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), to the preparation of said novel bicyclic substituted sulfonylurea compounds, to pharmaceutical compositions comprising said novel bicyclic substituted sulfonylurea compounds and to the use of said bicyclic substituted sulfonylurea compounds as therapeutic agents for the modulation of cytokines such as IL-10 and IL-18, the present invention relates to the use of a medicament for inhibiting diseases associated with the modulation of NLRP3, or the inhibition of the activation of NLRP3 or a component associated with an inflammatory process. # imgabs0 #

Description

Technical Field

[0001] The present application relates to novel bicyclic substituted sulfonylurea compounds and analogs, the preparation of the bicyclic substituted sulfonylurea compounds and analogs, pharmaceutical compositions comprising the bicyclic substituted sulfonylurea compounds and analogs, and the use of the bicyclic substituted sulfonylurea compounds and analogs as drugs for treating diseases associated with the regulation of cytokines such as IL-1β and IL-18, the regulation of NLRP3, or the inhibition of the activation of NLRP3 or related components of the inflammatory process. Background Art

[0002] Nucleotide-binding oligomerization domain-like receptors (or NOD-like receptors, NLRs) belong to the family of pattern recognition receptors and act as intracellular sensors of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Increasing evidence suggests that NLRs play an important role in the innate immune response to infection and cell 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 some other cell types, with some degree of tissue specificity. Formation of the NLRP3 inflammasome activates caspase-1, which in turn catalyzes proteolytic reactions, releasing 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 that occurs through the formation of membrane pores by the gasdermin D fragment.

[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 lead to inherited diseases characterized by systemic inflammation mediated by IL-1β, such as cryptopyrin-associated periodic syndrome (CAPS). Additionally, aberrant activation of the NLRP3 inflammasome exacerbates human chronic diseases such as neurodegenerative disorders (multiple sclerosis, AD, and PD), metabolic diseases (atherosclerosis and type 2 diabetes), and inflammatory syndromes (gout attacks and osteoarthritis). Recently, a role for NLRP3 in cancer development and progression has been documented [Nat Immunol. 2021 Mar 11. doi:10.1038 / s41590-021-00886-5].

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

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

[0007] There is a need to provide compounds with improved pharmaceutical properties and / or compounds that provide useful alternatives to known compounds that may help achieve therapeutic efficacy while reducing undesirable side effects. Summary of the invention

[0008] The present technology provides novel compounds that effectively inhibit inflammasomes (such as NLRP3 inflammasomes) and regulate interleukins. In addition, the small molecule compounds disclosed herein show good pharmaceutical properties, including solubility, ADME (absorption, distribution, metabolism and excretion), pharmacokinetics, CYP inhibition and other safety characteristics, which help to obtain therapeutic efficacy while minimizing undesirable properties.

[0009] In one aspect, the present invention relates to a compound of formula (II)-(IV):

[0010]

[0011] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0012] in:

[0013] Ring Q is independently

[0014] Q 1is independently N or CH at each occurrence, provided that at least one Q 1 is N;

[0015] Q 2 O, S, S (=O 2 ), CH 2 or NR 12 ,

[0016] X 1 and X 5 are independently N or C, X 2 , X 3 and X 4 Each independently is N or CR 7 , and the dotted circle represents the bond forming the five-membered aromatic ring; provided that X 1 , X 2 , X 3 , X 4 and X 5 At least two but no more than three of them are N;

[0017] Y 1 N or CH, Y 2 Yes N, NR 8 or CH, and Y 3 Yes N, NR 8 or CH, and in formula (III) express

[0018] Z 1 N or CH, Z 2 Is N or CR 9 , and Z 3 is N or CH;

[0019] R 1 is independently hydrogen, C 1-4 Alkyl, halogenated C 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 NR b C(=O)R a 、C(=O)NHC(=O)R a or a 4-6 membered heterocyclic group, each of which is optionally substituted by one to three R 11replace;

[0020] R 2 is independently hydrogen, C 1-4 Alkyl, halogenated C 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 a 4-6 membered heterocyclic group, each of which is optionally substituted by one to two R 11 Substitution, or two R in geminal position 2 The group may optionally form a spiro C 3-5 Cycloalkyl;

[0021] R 3 , R 4 , R 5 and R 6 are independently hydrogen, halogen, CN, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0022] R 7 is independently hydrogen or C 1-4 alkyl;

[0023] R 8 is independently hydrogen or C 1-4 alkyl;

[0024] R 9 is independently hydrogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0025] R 10 is independently hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl or optionally C 1-4 Alkyl-substituted 4-6 membered heterocyclic group;

[0026] R 11 is independently hydrogen, C 1-4 Alkyl, halogenated C 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)Ra 、C(=O)NR a R b NR b C(=O)R a 、C(=O)NHC(=O)R a or a 4-6 membered heterocyclic group;

[0027] R 12 is independently hydrogen, C 1-4 Alkyl, halogenated C 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 a 4-6 membered heterocyclic group optionally substituted by one to three groups selected from the following: C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, CN, OH, C 1-4 Alkoxy, C 3-7 Cycloalkoxy or NR a R b ;

[0028] R a and R b is independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, or R a and R b Together with the nitrogen atom to which it is attached, it forms a saturated or unsaturated heterocyclic ring containing three to seven ring atoms, which ring may optionally contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by one to three groups which may be the same or different and are selected from C 1-4 the group consisting of alkyl, phenyl and benzyl; and

[0029] n is independently 0, 1 or 2 at each occurrence.

[0030] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I)-(IV), the preparation of the compound, and the use of the compound as a drug for treating or preventing diseases associated with the regulation of cytokines such as IL-1β and IL-18, the regulation of NLRP3, or the inhibition of the activation of NLRP3 or related components of inflammatory processes. Therefore, the compounds of formula (I)-(IV) can be used to treat or prevent genetic diseases (cryptopyrin-associated periodic syndrome, CAPS), neurodegenerative diseases (multiple sclerosis, AD and PD), metabolic diseases (atherosclerosis and type 2 diabetes), inflammatory syndromes (gout attacks and osteoarthritis), cancer and other related human diseases. DETAILED DESCRIPTION

[0031] In one aspect, the present technology provides compounds and pharmaceutically acceptable forms of the compounds, including but not limited to salts, hydrates, solvates, isomers, stereoisomers, enantiomers, prodrugs and isotopically labeled derivatives thereof.

[0032] On the other hand, the technology of the present invention provides a method for treating and / or controlling various diseases and disorders, the method comprising administering to a patient a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable form thereof (e.g., salt, hydrate, solvate, isomer, stereoisomer, enantiomer, prodrug and isotope-labeled derivative). Non-limiting examples of diseases and disorders are described herein.

[0033] Also provided herein are pharmaceutical compositions (e.g., single unit dosage forms) that can be used for the methods provided herein. In one embodiment, the pharmaceutical composition includes a compound provided herein or a pharmaceutically acceptable form thereof (e.g., salts, hydrates, solvates, isomers, stereoisomers, prodrugs, and isotope-labeled derivatives).

[0034] Although specific embodiments have been discussed, the description is illustrative rather than restrictive. Many variations of the present disclosure will become apparent to those skilled in the art after reading this description.

[0035] Unless defined otherwise, 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 specification belongs.

[0036] definition

[0037] As used in the specification and claims, the singular form of "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0038] As used herein, "agent", "biologically active agent" or "second active agent" refers to a biological, drug 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 metabolites thereof. Various compounds can be synthesized, such as small molecules and oligomers (e.g., oligopeptides and oligonucleotides) and synthetic organic compounds based on various core structures. In addition, various natural sources can provide active compounds, such as plant or animal extracts, etc. The skilled person can easily recognize that there is no limitation on the structural properties of the agents disclosed herein.

[0039] "Administration" of a disclosed compound encompasses delivering a compound described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, to a subject using any suitable formulation or route of administration as discussed herein.

[0040] As used herein, the terms "co-administration", "combination administration", and grammatical equivalents thereof encompass administration of two or more agents to a subject such that the two agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in the form of separate compositions, administration at separate times in the form of separate compositions, or administration in a composition in which the two agents are present at the same time.

[0041] The term "effective amount" or "therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition described herein that is sufficient to affect the intended application (including but not limited to disease treatment), as shown below. In some embodiments, the amount is an amount that is effective for detectable inhibition of NLRP3, which can be determined, for example, in a bioassay as described herein. The therapeutically effective amount can vary depending on the intended application (in vitro or in vivo) or the subject being treated and the condition (e.g., the subject's weight and age, the severity of the condition, the mode of administration, etc.) that can be easily determined by a person of ordinary skill in the art. The term also applies to doses that will induce a response in target cells, such as a reduction in cell migration. The specific dose will vary depending on, for example, the selected compound, the species of the subject, and its age / existing health condition or health condition risk, the dosing regimen 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 carried.

[0042] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0043] As used herein, the terms "treatment," "treating," "mitigation," "control," and "improvement" are used interchangeably herein. These terms refer to an approach to obtaining a beneficial or desired result, including but not limited to a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying condition being treated. In addition, a therapeutic benefit is achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, even though the patient may still be suffering from the underlying condition. For a prophylactic benefit, a pharmaceutical compound and / or composition may be administered to a patient at risk of developing a disease, or to a patient reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease has not yet been made.

[0044] As used herein, the terms "preventing" and "prophylaxis" refer to the administration of a pharmaceutical compound or drug, or a composition comprising a pharmaceutical compound or drug, to a subject before a disease, disorder, or condition fully manifests itself, to prevent the occurrence and / or reduce the severity of one or more symptoms of the disease, disorder, or condition. One of ordinary skill in the art recognizes that the term "prevention" is not an absolute term. In the medical field, "prevention" is understood to refer to the prophylactic administration of a drug to reduce the likelihood or severity of a disease, disorder, or condition, or its symptoms, and this is the sense in which such terms are used in this disclosure.

[0045] As used herein, the term "therapeutic effect" encompasses therapeutic benefits and / or prophylactic benefits as described above. A prophylactic effect comprises delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of a disease or condition, slowing, stopping or reversing the progression of a disease or condition, or any combination thereof.

[0046] "Subjects" contemplated for administration include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged or elderly)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail and / or turkeys.

[0047] The term "in vivo" refers to events that occur within the body of a subject. In vivo also includes events that occur in rodents such as rats, mice, guinea pigs, etc.

[0048] The term "in vitro" refers to an event that occurs outside of a subject. For example, an in vitro assay encompasses any assay performed outside of a subject. In vitro assays encompass cell-based assays in which live or dead cells are employed. In vitro assays also encompass cell-free assays in which intact cells are not employed.

[0049] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with the tissues of a subject without excessive toxicity, irritation, allergic response, etc. and commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in "Journal of Pharmaceutical Sciences (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 inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or 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) formed salts. For example, pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, Salts include, for example, iodide, 2-hydroxy-ethanesulfonate, 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, valerate, etc. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0050] 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 salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 alkyl) 4 Salt. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. 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 when appropriate. Organic bases from which salts can be derived include, for example, primary amines, secondary amines and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts can be selected from ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts.

