were washed successively with brine, saturated aqueous NaHCO3, and saturated aqueous NaHSO3, dried over Na2SO4, 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) + .

[0188] 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 pre-cooled 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 another 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 Na2SO4, 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) + .

[0189] 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 K2CO3 (34.7 g, 251 mmol) in 1,4-dioxane (70 mL) and HO (15 mL) was added Pd(dppf)Cl2 (1.71 g, 2.34 mmol) under N2 atmosphere, and the mixture was degassed three times under N2 atmosphere and stirred at 100° C. 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 (0-20% EtOAc in PE) to give the title compound (2.9 g, 52.9% yield) as a yellow solid. 1 H 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) + .

[0190] 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 Na2SO4, filtered and concentrated to dryness to give the title compound (2.1 g, 88.3% yield) as a yellow solid. 1H 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) + .

[0191] 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 CH3CN (30 mL) was heated to 55 °C, CuBr2 (2.44 g, 10.9 mmol) was added under N2 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 x 20 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, 0-10% 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) + .

[0192] 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. 1 H 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) + .

[0193] Step 8: 6-Methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine To a mixture of pyrazolo[1,5-a]pyridin-5-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 K2CO3 (260 mg, 1.9 mmol) followed by Pd(dppf)Cl2 (50 mg, 0.07 mmol) under N2 atmosphere. The mixture was degassed three times under N2 atmosphere and stirred at 90 °C for 16 h. After cooling, the reaction was diluted with EtOAc and filtered through a pad of Celite. 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 (110 mg, 67.7% yield) as a white solid. 1H NMR(400MHz,CDCl3) δ 8.55(d,J=7.1Hz,1H),7.99(d,J=2.2Hz,1H),7.44(s,1H),6.74-6.62(m,2H),6.53(d,J=1.9Hz,1H),2. 94(t,J=7.5Hz,2H),2.74(t,J=7.3Hz,2H),2.18-2.11(m,2H),2.06(s,3H).LC / MS(ESI)(m / z):264(M+H) + .

[0194] The intermediates in Table 1 below were prepared by using methods and starting materials similar to those used to prepare the intermediates described herein.

[0195] [Table 1] TIFF2025508790000058.tif215147TIFF2025508790000059.tif174147

[0196] Example 1: (R)-4-Cyclopropyl-N-((5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000060.tif38128To a mixture of 5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B5, 30 mg, 0.12 mmol) and EtN (36 mg, 0.36 mmol) in THF (3 mL) was added triphosgene (21 mg, 0.07 mmol) in portions under N2 atmosphere at 0° C. After stirring at 0° C. for 0.5 h, the mixture was filtered and the filtrate was used directly in the next reaction. To a solution of (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A1, 40 mg, 0.18 mmol) in THF (1 mL), NaH (22 mg, 0.54 mmol, 60% dispersion in mineral oil) was added portionwise at 0° C., and after stirring at 0° C. for 0.5 h, the above filtrate was added dropwise to the mixture. The resulting mixture was stirred at room temperature for 0.5 h. The mixture was poured into ice water and acidified to pH ∼4 with 1N aqueous HCl. The mixture was extracted with EtOAc (3×10 mL), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, 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 (10 mg, 10.7% yield) as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.56(d,J=7.2Hz,1H),8.00(d,J=2.2Hz,1H),7.79(s,1H),7.58(s,1H),7.18(d,J=2.6Hz,2H),6.80(d,J =7.1Hz,1H),6.59(d,J=1.6Hz,1H),6.49(s,1H),4.31-4.24(m,1H),4.17-4.07(m,2H),3.98(d,J=8.8Hz, 1H),3.95-3.87(m,1H),2.92(t,J=7.4Hz,2H),2.72(t,J=7.3Hz,2H),2.05-1.90(m,2H),1.16-1.06(m,1 H),0.70-0.63(m,1H),0.61-0.64(m,1H),0.52-0.42(dt,J=8.5,5.0Hz,2H).LC / MS(ESI)(m / z):519(M+H) + .

[0197] Example 2: (R)-4-Cyclopropyl-N-((5-(pyrazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000061.tif35128 The title compound was prepared from (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A1) and 5-(pyrazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B6) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.54(s,1H),8.00(d,J=2.2Hz,1H),7.64(d,J=9.1Hz,1H),7.17(s,2H),7.12(d,J=9.1Hz ,1H),6.62(d,J=1.5Hz,1H),6.50(s,1H),4.28(dt,J=5.5,3.0Hz,1H),4.16-4.08(m,2H) ,4.00(d,J=9.0Hz,1H),3.94-3.87(m,1H),2.91(t,J=7.4Hz,2H),2.71(t,J=7.3Hz,2H), 2.05-1.95(m,2H),1.15-1.07(m,1H),0.67-0.54(m,2H),0.53-0.44(m,2H).LC / MS(ESI) m / z:519(M+H) + .