[0051] As used herein, the term "solvate" refers to a compound that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate can be a disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that can 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. It should be understood that the term "compound" as used herein encompasses compounds and solvates of compounds and mixtures thereof.

[0052] In some embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" refers to a compound that is converted in vivo to produce a disclosed compound or a pharmaceutically acceptable form of a compound. Prodrugs can be inactive when applied to a subject, but are converted into active compounds in vivo, for example, by hydrolysis (e.g., hydrolysis in the blood). In some cases, prodrugs have improved physical and / or delivery properties compared to the parent compound. Prodrugs can increase the bioavailability of compounds when applied to a subject (e.g., by allowing enhanced absorption into the blood after oral administration) or relative to the parent compound, enhance delivery to the biological compartment of interest (e.g., brain or lymphatic system). Exemplary prodrugs include derivatives of disclosed compounds that have enhanced water solubility or active transport by intestinal membranes relative to the parent compound.

[0053] Prodrug compounds often offer advantages of solubility, tissue compatibility or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). Higuchi, T. et al., Pro-drugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14 and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Publishers, 1996). A discussion of prodrugs is provided in the journals of the American Journal of Pharmaceutical Sciences, 1987, both of which are fully incorporated herein by reference. Exemplary advantages of prodrugs may include, but are not limited to, their physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it may enhance absorption from the digestive tract, or it may enhance the stability of the drug for long-term storage.

[0054] The term "prodrug" is also intended to include any covalently bonded carriers that release the active compound in vivo when such prodrugs are administered to an animal subject. Prodrugs of active compounds as described herein can be prepared by modifying functional groups present in the active compound in such a manner that the modifications are cleaved into the parent active compound during routine manipulation or in vivo. Prodrugs include compounds in which hydroxyl, amino or sulfhydryl groups are bonded to any group that cleaves to form free hydroxyl, free amino or free sulfhydryl groups, respectively, when the prodrug of the active compound is administered to a subject. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols or acetamides in the active compound, formamide and benzamide derivatives of amine functional groups, and the like. Other examples of prodrugs include, including -NO, -NO 2 , -ONO or -ONO 2Prodrugs can generally 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 Prodrug Design (H. Bundgaard, ed., Elsevier, New York, 1985).

[0055] For example, if a disclosed compound or a pharmaceutically acceptable form of a compound contains a carboxylic acid functional group, the prodrug may include a pharmaceutically acceptable ester formed by replacing the hydrogen atom of the acid group with a group such as: (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-crotonolactone, γ-butyrolactone-4-yl, di-N,N-(C 1-2 ) alkylamino (C 2-3 ) alkyl (such as [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.

[0056] Similarly, if a disclosed compound contains an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as: (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, succinyl, (C 1-6 ) alkanoyl, α-amino (C 1-4)alkanoyl, aryl acyl and α-aminoacyl or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl group is independently selected from naturally occurring L-amino acids, -P(O)(OH) 2 、-P(O)(O(C 1-6 )alkyl) 2 or glycosyl (a free radical resulting from the removal of a hydroxyl group from a hemiacetal carbohydrate).

[0057] If the disclosed compounds incorporate an amine functional group, a prodrug can be formed by replacing the hydrogen atom in the amine group with a group such as: R-carbonyl, RO-carbonyl, NRR'-carbonyl, wherein R and R' are each independently selected from (C 1–10 ) alkyl, (C 3-7 )cycloalkyl, benzyl, natural α-aminoacyl or natural α-aminoacyl-natural-α-aminoacyl, -C(OH)C(O)OY 1 , where Y 1 is H, (C 1-6 )alkyl or benzyl, -C(OY 2 )Y 3 , where Y 2 Yes (C 1-4 ) alkyl, and Y 3 Yes (C 1-6 ) alkyl, carboxyl (C 1-6 ) alkyl, amino (C 1-4 )alkyl or mono-N- or di-N,N-(C 1-6 )alkylaminoalkyl; and -C(Y 4 )Y 5 , where Y 4 is H or methyl, and Y 5 Is single-N- or di-N-(C 1 6 ) alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

[0058] In some embodiments, the disclosed compounds may encompass isomers. "Isomers" are different compounds with 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" encompasses any and all geometric isomers and stereoisomers. For example, "isomers" encompass geometric double bond cis and trans isomers, also known 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.

[0059] Geometric isomers can be identified by the symbol -----"Z" or "E" is a term used herein to describe a carbon-carbon double bond, wherein the term "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise indicated, the structure depicting the double bond encompasses both "E" and "Z" isomers.

[0060] Substituents around a carbon-carbon double bond may alternatively be referred to as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond and "trans" refers to 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" refers to substituents on the same side of the plane of the ring and "trans" refers to substituents on opposite sides of the plane of the ring. A mixture of compounds in which substituents are arranged on a common side and on opposite sides of the plane of the ring is designated "cis / trans."

[0061] "Enantiomer" is a pair of stereoisomers, which are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any ratio can be referred to as a "racemic" mixture. The term "(±)" is used to represent a racemic mixture where appropriate. "Diastereomer" is a stereoisomer with at least two asymmetric atoms but 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 can be specified by R or S. The unknown split compound of absolute configuration can be specified as (+) or (-), depending on the direction (right-handed or left-handed) of rotating plane polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers, and therefore enantiomers, diastereomers, and other stereoisomeric forms defined as (R)- or (S)- according to the absolute stereochemistry at each asymmetric atom can be produced. The chemical entities, pharmaceutical compositions and methods of the invention are intended to encompass all such possible isomers, including racemic mixtures, substantially optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0062] 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 one enantiomer, e.g., 90% of the S enantiomer, and another enantiomer, e.g., 10% of the R enantiomer.

[0063] ee = (90 - 10) / 100 = 80%.

[0064] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. In some embodiments, the compositions described herein contain the following enantiomeric excess of the S enantiomer: 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%, or between any two of the foregoing values ​​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 relative to the R enantiomer. In other embodiments, some compositions described herein contain an enantiomeric excess of the R enantiomer 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%, 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 relative to the S enantiomer. In cases where 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.

[0065] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. In some embodiments, the compositions described herein contain the following enantiomeric excess of the S enantiomer: 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%, or between any two of the foregoing values ​​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 relative to the R enantiomer. In other embodiments, some compositions described herein contain an enantiomeric excess of the R enantiomer 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%, 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 relative to the S enantiomer. In cases where 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.

[0066] Optical isomers can be obtained by resolving racemic mixtures according to conventional methods, for example by forming diastereomeric salts, by treating 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. The mixture of diastereoisomers is separated by crystallization, and the isomers are subsequently separated by releasing optically active bases from these salts. Another method involves synthesizing covalent diastereoisomer molecules by reacting the disclosed compounds with optically pure acids or optically pure isocyanates in an activated form. Synthesized diastereoisomers can be separated by conventional methods such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to provide compounds enriched in enantiomers. Optically active compounds can also be obtained by using active starting materials. In certain embodiments, these isomers can be in the form of free acids, free bases, esters or salts.

[0067] In any embodiment, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" is an isomer comprising two or more isomers of a type of interconvertible compounds, which is produced by at least one formal hydrogen atom migration and at least one valence change (e.g., single bond to double bond, triple bond to single bond, and vice versa). "Tautomerization" includes proton mutation or proton shift tautomerization, which is considered to be a subset of acid-base chemistry. "Proton mutation tautomerization" or "proton shift tautomerization" relates to proton migration with bond order changes. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. In the case where tautomerization may occur (e.g., in solution), the chemical equilibrium of tautomers can be reached. Tautomerization (i.e., providing a tautomer pair reaction) can be catalyzed by acid or base, or can occur in the absence of the effect or presence of an external agent. Exemplary tautomerizations include, but are not limited to, keto-enol; amide-imide; lactam-lactam; enamine-imine and enamine-(different)enamine tautomerizations. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers.

[0068] Unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. 13 C or 14 Compounds of the present structures other than C-enriched carbon substituted carbon are within the scope of the present disclosure.

[0069] The present disclosure also includes pharmaceutically acceptable forms that are "isotopically labeled derivatives," which are compounds identical to those described herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H. 3 H. 13 C 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36Cl. Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. Tritiated isotopes (i.e., 3 H) and carbon-14 isotopes (i.e., 14 C) can be easily prepared and detected. Further, the use of heavier isotopes (such as deuterium, i.e. 2 H) substitution can provide certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability. Isotope-labeled disclosed compounds can generally be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents. In some embodiments, provided herein are compounds that can also contain non-natural ratios of atomic isotopes at one or more atoms constituting such compounds. All isotopic changes (whether radioactive or non-radioactive) of the compounds disclosed herein are encompassed within the scope of the present disclosure. In some embodiments, radiolabeled compounds can be used to study the metabolism and / or tissue distribution of compounds or to change the rate or pathway of metabolism or other aspects of biological function.

[0070] "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, etc. Pharmaceutically acceptable carriers or excipients do not destroy the pharmacological activity of the disclosed compounds and are non-toxic when administered in doses sufficient to deliver therapeutic amounts of the compounds. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active ingredient, their use in the therapeutic compositions disclosed herein is contemplated. Non-limiting examples of pharmaceutically acceptable carriers and excipients include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as polyethylene glycol and propylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution (Ringer's solution); ethanol; phosphate buffered solution; nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; mold release agents; coating agents; sweeteners, flavorings and fragrances; preservatives; antioxidants; ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as da tocopherol polyethylene glycol 1000 succinate; surfactants used in pharmaceutical dosage forms, such as Tween or other similar polymer 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 silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based materials; 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 may also be used to enhance delivery of the compounds described herein.

[0071] 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 herein. In addition, general principles of organic chemistry as well as specific functional moieties and reactivities are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sansalito, 1999; Smith and March, 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.

[0072] Recitation of ranges of values ​​herein are merely intended to serve as a shorthand method of referring individually to each separate value and subrange falling within the range, unless otherwise indicated herein, and each separate value and subrange is incorporated into the specification as if it were individually recited herein. For example, "C 1-6 "Alkyl" will be understood to cover C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , 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 , C3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 Likewise, 1-4 substituents will be understood to encompass 1, 2, 3, 4, 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4 substituents.

[0073] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C 1-10 Alkyl). When it appears in this article, a numerical range such as "1 to 10" refers to each integer in the given range; for example, "1 to 10 carbon atoms" means that the alkyl group can be composed of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, but the definition of the present invention also covers the occurrence of the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6 or 1 to 3 carbon atoms. Representative saturated straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl; while saturated branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, etc. The alkyl group is connected to the parent molecule by a single bond. Unless otherwise stated in the specification, alkyl may be optionally substituted with one or more substituents disclosed herein. In non-limiting embodiments, substituted alkyl may be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, cyclopropylmethyl, cyclobutyloxymethyl, benzyl and phenethyl.

[0074] "Alkenyl" refers to a group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., C 2-10 In some embodiments, the alkenyl group includes two to eight carbon atoms. In other embodiments, the alkenyl group includes two to six carbon atoms (e.g., C 2-6Alkenyl). Alkenyl is attached to the parent molecular structure by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. One or more carbon-carbon double bonds can be located internally (such as in 2-butenyl) or terminally (such as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), 2-methylprop-2-enyl (C 4 ), butadiene (C 4 ) etc. 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Alkenyl and pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), 2,3-dimethyl-2-butenyl (C 6 ) etc. Other examples of alkenyl groups include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ) etc. Unless stated otherwise in the specification, an alkenyl group may be optionally substituted with one or more substituents disclosed herein.

[0075] "Alkynyl" refers to a group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., C 2-10 In some embodiments, the alkynyl group is a straight or branched hydrocarbon chain group (e.g., alkynyl). Whenever a numerical range such as "2 to 10" appears in this article, it refers to each integer in the given range. For example, "2 to 10 carbon atoms" means that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In any embodiment, the alkynyl group includes two to eight carbon atoms. In other embodiments, the alkynyl group has two to six carbon atoms (e.g., C 2-6 Alkynyl). Alkynyl is linked to the parent molecular structure by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, 3-methyl-4-pentynyl, hexynyl, etc. Unless otherwise stated in the specification, alkynyl may be optionally substituted with one or more substituents disclosed herein.

[0076] "Alkoxy" refers to the group -O-alkyl, which contains 1 to 10 carbon atoms in a straight chain, branched chain, saturated cyclic configuration and combinations thereof connected to the parent molecular structure through oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, cyclopropyloxy, cyclohexyloxy, and the like. "Lower alkoxy" refers to an alkoxy group containing one to six carbons. In some embodiments, C 1-4 Alkoxy is an alkoxy group containing both straight and branched chain alkyl groups of 1 to 4 carbon atoms. Unless otherwise stated in the specification, alkoxy groups may be optionally substituted with one or more substituents disclosed herein. The terms "alkenyloxy" and "alkynyloxy" are very similar to the above description of "alkoxy", wherein the prefix "alkane" is replaced by "alkene" or "alkyne", respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein.

[0077] "Aromatic" or "aryl" refers to a group having 6 to 14 ring atoms (e.g., C 6-14 Aromatic or C 6 14 aryl), the group having at least one ring having a carbocyclic conjugated π electron system (e.g., phenyl, fluorenyl, and naphthyl). In some embodiments, the aryl group is C 6-10 Aryl. For example, a divalent group formed by a substituted benzene derivative and having a free valence at a ring atom is named as a substituted phenylene. In other embodiments, a divalent group derived from a monovalent polycyclic hydrocarbon group whose name ends with "-" by removing a hydrogen atom from a carbon atom with a free valence is named by adding "idene" to the name of the corresponding monovalent group. For example, a naphthyl group with two connection points is called a naphthylene group. Whenever it appears in this article, a numerical range such as "6 to 14 aryl groups" refers to each integer within a given range, for example, "6 to 14 ring atoms" means that an aryl group can be composed of 6 ring atoms, 7 ring atoms, etc., up to and including 14 ring atoms. The term includes a monocyclic or condensed ring polycyclic (i.e., a ring sharing adjacent ring atom pairs) group. Polycyclic aromatic groups include bicyclic, tricyclic, tetracyclic, etc. In polycyclic groups, only one ring is required to be aromatic, so groups such as indanyl are included in the definition of aryl. Non-limiting examples of aryl groups include phenyl, phenylnaphthyl, naphthyl, tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl, indanyl, etc. Unless stated otherwise in the specification, an aryl group may be optionally substituted with one or more substituents disclosed herein.

[0078] "Cycloalkyl" and "carbocyclyl" each refer to a monocyclic or polycyclic radical containing only carbon and hydrogen, and may be saturated or partially unsaturated. A partially unsaturated cycloalkyl may be referred to as a "cycloalkenyl" if the carbocyclic ring contains at least one double bond, or a partially unsaturated cycloalkyl may be referred to as a "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyl includes groups having 3 to 13 ring atoms (i.e., C 3-13 Cycloalkyl). Whenever it appears in this article, 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 can be composed of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused polycyclic (i.e., rings that share adjacent ring atom pairs) groups. Polycyclic cycloalkyls include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" can be C 3-8 In some embodiments, "cycloalkyl" can be C 3-5 Cycloalkyl. Illustrative examples of cycloalkyl include, but are not limited to, the following moieties: C 3-6 Carbocyclic groups include but are not limited to cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) etc. 3-7 Examples of carbocyclic groups include norbornyl (C 7 ). C 3-8 Examples of the carbocyclic group include the aforementioned C 3-7 Carbocyclic and cycloheptyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, etc. 3-13 Examples of the carbocyclic group include the above-mentioned C 3-8Carbocyclyl and octahydro-1H indenyl, decahydronaphthyl, spiro [4.5] decyl etc.. Unless otherwise stated in the specification, cycloalkyl can be optionally substituted by one or more substituents disclosed herein. The terms "cycloalkenyl" and "cycloalkynyl" are very similar to the above description of "cycloalkyl", wherein the prefix "alkane" is replaced by "alkene" or "alkyne", respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, cycloalkenyl can have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, cycloalkynyl can have 5 to 13 ring atoms.

[0079] "Halo", "halide" or alternatively "halogen" means fluorine, chlorine, bromine or iodine. 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, respectively, where halo is fluorine, such as but not limited to trifluoromethyl, difluoromethyl, 2,2,2 trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, -O-CHF 2 Etc. Each of alkyl, alkenyl, alkynyl and alkoxy is as defined herein and may be optionally further substituted as defined herein.

[0080] "Heteroaryl" or alternatively "heteroaromatic" refers to a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) group having one or more ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-18 membered heteroaryl"). The 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 to 18" refers to each integer in the given range, for example, "5 to 18 ring atoms" means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. In some examples, the heteroaryl group may have 5 to 14 ring atoms. In some embodiments, the heteroaryl group has a divalent radical derived from a monovalent heteroaryl group whose name ends in "-yl", for example, by removing a hydrogen atom from the atom with the free valence, and the divalent radical is named by adding "-ene" to the name of the corresponding monovalent radical. For example, a pyridyl group with two points of attachment is a pyridinium.

[0081] For example, an N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the backbone atoms of the ring is a nitrogen atom. One or more heteroatoms in a heteroaryl group may be optionally oxidized. One or more nitrogen atoms, if present, may also be optionally quaternized. Heteroaryl groups also include ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridyl N-oxides. A heteroaryl group is attached to the parent molecular structure through any atom of the ring.

[0082] "Heteroaryl" also includes a ring system in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of connection to the parent molecular structure is on the aryl group or on the heteroaryl ring, or wherein the heteroaryl ring as defined above is fused to one or more cycloalkyl or heterocyclyl groups, wherein the point of connection to the parent molecular structure is on the heteroaryl ring. For polycyclic heteroaryls, one of the rings does not contain heteroatoms (e.g., indolyl, quinolyl, carbazolyl, etc.), and the point of connection to the parent molecular structure can be on any ring, i.e., a ring with heteroatoms (e.g., 2-indolyl) or a ring without heteroatoms (e.g., 5-indolyl). In some embodiments, heteroaryl 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, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus and sulfur ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. In some embodiments, 5-6 membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. In some embodiments, 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus and sulfur.

[0083] Examples of heteroaryl groups include, but are not limited to, azacyclyl, 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, benzopyrone, benzofuranyl, benzopyrone, benzofurazyl, benzothiazolyl, benzothiophenyl (benzothiophenyl), benzothiophene[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazolyl, [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]quinazoline, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridinyl yl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methanol-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazacyclyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-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, quinolyl, isoquinolyl, tetrahydroquinolyl, 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[2,3-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]pyridinyl, and phenylthio (i.e., thienyl). Unless stated otherwise in the specification, a heteroaryl group may be optionally substituted with one or more substituents disclosed herein.

[0084] "Heterocyclyl", "heterocycloalkyl" or "heterocarbocyclyl" each refers to any 3- to 18-membered non-aromatic monocyclic or polycyclic moiety comprising at least one carbon atom and at least one heteroatom selected from nitrogen, oxygen, phosphorus and sulfur. The heterocyclyl may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the polycyclic ring system may be a fused ring, a bridged ring or a spirocyclic ring system. The heterocyclyl polycyclic ring system may contain one or more heteroatoms in one or both rings. The heterocyclyl may be saturated or partially unsaturated. If the heterocyclyl contains at least one double bond, the partially unsaturated heterocyclylalkyl may be referred to as a "heterocycloalkenyl", or if the heterocyclyl contains at least one triple bond, the partially unsaturated heterocyclylalkyl may be referred to as a "heterocycloalkynyl". Whenever it appears in this article, a numerical range such as "5 to 18" refers to each integer in the given range, for example, "5 to 18 ring atoms" means that the heterocyclyl may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. For example, a divalent radical derived from a monovalent heterocyclic radical whose name ends in "-yl" by removing one hydrogen atom from the atom with the free valence is named by adding "-ene" to the name of the corresponding monovalent radical. For example, a piperidinyl radical having two points of attachment is a piperidinylene radical.

[0085] The N-containing heterocyclic moiety refers to a non-aromatic group in which at least one ring atom is a nitrogen atom. The heteroatoms in the heterocyclic group may be optionally oxidized. One or more nitrogen atoms (if present) may be optionally quaternized. The heterocyclic group also includes a ring system substituted with one or more nitrogen oxide (-O-) substituents, such as piperidinyl N-oxide. The heterocyclic group is connected to the parent molecular structure through any atom of any ring in the ring.

[0086] "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused to one or more carbocyclyls, wherein the point of attachment is on a carbocyclyl or heterocyclyl ring or ring system, wherein a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment to the parent molecular structure is on the heterocyclyl ring. In some embodiments, the heterocyclyl is a 5-14-membered non-aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus and sulfur ("5-14-membered heterocyclyl"). In some embodiments, the heterocyclyl is a 3-10-membered non-aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus and sulfur ("3-10-membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-8 membered non-aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having one or more ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus and sulfur ("5-6 membered heterocyclyl"). In some embodiments, 5-6 membered heterocyclyl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. In some embodiments, 5-6 membered heterocyclyl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. In some embodiments, 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus and sulfur.

[0087] "Heterocyclyl" may contain one or more keto groups (-C(=O)-) as part of the ring. Examples of keto heterocycles include, but are not limited to, pyridin-2(1H)-one, pyrazin-2(1H)-one, pyrimidine-2(1H)-one, pyrimidine-4(3H)-one, pyridazin-3(2H)-one, pyridin-4(1H)-one, imidazolidin-2-one, 1,3-dihydro-2H-imidazole-2-one, 2,4-dihydro-3H-1,2,4-triazol-3-one, oxazol-2(3H)-one and oxazolidin-2-one. Keto heterocyclyls can be obtained by removing hydrogen atoms from their corresponding keto heterocycles at any available NH or CH positions.