[0198] Example 3: (R)-N-((5-([1,2,3]triazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000062.tif40128 The title compound was prepared from (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A1) and 5-([1,2,3]triazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B9) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.97(d,J=6.8Hz,1H),8.17(s,1H),7.83(s,1H),7.21(s,2H),7.08(d,J=6.7 Hz,1H),6.46(s,1H),4.30-4.25(m,1H),4.14-4.07(m,2H),3.97-3.89(m,2H) ,2.93(t,J=7.3Hz,2H),2.74(t,J=7.1Hz,2H),2.03-1.99(m,2H),1.13-1.07 (m,1H),0.68-0.63(m,1H),0.59-0.54(m,1H),0.49-0.44(m,2H).LC / MS(ESI) m / z: 520 (M+H) + .

[0199] Example 4: (R)-N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000063.tif35128 The title compound was prepared from (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A1) and 5-([1,2,4]triazolo[1,5-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 give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.80(s,1H),8.47(s,1H),7.72(d,J=9.2Hz,1H),7.64(d,J=9.1Hz,1H),7.14 (dd,J=17.0,7.6Hz,2H),6.28(s,1H),4.25(d,J=11.5Hz,2H),4.04(s,3H),2 .91(t,J=7.3Hz,2H),2.79(t,J=7.2Hz,2H),2.02-1.95(m,2H),1.14-1.06(m ,1H),0.65(s,1H),0.57(d,J=8.1Hz,1H),0.47(d,J=9.2Hz,2H).LC / MS(ESI) m / z:520(M+H) + .

[0200] Example 5: (S)-4-Cyclopropyl-N-((5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000064.tif39128 The title compound was prepared from (S)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A2) and 5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B5) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.57(d,J=7.2Hz,1H),8.01(d,J=2.1Hz,1H),7.59(s,1H),7.20-7.16(m,2H),6.80(d,J=7.4 Hz,1H),6.59(d,J=1.7Hz,1H),6.49(s,1H),4.30-4.26(m,1H),4.13-4.10(m,2H),3.98(d,J =8.9Hz,1H),3.95-3.88(m,1H),2.92(t,J=7.4Hz,2H),2.72(t,J=7.3Hz,2H),2.04-1.96(m, 2H),1.15-1.07(m,1H),0.70-0.63(m,1H),0.60-0.55(m,1H),0.53-0.44(m,2H).LC / MS(ESI) m / z:519(M+H) + .

[0201] Example 6: (S)-4-Cyclopropyl-N-((5-(pyrazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000065.tif35128 The title compound was prepared from (S)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A2) and 5-(pyrazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B6) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.55(s,1H),8.00(d,J=2.1Hz,1H),7.64(d,J=9.2Hz,1H),7.15(d,J=9.9Hz,3H),6.62(s, 1H),6.47(s,1H),4.27(d,J=12.1Hz,1H),4.10(s,2H),3.99(d,J=9.1Hz,1H),3.90(dt,J=1 3.8,6.7Hz,1H),2.92(t,J=7.4Hz,2H),2.73(t,J=7.2Hz,2H),2.04-1.94(m,2H),1.15(t, LC / MS(ESI) m / z:519(M+H) + .

[0202] Example 7: (S)—N-((5-([1,2,3]triazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000066.tif41128 The title compound was prepared from (S)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A2) and 5-([1,2,3]triazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B9) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.80(s,1H),8.47(s,1H),7.72(d,J=9.2Hz,1H),7.64(d,J=9.1Hz,1H),7.14 (dd,J=17.0,7.6Hz,2H),6.28(s,1H),4.25(d,J=11.5Hz,2H),4.04(s,3H),2 .91(t,J=7.3Hz,2H),2.79(t,J=7.2Hz,2H),2.02-1.95(m,2H),1.14-1.06(m ,1H),0.65(s,1H),0.57(d,J=8.1Hz,1H),0.47(d,J=9.2Hz,2H).LC / MS(ESI) m / z:520(M+H) + .

[0203] Example 8: (S)—N-((5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000067.tif35128 The title compound was prepared from (S)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A2) and 5-([1,2,4]triazolo[1,5-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 give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.81(s,1H),8.50(s,1H),7.74(d,J=9.1Hz,1H),7.61(d,J=9.0Hz,1H),7 .17(q,J=7.8Hz,2H),6.37(s,1H),4.27(d,J=11.8Hz,1H),4.08(s,2H),3 .99-3.86(m,2H),2.92(t,J=7.7Hz,3H),2.77(t,J=7.3Hz,2H),2.08(s,1 H),2.04-1.95(m,2H),1.19-1.10(m,2H),0.71-0.43(m,4H).LC / MS(ESI) m / z: 520 (M+H) + .