[0088] Exemplary 3-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, dioxolane, oxathiolanyl, tetrahydrothiazolyl, and dithiolanyl. Exemplary 5-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazolinyl, diazolone, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiacyclohexane. Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, and triazinyl. Exemplary 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyls include, but are not limited to, indolyl, isoindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzofuranyl, benzooxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, benzothianyl, tetrahydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, 3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthopyridinyl, decahydro-1,8-naphthopyridinyl, octahydropyrrolo[3,2-b]pyrrole, phenanthridinyl, indolyl, phthalimidyl , naphthylimide, chromanyl, benzothiophenyl, 1H-benzo[e][1,4]diazapyridinyl, 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 1,2,3,4-tetrahydro-1,6-naphthyridinyl, 2,3-dihydro-1H-pyrrolo[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.

[0089] Unless stated otherwise in the specification, a heterocyclyl group may be optionally substituted with one or more substituents disclosed herein.

[0090] When substituents are specified by their conventional chemical formula (written from left to right), they equally encompass chemically identical substituents that would result if the structure were written from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.

[0091] A "leaving group or atom" is any group or atom that will cleave from the starting material under the reaction conditions, thereby promoting the reaction at a specific site. Unless otherwise specified, suitable non-limiting examples of such groups include halogen atoms, methanesulfonyloxy, p-nitrobenzenesulfonyloxy, trifluoromethoxy, and toluenesulfonyloxy.

[0092] "Protecting group" has the meaning usually associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound, so that a chemical reaction can be selectively carried out on another unprotected reactive site, and after the selective reaction is completed, the group can be easily removed. Non-limiting examples of functional groups that can be masked with a protecting group include amines, hydroxyls, thiols, carboxylic acids, and aldehydes. For example, a hydroxyl-protected form is to protect at least one hydroxyl present in a compound with a hydroxyl-protecting group. Various protecting groups are disclosed, for example, Greene's Protective Groups in Organic Synthesis, Fifth Edition, Wiley (2014), which is incorporated herein by reference in its entirety. For additional background information on protecting group methodology (materials, methods and strategies for protection and deprotection) and other synthetic chemistry transformations that can be used to produce the compounds described herein, see R. Larock, Comprehensive organic transformations, VCH Publishers (1989); Green's Protecting 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 entirety.

[0093] The term "substituted" or "substitution" means that at least one hydrogen present on an atom of a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, when substituted for the 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 may 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 substituent may be the same or different at each position. The substituents comprise one or more groups individually and independently selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, alkaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, thiol, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphite, silyl, sulfinyl, sulfonyl, sulfonamido, sulfoxylate, 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 (where t is 1 or 2), -P(=O)(R a )(R a ) or -OP(=O)(OR a ) 2 , where each R ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties (except hydrogen) may be optionally substituted with one or more substituents (up to six, valence permitting) independently selected from the group consisting of OH, NH 2 , oxo, halogen, nitro, COOH, C(O)NH 2 For example, a cycloalkyl substituent may have a halide substituted at one or more ring carbons, etc. Protecting groups that can form protective derivatives of the above substituents are known to those skilled in the art and can be found in references such as Greene and Wuts mentioned above.

[0094] Suitable substituents include, but are not limited to, haloalkyl and trihaloalkyl, alkoxyalkyl, halophenyl, -M-heteroaryl, -M-heterocycle, -M-aryl, -M-OR a 、-M-SR a 、-MN(R a ) 2 、-M-OC(O)N(R a ) 2 、-MC(=NR a )N(R a ) 2 、-MC(=NR a )OR a 、-MP(O)(R a ) 2 、Si(R a ) 3 、-M-NR a C(O)R a 、-M-NR a C(O)OR a 、-MC(O)R a 、-MC(=S)R a 、-MC(=S)NR a R a 、-MC(O)N(R a ) 2 、-MC(O)NR a -MN(R a ) 2 、-M-NR a C(NR a )N(R a ) 2 、-M-NR a C(S)N(R a ) 2 、-MS(O) 2 Ra 、-MC(O)R a 、-M-OC(O)R a 、-MC(O)SR a 、-MS(O) 2 N(R a ) 2 、-C(O)-MC(O)R a 、-MCO 2 R a 、-MC(=O)N(R a ) 2 、-MC(=NH)N(R a ) 2 and -M-OC(=NH)N(R a ) 2 (where M is C 1-6 alkyl).

[0095] When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl) is substituted with several substituents that vary within a well-defined range, it is understood that the total number of substituents does not exceed the normal available valences under the existing conditions. Thus, for example, a phenyl ring substituted with a "p" substituent (where "p" ranges from 0 to 5) can have 0 to 5 substituents, while it is understood that a pyridyl ring substituted with a "p" substituent has several substituents ranging from 0 to 4. The maximum number of substituents that a group in a disclosed compound can have can be easily determined. Substituted groups only encompass those combinations of substituents and variables that produce stable or chemically feasible compounds. A stable compound or a chemically feasible compound is one that has stability sufficient to allow its preparation and testing, among other factors. In some embodiments, the disclosed compounds are sufficiently stable that the compounds do not undergo substantial changes when maintained at a temperature of 40° C. or less, in the absence of moisture (e.g., less than about 10%, less than about 5%, less than about 2%, less than about 1%, or less than about 0.5%) or other chemically reactive conditions, for, e.g., at least about 3 days, at least about a week, at least about 2 weeks, at least about 4 weeks, or at least about 6 weeks.

[0096] The term "combine, combining, to combine, combination" refers to the action of adding at least one chemical substance to another chemical substance sequentially or simultaneously. In some embodiments, putting these chemicals together may cause the initial chemical substance to be converted into one or more different chemical substances. This conversion can occur through one or more chemical reactions, such as the case of covalent bond formation, rupture, rearrangement, etc. A non-limiting example can include the hydrolysis of esters into alcohols and carboxylic acids, which can be produced by the combination of esters with suitable bases. In another non-limiting example, aryl fluorides can be combined with amines to provide aryl amines through a substitution process. These terms also include changes in the association of charged chemical substances and the generation of charged chemical substances, 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 free radical chemicals and isotope-labeled chemicals.

[0097] The term "convert", "converting", "to convert", "conversion" refers to a subset of "combination" and its grammatical equivalents, wherein the action of one or more reagents converts one or more functional groups on a chemical substance into another functional group. For example, conversion includes, but is not limited to, converting a nitro functional group on a chemical substance to an amine with a reducing agent. Conversion also includes changes in charged chemicals, free radical chemicals, and isotopically labeled chemicals. However, the term "conversion" does not include changes in conservative bonds in the disclosed genera and compounds.

[0098] Compound

[0099] In one aspect, the present invention relates to a compound of formula (I):

[0100]

[0101] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0102] in:

[0103] Ring A is a fused 6,5-bicyclic aryl or heteroaryl ring system, wherein the heteroaryl ring system includes 1, 2, 3 or 4 nitrogen atoms as ring members, and Ring A carries R 5 and R 6 substituent, and in the group selected from R 7 or R 9 The ring carbon of the present invention carries 1, 2 or 3 substituents, and / or is selected from R 8 and R 10 The ring nitrogen of the compound carries 1 or 2 substituents;

[0104] Ring Q is a fused 6,5-bicyclic heteroaryl or fused 6,6-bicyclic heteroaryl ring system comprising 1, 2 or 3 nitrogen atoms as ring members and optionally comprising 1 or 2 selected from O, S or S(═O 2 ), wherein the ring Q carries R as indicated by formula (I) 1 and R 2 substituent, and optionally carrying 1 or 2 R 12 Substituents;

[0105] R 1 is independently hydrogen, C 1-4 Alkyl, halogenated C 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 NR b C(=O)R a 、C(=O)NHC(=O)R a or a 4-6 membered heterocyclic group, each of which is optionally substituted by one to three R 11 replace;

[0106] R 2 C independently at each occurrence 1-4 Alkyl, halogenated C 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 a 4-6 membered heterocyclic group, each of which is optionally substituted by one to two R 11 Substitution, or two R in the geminal position 2 The group can optionally form a spiro C 3-5 Cycloalkyl;

[0107] R 3 and R 4 are independently hydrogen, halogen, CN, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0108] R 7 is independently hydrogen or C 1-4 alkyl;

[0109] R 8 is independently hydrogen or C 1-4 alkyl;

[0110] R 9 is independently hydrogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0111] R 10 is independently hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl or optionally C 1-4 Alkyl-substituted 4-6 membered heterocyclic group;

[0112] R 11 C independently at each occurrence 1-4 Alkyl, halogenated C 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 NR b C(=O)R a 、C(=O)NHC(=O)R a or a 4-6 membered heterocyclic group;

[0113] R 12 is independently hydrogen, C 1-4 Alkyl, halogenated C 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 a 4-6 membered heterocyclic group optionally substituted by one to three groups selected from the following: C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, CN, OH, C 1-4 Alkoxy, C 3-7 Cycloalkoxy or NR a R b ;

[0114] R a and R b is independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, or R a and R b Together with the nitrogen atom to which it is attached, it forms a saturated or unsaturated heterocyclic ring containing three to seven ring atoms, which ring may optionally contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by one to three groups which may be the same or different and are selected from C 1-4 the group consisting of alkyl, phenyl and benzyl; and

[0115] n is independently 0, 1 or 2 at each occurrence.

[0116] In some embodiments, the present technology relates to a compound of formula (I) having a structure of any one of formulas (II)-(IV):

[0117]

[0118] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0119] in:

[0120] Ring Q is independently

[0121] Q 1 is independently N or CH at each occurrence, provided that at least one Q 1 is N;

[0122] Q 2 O, S, S (=O 2 ), CH 2 or NR 12 , the condition is that when two Q 2 When adjacent in the ring, at least one Q 2 It is CH;

[0123] X 1 and X 5 are independently N or C, X 2 , X 3 and X 4 Each independently is N or CR 7 , and the dotted circle represents the bond forming the five-membered aromatic ring; provided that X 1 , X 2 , X 3 , X 4 and X 5At least two but no more than three of them are N;

[0124] Y 1 N or CH, Y 2 Yes N, NR 8 or CH, and Y 3 Yes N, NR 8 or CH, and in formula (III) express

[0125] Z 1 N or CH, Z 2 Is N or CR 9 , and Z 3 is N or CH;

[0126] R 1 is independently hydrogen, C 1-4 Alkyl, halogenated C 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 NR b C(=O)R a 、C(=O)NHC(=O)R a or a 4-6 membered heterocyclic group, each of which is optionally substituted by one to three R 11 replace;

[0127] R 2 is independently hydrogen, C 1-4 Alkyl, halogenated C 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 a 4-6 membered heterocyclic group, each of which is optionally substituted by one to two R 11 Substitution, or two R in the geminal position 2 The group may optionally form a spiro C 3-5 Cycloalkyl;

[0128] R 3 , R 4 , R 5 and R6 are independently hydrogen, halogen, CN, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0129] R 7 is independently hydrogen or C 1-4 alkyl;

[0130] R 8 is independently hydrogen or C 1-4 alkyl;

[0131] R 9 is independently hydrogen, C 1-4 Alkyl or C 1-4 Alkoxy;

[0132] R 10 is independently hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl or optionally C 1-4 Alkyl-substituted 4-6 membered heterocyclic group;

[0133] R 11 is independently hydrogen, C 1-4 Alkyl, halogenated C 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 NR b C(=O)R a 、C(=O)NHC(=O)R a or a 4-6 membered heterocyclic group;

[0134] R 12 is independently hydrogen, C 1-4 Alkyl, halogenated C 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 bor a 4-6 membered heterocyclic group optionally substituted by one to three groups selected from the following: C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, CN, OH, C 1-4 Alkoxy, C 3-7 Cycloalkoxy or NR a R b ;

[0135] R a and R b is independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, or R a and R b Together with the nitrogen atom to which it is attached, it forms a saturated or unsaturated heterocyclic ring containing three to seven ring atoms, which ring may optionally contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by one to three groups which may be the same or different and are selected from C 1-4 the group consisting of alkyl, phenyl and benzyl; and

[0136] n is independently 0, 1 or 2 at each occurrence.