[0204] Example 9: (R)-4-Cyclopropyl-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000068.tif38128 The title compound was prepared from (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A1) and 6-methyl-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 give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.58(s,1H),8.00(d,J=2.0Hz,1H),7.39(s,1H),7.24(s,1H),7.02(s,1H),6.54(dd,J =16.6,9.6Hz,2H),6.39(s,1H),4.27(d,J=12.3Hz,1H),4.08(s,2H),3.99(d,J=8.4Hz ,1H),3.95-3.85(m,1H),2.86(t,J=7.3Hz,2H),2.71-2.58(m,2H),2.03(s,3H),1.94( d,J=8.8Hz,2H),1.18-1.05(m,1H),0.70-0.61(m,1H),0.59-0.40(m,3H).LC / MS(ESI) m / z:533(M+H) + .

[0205] Example 10: (R)-4-Cyclopropyl-N-((5-(imidazo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000069.tif38128 The title compound was prepared from (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A1) and 5-(imidazo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B4) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.38(s,1H),8.29(d,J=7.3Hz,1H),7.43(s,1H),7.34(s,1H),7.15(q,J=8.0Hz,2H),6 .55(dd,J=27.8,7.4Hz,2H),4.27(d,J=11.8Hz,1H),4.08(d,J=20.7Hz,2H),3.98(d,J =9.1Hz,1H),3.95-3.85(m,1H),2.90(t,J=7.4Hz,2H),2.72-2.64(m,2H),1.99(dd,J= 16.7,9.5Hz,2H),1.16-1.06(m,1H),0.74-0.62(m,1H),0.60-0.40(m,3H).LC / MS(ESI) m / z:519(M+H) + .

[0206] Example 11: (R)-4-Cyclopropyl-N-((5-(imidazo[1,2-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000070.tif38128 The title compound was prepared from (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A1) 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 give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.53(d,J=6.9Hz,1H),7.98(s,1H),7.61(s,1H),7.44(s,1H),7.21(q,J=7.6Hz,2H),6 .82-6.80(m,1H),6.60(s,1H),4.32-4.27(m,1H),4.18-4.14(m,2H),4.03(d,J=8.7Hz, 1H),3.96-3.90(m,1H),2.92(t,J=7.2Hz,2H),2.70-2.66(m,2H),2.03-1.96(m,3H),1 .16-1.10(m,1H),0.69-0.63(m,1H),0.61-0.50(m,2H),0.49-0.43(m,1H).LC / MS(ESI) m / z:519(M+H) + .

[0207] Example 12: (R)-4-Cyclopropyl-N-((5-(imidazo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000071.tif39128 The title compound was prepared from (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A1) and 5-(imidazo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B10) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.35(s,1H),8.26(s,1H),7.51(d,J=9.7Hz,1H),7.38(s,1H),7.21(d,J=7.9Hz,1H),7.16( d,J=7.6Hz,1H),6.66(d,J=9.2Hz,1H),6.58(s,1H),4.29(d,J=11.9Hz,1H),4.14(s,2H),4 .01(d,J=8.8Hz,1H),3.94(d,J=13.1Hz,1H),2.92(t,J=7.2Hz,2H),2.68(d,J=6.9Hz,2H), 2.00(t,J=7.3Hz,2H),1.16-1.08(m,1H),0.70-0.62(m,1H),0.60-0.45(m,3H).LC / MS(ESI) m / z:519(M+H) + .

[0208] Example 13: (R)-N-((5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000072.tif39128 The title compound was prepared from (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A1) and 5-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B3) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.86(d,J=7.1Hz,1H),8.51(s,1H),7.71(s,1H),7.22(s,2H),7.13(d,J=7.0Hz,1H),6.49(d,J=14 .2Hz,1H),4.28(dt,J=11.6,3.3Hz,1H),4.13(d,J=4.5Hz,2H),3.99(d,J=8.9Hz,1H),3.96-3.89( m,1H),2.93(t,J=7.4Hz,2H),2.74(t,J=7.2Hz,2H),2.04-1.97(m,2H),1.11(ddd,J=12.2,8.4,3. 8Hz,1H),0.65(dt,J=8.5,4.3Hz,1H),0.57(dd,J=7.9,3.6Hz,1H),0.51-0.42(m,2H).LC / MS(ESI) m / z:520(M+H) + .

[0209] Example 14: (R)-N-((5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000073.tif38128 The title compound was prepared from (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A1) and 5-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B8) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 9.21(d,J=9.4Hz,1H),8.48(d,J=14.7Hz,1H),7.63(d,J=9.6Hz,1H),7.35(d, J=8.8Hz,1H),7.12(s,2H),6.29(s,1H),4.26(s,1H),4.04(s,1H),3.94(d,J= 9.4Hz,1H),2.91(t,J=7.5Hz,2H),2.79(t,J=7.1Hz,2H),2.33(s,1H),2.02-1 .92(m,2H),1.24(s,1H),1.07(d,J=8.1Hz,1H),0.70-0.41(m,5H).LC / MS(ESI) m / z: 520 (M+H) + .

[0210] Example 15: (R)-4-Cyclopropyl-N-((5-(imidazo[1,2-a]pyridin-7-yl)-6-methyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000074.tif38128 The title compound was prepared from (R)-4-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A1) and 5-(imidazo[1,2-a]pyridin-7-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate B11) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.55(d,J=5.9Hz,1H),8.01(s,1H),7.62(s,1H),7.26(s,1H),7.09(s,1H),6.57(d,J= 6.6Hz,2H),4.29-4.30(m,1H),4.15-4.17(m,2H),4.06(d,J=8.3Hz,1H),3.93-3.95(m ,1H),2.88(t,J=7.5Hz,2H),2.66(d,J=21.1Hz,2H),2.05(s,3H),1.98-1.92(m,2H),1 .14-1.16(m,1H),0.66-0.67(m,1H),0.63-0.52(m,2H),0.47-0.48(m,1H).LC / MS(ESI) m / z:533(M+H) + .

[0211] Example 16: 7-Cyclopropyl-N-((5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000075.tif39128 The title compound was prepared from 7-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A8) and 5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B5) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,CDCl3) δ 8.34(d,J=7.2Hz,1H),7.93(d,J=2.1Hz,1H),7.45(s,1H),7.22(d,J=7.7Hz,1H),7.15(d,J=7.6Hz, 1H),6.70(dd,J=7.2,1.6Hz,1H),6.47(d,J=1.8Hz,1H),6.24(s,1H),4.77(d,J=15.3Hz,1H),4.67(d ,J=15.2Hz,1H),4.03-3.94(m,2H),3.29-3.23(m,1H),2.98(t,J=7.4Hz,2H),2.78(t,J=7.3Hz,2H) ,2.07(dt,J=14.0,7.0Hz,2H),1.18-1.08(m,1H),0.69-0.52(m,3H),0.33-0.24(m,1H).LC / MS(ESI) m / z:519(M+H) + .

[0212] Example 17: N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6',7'-dihydrospiro[cyclobutane-1,4'-pyrazolo[5,1-c][1,4]oxazine]-2'-sulfonamide TIFF2025508790000076.tif37128 The title compound was prepared from 6',7'-dihydrospiro[cyclobutane-1,4'-pyrazolo[5,1-c][1,4]oxazine]-2'-sulfonamide (Intermediate A3) and 6-methyl-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 give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.59(dd,J=15.4,7.1Hz,1H),8.01(d,J=8.1Hz,1H),7.41(d,J=5.3Hz,2H), 7.04(d,J=18.8Hz,1H),6.56(dd,J=15.0,8.5Hz,2H),4.07(d,J=28.8Hz,2H) ,2.87-2.88(m,2H),2.68-2.69(m,2H),2.35(d,J=8.3Hz,4H),2.05(s,3H), 1.96(d,J=8.3Hz,4H),1.51(d,J=8.2Hz,1H),1.24-1.25(m,1H).LC / MS(ESI) m / z: 533 (M+H) + .

[0213] Example 18: 8-Cyclopropyl-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000077.tif39128 The title compound was prepared from 8-cyclopropyl-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-sulfonamide (Intermediate A4) and 6-methyl-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 give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.61(t,J=6.7Hz,1H),8.01(d,J=2.2Hz,1H),7.39(d,J=6.1Hz,2H),7.04(s,1H),6.58( d,J=1.7Hz,1H),6.55-6.47(m,1H),4.17(dd,J=23.8,10.7Hz,2H),4.04-3.99(m,2H),3 .87-3.82(m,1H),2.86(t,J=6.9Hz,2H),2.64-2.59(m,2H),2.03(s,3H),1.93(t,J=8.0 Hz,2H),1.23(br,1H),0.62(dd,J=10.6,9.7Hz,1H),0.47(d,J=4.7Hz,3H).LC / MS(ESI) m / z:533(M+H) + .