[0137] In some embodiments, the present technology relates to compounds of formula (II):

[0138]

[0139] or a pharmaceutically 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 are each as defined above, or may have any of the values ​​disclosed herein.

[0140] In any embodiment of the compound of formula (II), yes Where R 5 and R6 Each is as defined above, or may have any of the values ​​disclosed herein.

[0141] In some embodiments, the present technology relates to compounds of formula (III):

[0142]

[0143] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0144] Among them, 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 are each as defined above, or may have any of the values ​​disclosed herein.

[0145] In any embodiment of the compound of formula (III), yes Where R 5 , R 6 and R 8 Each is as defined above, or may have any of the values ​​disclosed herein.

[0146] In some embodiments, the present technology relates to compounds of formula (IV):

[0147]

[0148] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,

[0149] Among them, 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 , R11 , R 12 , R a , R b and n are each as defined above, or may have any of the values ​​disclosed herein.

[0150] In any embodiment of the compound of formula (IV), yes Where R 5 , R 6 , R 9 and R 8 Each is as defined above, or may have any of the values ​​disclosed herein.

[0151] In any embodiment of the compounds of the present invention (including but not limited to compounds of Formula I, II, III and IV), Q at 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 at each occurrence is independently In some embodiments, Q at 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

[0152] In some embodiments, Q is associated with R at each occurrence. 1 and R 2 Together and independently In some embodiments, Q is associated with R at each occurrence. 1 and R 2 Together and independently In some embodiments, Q is associated with R at each occurrence. 1 and R 2 Together and independently In some embodiments, Q is associated with R at each occurrence. 1 and R 2 Together and independently In some embodiments, Q is associated with R at each occurrence. 1 and R 2 Together and independently In some embodiments, Q is associated with R at each occurrence. 1 and R 2 Together and independently In some embodiments, Q is associated with R at each occurrence. 1 and R 2 Together and independently

[0153] In any embodiment of the present compound, Q 1 is independently N or CH at each occurrence, provided that there is only one Q in each ring 1 is N. In some embodiments, Q 2 O, CH independently at each occurrence 2 or NR 12 , the condition is that when there are two adjacent Q 2 When the group is at least one Q 2 It is CH.

[0154] In any embodiment of the compounds of the present invention, R 1 C independently at each occurrence 1-4 Alkyl, halogenated C 1-4 Alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy, cyclobutyloxy, NR a R b or a 4-6 membered heterocyclic group, each of which is optionally substituted by one to three R 11 In some embodiments, R 1 C independently at each occurrence 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, NR a R b or a 4-6 membered heterocyclic group, each of which is optionally substituted by one to three R 11 In some embodiments, the C 3-5 Cycloalkyl is cyclopropyl or cyclobutyl, and the C 3-5 Cycloalkoxy is cyclopropyloxy or cyclobutyloxy. In some embodiments, R 1 C independently at each occurrence 1-4 In some embodiments, R 1 is independently at each occurrence optionally replaced by one to three R 11 Substituted C 1-4 In some embodiments, R 1 In some embodiments, R 1 Each occurrence is independently optionally replaced by an R 11 In some embodiments, R 1 is independently methoxy at each occurrence. 1is independently cyclopropyl at each occurrence. In some embodiments, R 1 Each occurrence is independently optionally replaced by an R 11 In some embodiments, R 1 is independently cyclobutyl at each occurrence. In some embodiments, R 1 Each occurrence is independently optionally replaced by an R 11 In some embodiments, R 1 In some embodiments, R 1 Each occurrence is independently optionally replaced by an R 11 In some embodiments, R 1 In each occurrence, independently In some embodiments, R 1 In each occurrence, independently In some embodiments, R 1 In each occurrence, independently

[0155] In any embodiment of the compounds of the present invention, R 2 is independently hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-5 Cycloalkyl, halogen, CN, OH, C 1-4 Alkoxy, NR a R b or a 4-6 membered heterocyclic group, each of which is optionally substituted by one to two R 11 In some embodiments, the two R 2 The group may optionally form a spiro C 3-5 In some embodiments, the two R 2 The group may optionally form a spirobutyl group. In some embodiments, R 3 R is independently hydrogen, methyl, F or Cl at each occurrence. In some embodiments, R 4 is independently hydrogen, methyl or halogen at each occurrence. In some embodiments, R 5 is independently hydrogen or methyl at each occurrence. In some embodiments, R 6 is independently hydrogen or methyl at each occurrence. In some embodiments, R 7 is independently hydrogen or methyl at each occurrence. In some embodiments, R 8 is independently hydrogen or methyl at each occurrence. In some embodiments, R 9Each occurrence of is independently hydrogen, methyl or methoxy. 10 is independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl or optionally C 1-4 alkyl-substituted 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group contains one to two heteroatoms selected from N, O and S. In some embodiments, R 11 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 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group contains one to two heteroatoms selected from N, O and S. In some embodiments, R 11 is independently cyclopropyl at each occurrence. In some embodiments, R 11 is independently cyclobutyl at each occurrence. In some embodiments, R 11 In some embodiments, R 12 is independently hydrogen, C 1-4 Alkyl, halogenated C 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 a 4-6 membered heterocyclic group optionally substituted by one to three groups selected from the following: C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-5 Cycloalkyl, halogen, CN, OH, C 1-4 Alkoxy, C 3-5 Cycloalkoxy or NR a R b , wherein the 4-6 membered heterocyclyl contains one to two heteroatoms selected from N, O and S. In some embodiments, R 12 C independently at each occurrence 1-4 In some embodiments, R 12 In some embodiments, R 12 C independently at each occurrence 3-5 In some embodiments, R12 is independently at each occurrence cyclopropyl.

[0156] In any embodiments of the compounds of the invention, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0157] In any embodiment, the compound is selected from:

[0158]

[0159] In any embodiment, the compound is selected from:

[0160]

[0161] In some embodiments, the present technology relates to a compound of formula (I), (II), (III) and (IV), including each exemplary compound, wherein at least one hydrogen (H) is replaced by deuterium (D). Deuterium enrichment can provide certain therapeutic advantages, such as increasing half-life in vivo or reducing dosage requirements, or can provide compounds that can be used as standards for characterizing biological samples. In some other embodiments, the compounds provided herein can have an isotopic enrichment factor for each deuterium present at a site designated as a potential deuteration 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 incorporation), 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).

[0162] On the other hand, 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 pharmaceutically acceptable carrier.

[0163] 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, the method comprising administering to the subject an effective amount of a compound disclosed herein (including but not limited to compounds of formula (I), (II), (III) and (IV)).

[0164] In yet another aspect, the technology of the present invention relates to a method for treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein (including but not limited to compounds of formula (I), (II), (III) and (IV)), wherein the disease or condition is a hereditary disease, a neurodegenerative disorder, a metabolic disease, an inflammatory syndrome or cancer. In some embodiments, the hereditary disease is a periodic syndrome associated with cryptopyrin. In some embodiments, the neurodegenerative disorder is multiple sclerosis, Alzheimer's disease or Parkinson's disease. In some embodiments, the metabolic disease is atherosclerosis or type 2 diabetes. In some embodiments, the inflammatory syndrome is a gout attack or osteoarthritis.

[0165] In yet another aspect, the present technology relates to a method of preparing compounds of formula (I), (II), (III) and (IV), comprising each of the exemplary compounds and intermediates described herein.

[0166] Examples

[0167] General synthetic method

[0168] 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 as variations thereon as understood by those skilled in the art. Preferred methods include but are not limited to those illustrative schemes and working examples described below. Unless otherwise indicated, all substituents are as defined above. The reaction is carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for the proposed transformation. This will sometimes require judgment to modify the order of the synthesis steps or select a specific method scheme rather than another to obtain the desired compound of the present technology.

[0169] It will be appreciated that another major consideration in the planning of any synthetic route in this area is the judicious choice of protecting groups for protecting reactive functional groups present in the compounds described in the technology of the present invention. An authoritative description of many alternatives for well-trained practitioners is Greene et al., "Protective Groups in Greene's Organic Synthesis", Fifth Edition, Wiley Press (2014). It will also be appreciated that the names of the compounds mentioned in the descriptions of Schemes 1-3 are for convenience only and do not necessarily reflect the actual chemical names of those compounds.

[0170] Solution 1

[0171]

[0172] Scheme 1 describes the general synthetic route for compounds of formula (II). In a suitable solvent (e.g. 1,4-dioxane / water), in the presence of a Pd catalyst (e.g. Pd(dppf)Cl 2 ) and bases (such as K 2 CO 3 ), compound 1 and compound 2 are treated under Suzuki coupling conditions to obtain compound 3. In a suitable solvent (e.g., DCM, THF), compound 3 is treated with triphosgene in the presence of a base (e.g., TEA, DIPEA) to produce an isocyanate intermediate, which is then reacted with compound 4 in a suitable solvent (e.g., THF, CH 3 CN), in the presence of a base (eg NaH, t-BuONa) to give the desired compound of formula (II).

[0173] Solution 2

[0174]

[0175] Scheme 2 describes a general synthetic route for compounds of formula (III). In a suitable solvent (e.g. 1,4-dioxane / water), in the presence of a Pd catalyst (e.g. Pd(dppf)Cl 2 ) and bases (such as K 2 CO 3 ), compound 1 and compound 5 are treated under Suzuki coupling conditions to obtain compound 6. Compound 6 is treated with triphosgene in a suitable solvent (e.g., DCM, THF) in the presence of a base (e.g., TEA, DIPEA) to produce an isocyanate intermediate, which is then reacted with compound 4 in a suitable solvent (e.g., THF, CH 3 CN), in the presence of a base (such as NaH, t-BuONa) to give a compound of formula (III).

[0176] Solution 3

[0177]

[0178] Scheme 3 describes a general synthetic route for compounds of formula (IV). In a suitable solvent (e.g. 1,4-dioxane / water), in the presence of a Pd catalyst (e.g. Pd(dppf)Cl 2 ) and bases (such as K 2 CO 3), compound 1 and compound 7 are treated under Suzuki coupling conditions to obtain compound 8. Compound 8 is treated with triphosgene in a suitable solvent (e.g., DCM, THF) in the presence of a base (e.g., TEA, DIPEA) to produce an isocyanate intermediate, which is then reacted with compound 4 in a suitable solvent (e.g., THF, CH 3 CN), in the presence of a base (such as NaH, t-BuONa) to give a compound of formula (IV).