[0214] Example 19: 8-Cyclopropyl-N-((6-methyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000078.tif37141 Step 1: tert-Butyl 4-(4-(3-((8-cyclopropyl-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)sulfonyl)ureido)-6-methyl-2,3-dihydro-1H-inden-5-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate To a solution of tert-butyl 4-(4-amino-2,3-dihydro-1H-inden-5-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (B14, 86 mg, 0.25 mmol) and TEA (75 mg, 0.75 mmol) in THF (4 mL) was added triphosgene (24 mg, 0.08 mmol) at 0° C. After stirring at 0° C. for 0.5 h, the mixture was filtered and the filtrate was used directly in the next reaction. To a solution of 8-cyclopropyl-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-sulfonamide (A4, 60 mg, 0.247 mmol) in THF (4 mL) was added NaH (30 mg, 0.75 mmol, 60% dispersion in mineral oil) at 0° C. and the mixture was stirred at room temperature for 30 min. The above filtrate was added to the mixture at 0° C., and the resulting mixture was stirred at room temperature for 3 h. The mixture was poured into ice water and acidified to pH ∼4 with 1N aqueous HCl. The mixture was extracted with EtOAc (3×10 mL), and 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, 0-8% MeOH in PE) to give the title compound (100 mg, 64% yield) as a white solid. LC / MS (ESI) m / z: 633 (M+H) + .

[0215] Step 2: 3-({8-cyclopropyl-5H,6H,8H-imidazo[2,1-c][1,4]oxazin-2-yl}sulfonyl)-1-(6-methyl-5-{1H-pyrrolo[2,3-b]pyridin-4-yl}-2,3-dihydro-1H-inden-4-yl)urea To a solution of tert-butyl 4-(4-(3-((8-cyclopropyl-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)sulfonyl)ureido)-6-methyl-2,3-dihydro-1H-inden-5-yl)-1H-pyrrolo-[2,3-b]pyridine-1-carboxylate (100 mg, 0.16 mmol) in DCM (8 mL) was added TFA (2 mL) and the reaction was stirred at room temperature for 1 h. The reaction was poured into aqueous NaHCO3 and extracted with DCM (2 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by preparative HPLC to give the title compound (15 mg, 18% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 11.69(s,1H),8.23-8.15(m,1H),7.48(d,J=8.7Hz,1H),7.40-7.35(m,1H),7.08(d,J=15.7Hz,2H),6.73( dd,J=8.3,4.9Hz,1H),5.98-5.87(m,1H),4.21(dt,J=12.1,3.7Hz,1H),4.14(dd,J=7.5,5.7Hz,1H),4.05( dd,J=6.0,3.7Hz,2H),3.87(ddd,J=8.3,6.7,2.6Hz,1H),2.89(t,J=7.5Hz,2H),2.61-2.54(m,2H),2.00- 1.91(m,2H),1.88(s,3H),1.21(dd,J=13.0,7.8Hz,1H),0.69-0.58(m,1H),0.55-0.44(m,3H).LC / MS(ESI) m / z:533(M+H) + .

[0216] Example 20: 4,4-Dimethyl-N-((6-methyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000079.tif32136 The title compound was prepared from 4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A5) and tert-butyl 4-(4-amino-6-methyl-2,3-dihydro-1H-inden-5-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate B14) as described for Example 19. The residue was purified by preparative HPLC to give the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 11.67(s,1H),8.19(d,J=4.8Hz,1H),7.35(s,1H),7.01(s,1H),6.74(d,J=4.7Hz,1H),5.92(s,1H),4.0 5(s,4H),2.87(t,J=7.6Hz,2H),2.59(s,2H),1.95-1.90(m,2H),1.87(s,3H),1.46(s,6H).LC / MS(ESI) m / z:521(M+H) + .

[0217] Example 21: N-((6-methyl-5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-sulfonamide TIFF2025508790000080.tif31141 The title compound was prepared from 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-sulfonamide (Intermediate A7) and tert-butyl 4-(4-amino-6-methyl-2,3-dihydro-1H-inden-5-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (Intermediate B14) as described for Example 19. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,CD3OD) δ 8.13(d,J=4.9Hz,1H),7.58(s,1H),7.28(d,J=3.5Hz,1H),7.11(s,1H),6.82(d,J=4.9Hz,1H),6.04(d,J=3.5Hz,1H),4.85-4.84(m,2H),4. 19(t,J=5.0Hz,2H),4.08(t,J=5.0Hz,2H),2.96(t,J=7.4Hz,2H),2.79(s,2H),2.11-2.02(m,2H),1.94(s,3H).LC / MS(ESI)(m / z):493(M+H) + .

[0218] Example 22: 4,4-Dimethyl-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000081.tif35128 The title compound was prepared from 4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A5) and 6-methyl-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 give the title compound as a white solid. 1 H NMR(400MHz,CD3OD) δ 8.50(d,J=7.1Hz,1H),7.97(d,J=2.3Hz,1H),7.44(s,1H),7.10(s,1H),6.65(dd,J=7.1,1.5Hz,1H),6.59(d,J=1.7Hz,1H),6.53(s,1 LC / MS(ESI) m / z:521(M+H) + .

[0219] Example 23: N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide TIFF2025508790000082.tif35128 The title compound was prepared from 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide (Intermediate A6) and 6-methyl-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 give the title compound as a white solid. 1 H NMR(400MHz,CD3OD) δ 8.47(d,J=7.1Hz,1H),7.97(d,J=2.3Hz,1H),7.42(s,1H),7.08(d,J=13.5Hz,1H),6.64(d,J=7.1Hz,1H),6.57(d,J=2.0Hz,1H), 6.30(s,1H),4.80(s,2H),4.13(s,4H),2.93(t,J=7.3Hz,2H),2.82-2.66(m,2H),2.13-1.99(m,5H).LC / MS(ESI)(m / z):493(M+H) + .

[0220] Example 24: 1-Cyclopropyl-N-((5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonamide TIFF2025508790000083.tif39128 The title compound was prepared from 1-cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonamide (Intermediate A9) and 5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B5) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.51-8.43(m,1H),7.99(d,J=2.2Hz,1H),7.95-7.90(m,1H),7.69(d,J=2. 1Hz,1H),7.50(s,1H),7.16(s,2H),6.72-6.62(m,1H),6.54(d,J=1.7Hz,1 H),4.40(s,3H),2.92(s,2H),2.70-2.66(m,2H),2.37-2.23(m,2H),1.99( s,3H),1.07(d,J=5.2Hz,1H),0.82-0.77(m,2H),0.56(s,2H).LC / MS(ESI) m / z: 531 (M+H) + .

[0221] Example 25: 1-Cyclopropyl-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonamide TIFF2025508790000084.tif40128 The title compound was prepared from 1-cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonamide (Intermediate A9) and 6-methyl-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 give the title compound as a white solid. 1H NMR(400MHz,DMSO-d6) δ 8.51(d,J=7.1Hz,1H),8.00(d,J=2.1Hz,1H),7.85(d,J=1.9Hz,1H),7.64(d,J=2 .0Hz,1H),7.33(s,1H),7.05(s,1H),6.56(d,J=1.5Hz,1H),6.46(d,J=8.1Hz,1H ),4.40(s,2H),2.91-2.83(m,4H),2.60(d,J=7.3Hz,2H),2.29(br,1H),2.03(s, 3H),1.94(t,J=7.0Hz,2H),0.80(d,J=4.8Hz,2H),0.57-0.56(m,2H).LC / MS(ESI) m / z: 545 (M+H) + .

[0222] Example 26: N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-sulfonamide TIFF2025508790000085.tif35128 The title compound was prepared from 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-sulfonamide (Intermediate A7) and 6-methyl-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 give the title compound as a white solid. 1 H NMR(400MHz,CD3OD) δ 8.45(d,J=7.1Hz,1H),7.96(d,J=2.3Hz,1H),7.66(s,1H),7.35(s,1H),7.11(s,1H),6.59-6.54(m,2H),4.93(d,J=4.8Hz,2H),4.19(t,J=5 .1Hz,2H),4.07(dd,J=7.5,3.6Hz,2H),2.94(t,J=7.5Hz,2H),2.75(dd,J=10.7,7.2Hz,2H),2.10-2.04(m,5H).LC / MS(ESI)(m / z):493(M+H) + .

[0223] Example 27: (S)-6-Methoxy-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide TIFF2025508790000086.tif37128 The title compound was prepared from (S)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (Intermediate A10) and 6-methyl-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 give the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 8.62(d,J=19.4Hz,1H),8.03(s,1H),7.47(s,1H),7.40(s,1H),7.07(s,1H),6.5 9(s,1H),6.49(d,J=13.5Hz,1H),4.54(d,J=13.0Hz,1H),4.25(d,J=15.0Hz,4H) ,4.05(s,1H),2.88(t,J=7.2Hz,2H),2.62(d,J=43.7Hz,3H),2.33-2.34(m,1H), 2.04(s,3H),2.01-1.92(m,3H),1.24-1.25(m,1H).LC / MS(ESI)(m / z):523(M+H) + .

[0224] Example 28: (S)—N-((5-(imidazo[1,2-a]pyridin-7-yl)-6-methyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide TIFF2025508790000087.tif37128 The title compound was prepared from (S)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (Intermediate A10) and 5-(imidazo[1,2-a]pyridin-7-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate B11) 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):523(M+H) + .