[0179] Pharmaceutical compositions and methods

[0180] The compounds used in the methods described herein can be formulated into pharmaceutically acceptable compositions together with a pharmaceutically acceptable carrier or adjuvant and then administered to a subject. In another embodiment, such pharmaceutically acceptable compositions further include an additional therapeutic agent, including those described herein, in an amount effective to achieve disease or disease symptom modulation.

[0181] 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 and does not interfere with its pharmacological activity, and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound.

[0182] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the present technology include but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants for pharmaceutical dosage forms such as Tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin. Cyclodextrins such as α-, β- and γ-cyclodextrin or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formula described herein.

[0183] The pharmaceutical composition of the technology of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectum, nasal cavity, oral cavity, vaginal or by implanted reservoir, preferably by oral administration or by injection. The pharmaceutical composition of the technology of the present invention may include any conventional nontoxic pharmaceutically acceptable carrier, adjuvant or vehicle. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acid, alkali 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, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0184] The pharmaceutical composition can be in the form of a sterile injectable preparation, for example, in the form of a sterile injectable aqueous or oily suspension. This suspension can be formulated using a suitable dispersant or wetting agent (e.g., Tween 80) and a suspending agent according to techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild non-volatile oil containing synthetic monoglycerides or diglycerides can be used. Fatty acids such as oleic acid and their glyceride derivatives can be used to prepare injectables, as can natural pharmaceutically acceptable oils (such as olive oil or castor oil, especially their polyoxyethylated forms). These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.

[0185] The pharmaceutical composition of the present technology can be orally administered in any oral acceptable dosage form, including but not limited to capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in the form of capsules, useful diluents include lactose and dry corn starch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oil phase, combined with an emulsifier and / or a suspending agent. If necessary, certain sweeteners and / or flavorings and / or coloring agents can be added.

[0186] The pharmaceutical compositions of the present technology can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present technology with suitable non-irritating excipients, which are solid at room temperature and liquid at rectal temperature, and thus will melt in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0187] When the desired treatment involves an area or organ that is easily accessible by topical application, the topical application of the pharmaceutical composition of the present invention is useful. Regarding topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing an active component suspended or dissolved in a carrier. The carrier for topical application of the compound of the present invention includes but is not limited to mineral oil, liquid vaseline, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing an active compound, which is suspended or dissolved in a carrier with a suitable emulsifier. Suitable carriers include but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, hexadecyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical composition of the present invention can also be topically applied to the lower intestinal tract by a rectal suppository formulation or with a suitable enema formulation. The present invention also includes a topical transdermal patch.

[0188] The pharmaceutical compositions of the present technology can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, fluorocarbons and / or other solubilizing or dispersing agents known in the art.

[0189] When the composition of the present invention technology includes a compound of the formula described herein and a combination of one or more additional therapeutic agents or preventive agents, the compound and additional medicament should be present at a dosage level between about 1 to 100% of the dosage usually applied in a monotherapy regimen, and more preferably between about 5% to 95%. As part of a multiple dose regimen, additional medicaments can be administered separately from the compound of the present invention technology. Alternatively, those medicaments can be part of a single dosage form, which is mixed in a single composition together with the compound of the present invention technology.

[0190] The compounds described herein can be administered, for example, by injection, intravenous, intraarterial, subdermal, intraperitoneal, intramuscular or subcutaneous; or orally, orally, nasally, transmucosally, topically, in ophthalmic preparations or by inhalation, with a dosage range of about 0.5 to about 100 mg / kg of body weight, alternatively, between 1 mg and 1000 mg / dose, once every 4 to 120 hours, or as required by the drug. The methods herein contemplate administering an effective amount of a compound or compound composition to achieve a desired or prescribed effect. Typically, the pharmaceutical composition of the present technology will be administered about 1 to about 6 times a day, or alternatively as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the mode of administration. A typical preparation will contain about 5% to about 95% of the active compound (w / w). Alternatively, such preparations contain about 20% to about 80% of the active compound.

[0191] Lower or higher doses than those described 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 specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition or symptom, the subject's predisposition to the disease, condition or symptom, and the judgment of the treating physician.

[0192] When the condition of the subject improves, if necessary, a maintenance dose of the compound, composition or combination of the present invention technology can be administered. Subsequently, as the symptoms change, when the symptoms have been alleviated to the desired level, the dosage or frequency of administration or both can be reduced to the level of the condition of the subject to maintain improvement. However, in the event of any recurrence of disease symptoms, the subject may require long-term intermittent treatment.

[0193] 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 the event of a conflict, the present application, including any definitions herein, will control.

[0194] Examples are provided herein to illustrate the advantages of the technology of the present invention and to further assist those of ordinary skill in the art in preparing or using compounds or salts, pharmaceutical compositions, derivatives, solvates, metabolites, prodrugs, racemic mixtures or tautomeric forms thereof of the technology of the present invention. Examples are also presented herein to more fully illustrate the preferred aspects of the technology of the present invention. Examples should never be interpreted as limiting the scope of the technology of the present invention as defined by the appended claims. Examples may include or incorporate any variant, one or more aspects of the technology of the present invention described above. The variants, one or more aspects described above may also further each include or incorporate any or all other variants, one or more aspects of the technology of the present invention.

[0195] Examples

[0196] The abbreviations used in this article are as follows:

[0197]

[0198]

[0199] General conditions and procedures

[0200] In the following examples, chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Company) and used without further purification. THF was continuously refluxed under nitrogen and freshly distilled from sodium and benzophenone, dichloromethane was continuously refluxed under nitrogen and freshly distilled from CaH 2 Freshly distilled.

[0201] Flash chromatography was performed on an Ez Purifier III column with 200-300 mesh silica gel particles. Analytical and preparative thin layer chromatography (TLC) plates were HSGF 254 (0.15-0.2 mm thickness, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were recorded at about 20-30°C using a Bruker AMX-300 or AMX-400 NMR (Brucker, Switzerland) unless otherwise stated. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, double doublet; ddd, doublet of double doublets; dt, double triplet; bs, broad signal. Chemical shifts are reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were run using electrospray ionization (ESI) of a Waters LCT TOF mass spectrometer (Waters, USA). Compound purification was performed as needed using a variety of conventional methods, including but not limited to preparative chromatography using normal or reverse phase HPLC or flash columns or Prep-TLC plates under acidic, neutral or basic conditions.

[0202] Preparative HPLC: Unless otherwise stated, compounds were analyzed using a HPLC-MS / MS instrument equipped with a YMC Pack Pro d 8 Purification was performed using a Waters Fractionlynx system with a column (5 μm, 120A, 50 × 20 mm) and the following solvent system: H 2 O, AcCN, and 2% TFA in HO 2 O. The specific elution gradient is based on the retention times obtained using analytical LC-MS, however, H 2 All elution gradients for O and MeCN were run at a flow rate of 35 ml / min over a run time of 7 min. An automated blending method was used to ensure that the concentration of TFA was 0.1% in each run. The specific elution gradients were based on retention times obtained with analytical LC-MS, however, H 2 All elution gradients of O and MeCN were run at a flow rate of 50 mL / min with a run time of 8 min.

[0203] Analytical LC-MS: On an ACQUITY UPLC BEH Ci 8 Analytical LC-MS was performed on a Waters Acquity UPLC-MS instrument with a 1.7 μm column (2.1×50 mm, 1.7 μm) at a column temperature of 45° C. and using the following solvent system: Solvent A: 0.1% HCOOH in H 2O; Solvent B: AcCN with 0.1% HCOOH. All compounds were run using the same elution gradient, ie, 5% to 95% solvent B in a 1.5 min run time with a flow rate of 0.6 ml / min.

[0204] Preparative chiral SFC separation: Stereoisomers 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); the chromatograph was performed using MeOH / CO containing 0.1% diethylamine. 2 or EtOH / CO containing 0.1% diethylamine 2 or isopropanol / CO containing 0.1% diethylamine 2 Elution was performed with a flow rate of 2.5 ml / min and a column temperature of 35°C.

[0205] Analytical chiral SFC separations: Stereoisomers 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); the separations were eluted with MeOH / CO containing 0.1% diethylamine. 2 or EtOH / CO containing 0.1% diethylamine 2 or isopropanol / CO containing 0.1% diethylamine 2 Elution was performed with a flow rate of 6.0 ml / min and a column temperature of 35°C.

[0206] Preparation of intermediates

[0207] 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

[0208]

[0209] Step 1: 3-iodo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole

[0210] 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 Cs 2 CO 3 (15 g, 46 mmol). After stirring at room temperature for 3 hours, the mixture was filtered. The filtrate was poured into water and extracted with EtOAc (2×10 mL). The combined organic phases were washed with water and brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (2 g, 40% yield) as a colorless oil. LC / MS (ESI) m / z: 323 (M+H) + .

[0211] Step 2: Cyclopropyl(3-iodo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-5-yl)methanol

[0212] 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) at -75 °C was added LDA (3.5 mL, 7 mmol, 2 M in THF) dropwise. After stirring at -75 °C for 30 min, cyclopropanecarboxaldehyde (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 x 10 mL). The combined organic phases were washed with water and brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc / PE) to give the title compound (1.4 g, 57% yield) as a colorless oil. LC / MS (ESI) m / z: 309 (M+H) + .

[0213] Step 3: 4-Cyclopropyl-2-iodo-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine

[0214] 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 hours. The mixture was poured into ice water and extracted with DCM (2 x 20 mL). The combined organic phases were washed with water and brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (400 mg, 38% yield) as a white solid. LC / MS (ESI) m / z: 291 (M+H) + .

[0215] Step 4: 2-(Benzylthio)-4-cyclopropyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine

[0216] In N 2 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 benzyl mercaptan (0.2 mL, 1.8 mmol), Pd 2 (dba) 3 (140 mg, 0.16 mmol), Xant-Phos (180 mg, 0.32 mmol) and DIPEA (1 mL, 6 mmol). The mixture was stirred under N 2 Degased three times under N atmosphere and 2 The mixture was stirred at 95°C for 3 hours under atmosphere. The mixture was diluted with EtOAc, washed with water and brine, and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (360 mg, 91% yield) as a yellow solid. LC / MS (ESI) m / z: 287 (M+H) + .

[0217] Step 5: 4-Cyclopropyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-2-sulfonyl chloride

[0218] 2-(Benzylthio)-4-cyclopropyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine (360 mg, 1.26 mmol) was dissolved in AcOH (8 mL) / H2O at 0 °C. 2To the stirred solution in 2% 4% dHO (2 mL) was added NCS (738 mg, 5.5 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water and extracted with EtOAc (2×10 mL). The combined organic phases were washed with water and brine, and then purified by Na 2 SO 4 Dried, filtered and concentrated to dryness to give the title compound as a yellow oil (300 mg, 90% yield), which was used directly in the next reaction without purification.