[0225] Example 29: (S)-6-Methoxy-N-((6-methyl-5-(pyrazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide TIFF2025508790000088.tif37128 The title compound was prepared from (S)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (Intermediate A10) and 6-methyl-5-(pyrazolo[1,5-a]pyridin-6-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B12) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 8.41(d,J=14.4Hz,1H),8.03(s,1H),7.68(dd,J=15.8,9.3Hz,1H),7.49(d,J=4 .7Hz,1H),7.08(s,1H),6.83(t,J=7.6Hz,1H),6.67(s,1H),4.56(d,J=11.7Hz, 1H),4.36-4.12(m,3H),4.05(s,1H),3.41(s,3H),2.88(t,J=7.3Hz,2H),2.64( d,J=33.4Hz,2H),2.05(s,3H),2.01-1.89(m,2H).LC / MS(ESI)(m / z):523(M+H) + .

[0226] Example 30: (S)—N-((5-(imidazo[1,2-a]pyridin-6-yl)-6-methyl-2,3-dihydro-1H-inden-4-yl)carbamoyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide TIFF2025508790000089.tif37128 The title compound was prepared from (S)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (Intermediate A10) and 5-(imidazo[1,2-a]pyridin-6-yl)-6-methyl-2,3-dihydro-1H-inden-4-amine (Intermediate B13) as described for Example 1. The residue was purified by preparative HPLC to give the title compound as a white solid. 1 H NMR(400MHz,DMSO-d6) δ 8.30(s,1H),7.90(d,J=10.4Hz,1H),7.60(s,1H),7.56(d,J=8Hz,1H) 7.52-7.47(m,1H),7.08(s,1H),6.87-6.78(m,1H),4.54(d,J=14.4Hz,1H),4.35-4.28(m,1H),4.23(s,2H),4.05(s,1H),3.3 8(s,3H),2.88(t,J=7.2Hz,2H),2.67(s,2H),2.62-2.56(m,1H),2.04(s,3H),2.02-1.85(m,2H).LC / MS(ESI)(m / z):523(M+H) + .

[0227] biological research The following method was used to screen the compounds. 1. Seed THP-1 cells (5.56*10^5 cells / mL) in 45uL of RPMI1640 medium (without FBS) containing 1.0ug / mL LPS (SIGMA, L6529) into a 384-well plate (Thermo Scientific, 164688). 2. Add 5 uL of compound (10 doses starting at 5 uM, 1:3 dilutions) or vehicle (0.05% DMSO in media) to appropriate wells. 3. Centrifuge the plate at 1000 rpm for 2 minutes and incubate at 37°C, 5% CO2 for 3 hours. 4. Add 5 uL of Nigericin (MEC, HY-100381) (final concentration 5 uM) to sample and positive control wells and 5 uL of RPMI1640 medium to negative control wells. 5. Centrifuge the plate at 1000 rpm for 2 minutes and incubate at 37°C, 5% CO2 for 1 hour. 6. At the end of the incubation period, the plate is centrifuged at 1000 rpm for 6 minutes and 8 uL of the supernatant is transferred to a 384-well assay plate (PerkinElmer, 6008280). 7. Add 8 ul of RPMI1640 medium to each well and spin down for 10 seconds. 8. Prepare the standard solution and premixed IL1β antibody solution of the human IL1β kit (PerkinElmer, 62HIL1BPEH) according to the instructions. 9. Add 16 uL of standard solution to clear wells of a 384-well assay plate. 10. Add 4 uL of pre-mixed IL1β antibody solution to all wells including sample wells, positive control wells, negative control wells, and standard wells. 11. Seal the plate, spin down for 10 seconds, incubate at room temperature overnight and read in an HTRF® compatible reader (BMG LABTECH, PHERAstar FS). 12. The concentration of IL1β for the treated wells is calculated by the standard curve. 13. IC 50 Data are fitted to a non-linear regression equation (log inhibitor vs. response--4 parameters with variable slope).

[0228] The results of the pyroptosis assay are shown in Table 2 below: 50 It is summarized as follows. *

[0229] [Table 2] *NLRP3 inhibitory activity - THP IC 50 : A: ≦100nM, B: >100nM and ≦500nM, C: >500nM and ≦1uM.

Claims

1. Formula (I): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, During the ceremony, Ring A is a fused 6,5-bicyclic aryl or heteroaryl ring system, said heteroaryl ring system containing 1, 2, 3, or 4 nitrogen atoms as ring members, said ring A being R ５ and R ６ bearing a substituent and R ７ Or R ９ and / or R ８ and R １０ and having one or two substituents on the ring nitrogen selected from Ring Q is a fused 6,5-bicyclic heteroaryl or a fused 6,6-bicyclic heteroaryl ring system containing 1, 2, or 3 nitrogen atoms as ring members and O, S, or S(=O ２ wherein the ring Q is selected from the group consisting of R １ and R ２ having a substituent and one or two R １２ optionally bearing substituents, 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, oxo (=O), 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 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 or two R in geminal positions ２ The group is spiro C ３～５ The cycloalkyl may optionally be formed R ３ and R ４ 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 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 １２ each occurrence of is independently hydrogen, C １～４ Alkyl, haloC １～４ Alkyl, C ３～７ Cycloalkyl, C １～４ Alkyl-C ３～７ Cycloalkyl, C １～４ Alkyl-NR ａ R ｂ , C(=O)R ａ , C(═O)NR ａ R ｂ , or C １～４ Alkyl, haloC １～４ Alkyl, C ３～７ Cycloalkyl, halogen, CN, OH, C １～４ Alkoxy, C ３～７ cycloalkoxy or NR ａ R ｂ is a 4- to 6-membered heterocyclyl optionally substituted by 1 to 3 groups selected from 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, said ring optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and 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; and each occurrence of n is independently 0, 1, or 2; The compound or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

2. Formulas (II) to (IV) and During the ceremony, Each occurrence of ring Q is independently and Q １ is independently N or CH, provided that at least one Q １ is N, Q ２ Each occurrence of is independently O, S, S (=O ２ ), C.H. ２ , or NR １２ and 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, with the proviso 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 in formula (III) but, indicates, Z １ is N or CH, and Z ２ But N or CR ９ and Z ３ is N or CH, and R １ ~R １２ and R ａ and R ｂ is as defined in claim 1 10. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

3. Formula (II):

2. The compound of claim 1 having the structure:

4. In formula (II), but, 3. The compound of claim 2, wherein:

5. Formula (III):

2. The compound of claim 1 having the structure:

6. In formula (III), but, 3. The compound of claim 2, wherein:

7. Formula (IV):

2. The compound of claim 1 having the structure:

8. In formula (IV), but, 3. The compound of claim 2, wherein:

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

10. R １ and R ２ and each occurrence of ring Q independently 2. The compound of claim 1, wherein:

11. Q １ each occurrence of is independently N or CH, with the proviso that there is only one Q per ring １ The compound of claim 2, provided that: is N.

12. R １ Each occurrence of １～４ Alkyl, haloC 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 The compound of claim 1, optionally substituted with

13. R １ Each occurrence of １～４ Alkyl, cyclopropyl, cyclobutyl, C １～４ Alkoxy, cyclopropyloxy, cyclobutyloxy, 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 The compound of claim 1, optionally substituted with

14. 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

15. R ３ 2. The compound of claim 1, wherein each occurrence of is hydrogen, methyl, F, or Cl.

16. R ４ 2. The compound of claim 1, wherein each occurrence of is hydrogen, methyl, or halogen.

17. R ５ 2. The compound of claim 1, wherein each occurrence of is hydrogen or methyl.

18. R ６ 2. The compound of claim 1, wherein each occurrence of is hydrogen or methyl.

19. R ７ 2. The compound of claim 1, wherein each occurrence of is hydrogen or methyl.

20. R ８ 2. The compound of claim 1, wherein each occurrence of is hydrogen or methyl.

21. R ９ 2. The compound of claim 1, wherein each occurrence of is hydrogen, methyl, or methoxy.

22. 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.

23. 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.

24. R １２ each occurrence of is independently hydrogen, C １～４ Alkyl, haloC １～４ Alkyl, C ３～５ Cycloalkyl, C １～４ Alkyl-C ３～５ Cycloalkyl, C １～４ Alkyl-NR ａ R ｂ , C(=O)R ａ , C(═O)NR ａ R ｂ , or C １～４ Alkyl, haloC １～４ Alkyl, C ３～５ Cycloalkyl, halogen, CN, OH, C １～４ Alkoxy, C ３～５ cycloalkoxy or NR ａ R ｂ and wherein the 4- to 6-membered heterocyclyl contains 1 to 2 heteroatoms selected from N, O, and S.

25. The compound of claim 1 selected from:

26. The compound of claim 1 selected from:

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26 and a pharmaceutically acceptable carrier.

28. 27. Use of a compound according to any one of claims 1 to 26 in the preparation of a medicament for the treatment or prevention of a disease or condition responsive to the inhibition of NLRP3.

29. 27. Use of a compound according to any one of claims 1 to 26 in the preparation of a medicament for the treatment or prevention of a genetic disease, a neurodegenerative disorder, a metabolic disorder, an inflammatory syndrome, or cancer.

30. 30. The use of claim 29, 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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