[0219] 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

[0220] 4-Cyclopropyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-2-sulfonyl chloride (300 mg, 1.14 mmol) was dissolved in NH 3 The mixture was stirred at room temperature for 1 hour in 2% 4% dextrin / THF (20 mL, 1 M). The mixture was poured into ice water and extracted with DCM (3×10 mL). The combined organic phases were washed with water and brine and purified by anhydrous Na 2 SO 4 The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / 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 any designated (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.

[0221] Intermediate A1 (peak 1, retention time: 5.728 minutes), 1 H NMR (400 MHz, DMSO-d 6)δ7.42(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) + .

[0222] Intermediate A2 (peak 2, retention time: 6.700 minutes), 1 H NMR (400 MHz, DMSO-d 6 )δ7.42(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) + .

[0223] SFC conditions: Column: ChiralPak IC-H, 250×21.2 mm ID, 5 μm; Mobile phase: A represents CO 2 and B represents methanol (0.1% NH 4 OH); gradient: B 25%; flow rate: 50 mL / min.

[0224] Intermediate A3: 6',7'-dihydrospiro[cyclobutane-1,4'-pyrazolo[5,1-c][1,4]oxazine]-2'-sulfonamide

[0225]

[0226] Step 1: N,N-bis(4-methoxybenzyl)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazolo-3-sulfonamide

[0227] 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 Cs 2 CO 3(3.4 g, 10.3 mmol), and the reaction mixture was heated at 65 °C under N 2 Stir under atmosphere for 16 hours. The reaction mixture was poured into water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (2.1 g, 94.3% yield) as a yellow solid. LC / MS (ESI) (m / z): 516 (M+H) + .

[0228] Step 2: 5-(1-Hydroxycyclobutyl)-N,N-bis(4-methoxybenzyl)-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole-3-sulfonamide

[0229] 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 hour. 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 hours. The reaction mixture was washed with ice-cold saturated NH 4 The solution was quenched with aqueous Cl solution and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc / PE) to give the title compound (200 mg, 24.6% yield) as a yellow solid. LC / MS (ESI) (m / z): 586 (M+H) + .

[0230] Step 3: 5-(1-Hydroxycyclobutyl)-1-(2-hydroxyethyl)-N,N-bis(4-methoxybenzyl)-1H-pyrazole-3-sulfonamide

[0231] 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 mixture was stirred at 50° C. for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (40 mg, 46.6% yield) as a yellow oil. LC / MS (ESI) (m / z): 502 (M+H) + .

[0232] Step 4: 2-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-5-(1-hydroxycyclobutyl)-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate

[0233] 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), TosCl (38 mg, 0.20 mol), DIPEA (77 mg, 0.60 mmol) and DMAP (24 mg, 0.20 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. 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 / PE) to give the title compound (105 mg, 80% yield) as a yellow solid. LC / MS(ESI)(m / z):656(M+H) + .

[0234] Step 5: N,N-bis(4-methoxybenzyl)-6',7'-dihydrospiro[cyclobutane-1,4'-pyrazolo[5,1-c][1,4]oxazine]-2'-sulfonamide

[0235] 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 mixture reaction was stirred at room temperature for 30 minutes. The reaction was quenched with ice water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc / PE) to give the title compound (40 mg, 67.8% yield) as a yellow solid. LC / MS (ESI) (m / z): 484 (M+H) + .

[0236] Step 6: 6',7'-dihydrospiro[cyclobutane-1,4'-pyrazolo[5,1-c][1,4]oxazine]-2'-sulfonamide

[0237] 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 hours. The mixture was concentrated to dryness and the residue was dissolved in EtOAc, washed with water and brine, and purified by Na 2 SO 4 Dry, filter and concentrate to dryness to give the title compound as a yellow solid (15 mg, 74.6% yield). LC / MS (ESI) (m / z): 244 (M+H) + .

[0238] Intermediate A4: 8-cyclopropyl-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-2-sulfonamide

[0239]

[0240] Step 1: 4-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-imidazole

[0241] 4-iodo-1H-imidazole (2.0 g, 10.3 mmol) and 2-(2-bromoethoxy)oxane (2.6 g, 12.4 mmol) were added to CH 3 Cs was added to the mixture in CN (30 mL). 2 CO 3(5.0 g, 15.5 mmol), and the mixture was stirred at 60° C. for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc / PE) to give the title compound (1.7 g, 51% yield) as a light yellow oil. LC / MS (ESI) m / z: 323 (M+H) + .

[0242] Step 2: Cyclopropyl({4-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-imidazol-2-yl})methanol

[0243] 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 hexanes) dropwise at -70 °C. After stirring at this temperature for 30 minutes, cyclopropanecarboxaldehyde (440 mg, 6.3 mmol) was added, and the resulting mixture was stirred at -70 °C to room temperature for 2 hours. The reaction was poured into ice water and extracted with EtOAc (2×20 mL). The organic layer was washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (1.2 g, 58% yield) as a colorless oil. LC / MS (ESI) m / z: 393 (M+H) + .

[0244] Step 3: 8-Cyclopropyl-2-iodo-5H,6H,8H-imidazo[2,1-c][1,4]oxazine

[0245] 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, and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc / PE) to give the title compound (240 mg, 32% yield) as a white solid. LC / MS (ESI) m / z: 291 (M+H)+ .

[0246] Step 4: 2-(Benzylthio)-8-cyclopropyl-5H,6H,8H-imidazo[2,1-c][1,4]oxazine

[0247] In N 2 To a solution of 8-cyclopropyl-2-iodo-5H,6H,8H-imidazo[2,1-c][1,4]oxazine (240 mg, 0.8 mmol), phenylmethyl mercaptan (133 mg, 1.0 mmol) and DIPEA (320 mg, 2.5 mmol) in toluene (8 mL) was added Pd 2 (dba) 3 (151 mg, 0.16 mmol), Xant-Phos (96 mg, 0.16 mmol). The mixture was stirred under N 2 Degased three times under N atmosphere and 2 Stir at 100° C. for 3 hours under atmosphere. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (230 mg, 97% yield) as a yellow oil. LC / MS (ESI) m / z: 286 (M+H) + .

[0248] Step 5: 8-Cyclopropyl-5H,6H,8H-imidazo[2,1-c][1,4]oxazine-2-sulfonamide

[0249] 2-(Benzylthio)-8-cyclopropyl-5H,6H,8H-imidazo[2,1-c][1,4]oxazine (100 mg, 0.35 mmol) was dissolved in AcOH (4 mL) and H at 0 °C. 2 0 (1 mL) was added portionwise 1,3-dichloro-5,5-dimethylhydantoin (206 mg, 1.0 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM, washed with water and brine, and washed with anhydrous Na 2 SO 4 The residue was dissolved in THF (1 mL) and NH 3 / THF (2 mL, 1 M). After stirring at room temperature for 1 hour, the mixture was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc / PE) to give the title compound as a white solid (40 mg, 47% yield). LC / MS (ESI) m / z: 244 (M+H) + .

[0250] Intermediate A5: 4,4-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide

[0251]

[0252] Step 1: 3-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-pyrazole

[0253] 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 Cs 2 CO 3 (17 g, 51 mmol), and the mixture was stirred at 40°C for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc / PE) to give the title compound (8 g, 96% yield) as a colorless oil. LC / MS (ESI) m / z: 323 (M+H) + .

[0254] Step 2: 2-{3-iodo-1-[2-(oxan-2-yloxy)ethyl]-1H-pyrazol-5-yl}propan-2-ol

[0255] 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, 2 M 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 hour. The mixture was poured into ice water and extracted with EtOAc (2 x 15 mL). The combined organic phases were washed with water and brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (1.1 g, 46% yield) as a light yellow oil. LC / MS (ESI) m / z: 381 (M+H) + .

[0256] Step 3: 2-iodo-4,4-dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine

[0257] 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 hours. The mixture was poured into ice water and extracted with DCM (2 x 20 mL). The combined organic phases were washed with water and brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-80% EtOAc / PE) to give the title compound (500 mg, 62% yield) as a yellow oil. LC / MS (ESI) m / z: 279 (M+H) + .

[0258] Step 4: 2-(Benzylthio)-4,4-dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine

[0259] In N 2 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 phenylmethyl mercaptan (0.2 mL, 1.9 mmol), Pd 2 (dba) 3 (140 mg, 0.16 mmol), Xant-Phos (190 mg, 0.33 mmol) and DIPEA (1 mL, 6 mmol) were stirred under N 2 Degased three times under N atmosphere and 2 The mixture was stirred at 95°C for 3 hours under atmosphere. The mixture was diluted with EtOAc, washed with water and brine, and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (400 mg, 81% yield) as a yellow solid. LC / MS (ESI) m / z: 275 (M+H) + .

[0260] Step 5: 4,4-Dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-2-sulfonyl chloride

[0261] 2-(Benzylthio)-4,4-dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine (200 mg, 0.72 mmol) in AcOH (8 mL) / H2O at 0 °C was added.2 To a stirred solution in 2% 4% dHO (2 mL) was added NCS (738 mg, 5.5 mmol) in portions, and the mixture was stirred at room temperature for 1 hour. The mixture was poured into water and extracted with DCM (2×10 mL). The combined organic layers were washed with water and brine, and then purified by anhydrous Na 2 SO 4 Dried, filtered and concentrated to dryness to give the title compound as a colorless oil (120 mg, 66% yield), which was used directly in the next reaction without purification.

[0262] Step 6: 4,4-Dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-2-sulfonamide

[0263] 4,4-Dimethyl-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-2-sulfonyl chloride (120 mg, 0.48 mmol) was dissolved in NH 3 The mixture was stirred at room temperature for 1 hour in 2% 4% dextrin / THF (20 mL, 2 M). The mixture was poured into ice water and extracted with DCM (3×10 mL). The combined organic phases were washed with water and brine, and then purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (40 mg, 36% yield) as a white solid. LC / MS (ESI) m / z: 232 (M+H) + .

[0264] Intermediate A6: 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide

[0265]

[0266] Step 1: 3-iodo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole-5-carbaldehyde

[0267] 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 hours. 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 hours. The reaction mixture was poured into saturated NH 4The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc / PE) to give the title compound (1.1 g, 50.6% yield) as a light yellow oil. LC / MS (ESI) (m / z): 351 (M+H) + .

[0268] Step 2: (3-iodo-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-5-yl)methanol

[0269] 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 NaBH in portions at 0 °C. 4 (178 mg, 4.7 mmol), and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was poured into ice water and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-20% EtOAc / PE) to give the title compound (950 mg, 85.8% yield) as a colorless oil. LC / MS (ESI) (m / z): 353 (M+H) + .

[0270] Step 3: 2-(5-(Hydroxymethyl)-3-iodo-1H-pyrazol-1-yl)ethan-1-ol

[0271] 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 hour. The mixture was filtered, and the filter cake was washed with PE and dried under vacuum to give the title compound as a white solid (500 mg, 72.9% yield). LC / MS (ESI) (m / z): 269 (M+H) + .

[0272] Step 4: 2-(5-(hydroxymethyl)-3-iodo-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate

[0273] 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 hours. The mixture was diluted with DCM, washed with water and brine, and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (240 mg, 50.7% yield) as a colorless oil. LC / MS (ESI) (m / z): 423 (M+H) + .

[0274] Step 5: 2-iodo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine

[0275] To a solution of 4-methylbenzene-1-sulfonic acid 2-[5-(hydroxymethyl)-3-iodo-1H-pyrazol-1-yl]ethyl ester (240 mg, 0.57 mmol) in THF (2 mL) was added NaH (68 mg, 1.7 mmol, 60% dispersion in mineral oil) portionwise at 0°C, and the mixture was stirred at room temperature for 1 hour. The mixture was poured into saturated NH 4 The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc / PE) to give the title compound (140 mg, 98.5% yield) as a light yellow oil. LC / MS (ESI) (m / z): 251 (M+H) + .

[0276] Step 6: 2-(Benzylthio)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine

[0277] In N 2 To a mixture of 2-iodo-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine (150 mg, 0.60 mmol), phenylmethyl mercaptan (0.07 mL, 0.6 mmol) and DIPEA (0.3 mL, 1.8 mmol) in 1,4-dioxane (10 mL) was added Pd 2 (dba) 3(110 mg, 0.1 mmol), XantPhos (139 mg, 0.2 mmol). The mixture was stirred under N 2 Degassing three times under atmosphere and stirring at 100° C. for 2 hours. The mixture was concentrated to dryness and the residue was purified by flash chromatography (silica gel, 0-40% EtOAc / PE) to give the title compound (140 mg, 94.7% yield) as a yellow oil. LC / MS (ESI) (m / z): 247 (M+H) +

[0278] Step 7: 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonyl chloride

[0279] 2-(Benzylthio)-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine (140 mg, 0.57 mmol) was added to H at 0 °C. 2 NCS (379 mg, 2.8 mmol) was added in portions to a solution of 2% 4-nitropropene (1 mL) and AcOH (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with EtOAc (2×5 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (90 mg, 70.9% yield) as a light yellow oil. LC / MS (ESI) (m / z): 223 (M+H) +

[0280] Step 8: 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide

[0281] 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 NH 3 / THF (2 mL, 1 M), and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated under vacuum to give the title compound as a white solid (55 mg, 86.2% yield). LC / MS (ESI) (m / z): 204 (M+H) + .

[0282] Intermediate A7: 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-sulfonamide

[0283]

[0284] Step 1: 5-(Hydroxymethyl)-N,N-bis[(4-methoxyphenyl)methyl]-1-(oxan-2-yl)-1H-pyrazole-4-sulfonamide

[0285] 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 minutes. Paraformaldehyde (380 mg, 12.7 mmol) was added and the mixture was stirred at -70 °C to room temperature for 2 hours. The reaction was poured into ice water and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-40% EtOAc / PE) to give the title compound (1.2 g, 56% yield) as a brown oil. LC / MS (ESI) (m / z): 323 (M+H) + .

[0286] Step 2: N,N-bis[(4-methoxyphenyl)methyl]-1-(oxan-2-yl)-5-{[2-(oxan-2-yloxy)ethoxy]methyl}-1H-pyrazole-4-sulfonamide

[0287] 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 minutes, 2-(2-bromoethoxy)oxane (150 mg, 0.72 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into ice water and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-60% EtOAc / PE) to give the title compound (270 mg, 72% yield) as a colorless oil. LC / MS (ESI) (m / z): 462 (M-2THP+H) + .

[0288] Step 3: 5-[(2-Hydroxyethoxy)methyl]-N,N-bis[(4-methoxyphenyl)methyl]-1H-pyrazole-4-sulfonamide

[0289] 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 HCl aqueous solution (3 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with ice water and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-8% MeOH / DCM) to give the title compound (150 mg, 76% yield) as a colorless oil. LC / MS (ESI) (m / z): 462 (M+H) + .

[0290] Step 4: N,N-bis[(4-methoxyphenyl)methyl]-4H,6H,7H-pyrazolo[3,2-c][1,4]oxazine-3-sulfonamide

[0291] In N 2 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 cyanomethylenetri-n-butylphosphine (157 mg, 0.6 mmol) under atmosphere, and the mixture was stirred at 120° C. for 2 hours under a CEM microwave reactor. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0-60% EtOAc / PE) to give the title compound (100 mg, 69% yield) as a pale yellow solid. LC / MS (ESI) (m / z): 444 (M+H) + .

[0292] Step 5: 6,7-Dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3-sulfonamide

[0293] 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 hours. The mixture was concentrated to dryness and the residue was purified by flash chromatography (silica gel, 0-60% EtOAc / PE) to give the title compound (35 mg, 86.1% yield) as a yellow solid. LC / MS (ESI) (m / z): 204 (M+H) + .

[0294] Intermediate A8: 7-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide

[0295]

[0296] Step 1: Ethyl 3-iodo-1H-pyrazole-5-carboxylate

[0297] at -10 °C in N 2 Under atmosphere, isoamyl nitrite (15.6 mL, 116 mmol) was added to a solution of ethyl 5-amino-1H-pyrazole-3-carboxylate (2 g, 12.9 mmol) in diiodomethane (30 mL) over 20 minutes. The mixture was stirred at room temperature for 1 hour and at 90 ° C for another 1 hour. The mixture was diluted with EtOAc (20 mL) and then with saturated Na 2 S 2 O 3 The mixture was washed with aqueous solution, 1N aqueous HCl and brine, and then with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc / PE) to give the title compound (1.4 g, 40.8% yield) as a yellow solid. LC / MS (ESI) m / z: 266 (M+H) + .

[0298] Step 2: 1-(1-cyclopropyl-2-ethoxy-2-oxoethyl)-3-iodo-1H-pyrazole-5-carboxylic acid ethyl ester

[0299] To a mixture of ethyl 3-iodo-1H-pyrazole-5-carboxylate (1.27 g, 4.76 mmol) and ethyl 2-bromo-2-cyclopropylacetate (920 mg, 4.76 mol) in MeCN (10 mL) was added K 2 CO 3(1.97 g, 14.3 mmol), and the mixture was stirred at 80° C. for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, and washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to dryness.The residue was purified by flash chromatography (silica gel, 0-9% EtOAc / PE) to give the title compound (1.4 g, 75% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 )δ7.00(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,J=7.1Hz,3H),1.24(t,J=7.1Hz,3H),0.97-0.86(m,1H),0.69-0.60(m,2H),0.69-0.60(m,1H). LC / MS(ESI)m / z:393(M+H) + .

[0300] Step 3: 3-(Benzylthio)-1-(1-cyclopropyl-2-ethoxy-2-oxoethyl)-1H-pyrazole-5-carboxylic acid ethyl ester

[0301] In N 2 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 Pd 2 (dba) 3 (171 mg, 0.19 mmol). The mixture was stirred at N 2 Degassed three times under atmosphere and stirred at 90° C. overnight. The mixture was diluted with EtOAc, washed with water and brine, and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-25% EtOAc / PE) to give the title compound (400 mg, 88% yield) as a yellow oil. LC / MS (ESI) m / z: 389 (M+H) + .

[0302] Step 4: 2-(3-(Benzylthio)-5-(hydroxymethyl)-1H-pyrazol-1-yl)-2-cyclopropylethan-1-ol

[0303] At 0°C in N 2 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 LiAlH 4 (118 mg, 3.09 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction was heated at 0 °C with Na 2 SO 4 .10H 2 O quenched and filtered. The filtrate was concentrated to dryness to give the title compound as a yellow solid (200 mg, 63.9% yield). LC / MS (ESI) m / z: 305 (M+H) + .

[0304] Step 5: 2-(Benzylthio)-7-cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine

[0305] At 0°C in N 2 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) under atmosphere, and the mixture was stirred at room temperature for 0.5 hours. 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 hour, the mixture was quenched with ice water and extracted with EtOAc (2×10 mL). The combined organic layers were washed with water and brine, and the mixture was stirred at room temperature for 0.5 hours. 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc / PE) to give the title compound (70 mg, 62% yield) as a yellow oil. LC / MS (ESI) m / z: 287 (M+H) + .

[0306] Step 6: 7-Cyclopropyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-sulfonamide

[0307] To 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 H 2To a solution of 4% paraformaldehyde (2 mL) in 4% paraformaldehyde (1% paraformaldehyde) was added NCS (135 mg, 1.0 mmol), and the mixture was stirred at 0° C. for 1 hour. The mixture was diluted with DCM, washed with water and brine, and washed with anhydrous Na 2 SO 4 Dry and filter. Add the filtrate to NH 3 / THF solution (10 mL, 1 M), and the resulting mixture was stirred at 0°C for 0.5 hours. The mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, 0-50% EtOAc / PE) to give the title compound (45 mg, 66.3% yield) as a colorless oil. LC / MS (ESI) m / z: 244 (M+H) + .

[0308] Intermediate A9: 1-cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonamide

[0309]

[0310] Step 1: Methyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)acetate

[0311] 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 dry 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 hour. The reaction mixture was poured into ice water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc / PE) to give the title compound (10 g, 90.3% yield) as a light yellow solid. LC / MS (ESI) (m / z): 291 / 293 (M+H) + .

[0312] Step 2: 7-Bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

[0313] 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 hour. The mixture was filtered through celite and the filtrate was poured into water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness under reduced pressure. The residue is purified by flash chromatography (silica gel, 0-25% EtOAc / 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) + .

[0314] Step 3: 7-Bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

[0315] 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 BH 3 -THF complex (90mL, 90mmol, 1M in THF), and the mixture was stirred at 70°C for 1 hour. The reaction was quenched with MeOH at 0°C, and the mixture was concentrated to dryness. The residue was dissolved in EtOH (20mL) and 6N HCl aqueous solution (5mL), and the mixture was stirred at 80°C for 2 hours. The mixture was basified with 1N NaOH aqueous solution and extracted with EtOAc (3×20mL). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc / 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) + .

[0316] Step 4: 7-Bromo-1-cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

[0317] 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 Na 2 CO 3 (1.30 g, 11.5 mmol), and the mixture was heated at 70 °C in O 2 Stir under atmosphere for 16 hours. Filter the mixture and dilute the filtrate with DCM, wash with water and brine, 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-18% EtOAc / PE) to give the title compound (1.2 g, 52.3% yield) as a white solid. LC / MS (ESI) (m / z): 255 (M+H) + .

[0318] Step 5: 7-(Benzylthio)-1-cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

[0319] In N 2 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 phenylmethyl mercaptan (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 mmol) and Pd 2 (dba) 3 (45 mg, 0.049 mmol), the mixture was stirred under N 2 The mixture was degassed three times in an atmosphere and stirred at 120°C for 16 hours. The mixture was diluted with EtOAc, washed with water and brine, and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness under reduced pressure. The residue was purified by chromatography (silica gel, 0-17% EtOAc / PE) to give the title compound (580 mg, 93.2% yield) as a yellow solid. LC / MS (ESI) (m / z): 299 (M+H) + .

[0320] Step 6: 1-Cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-sulfonamide

[0321] 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 hour. The mixture was poured into water and extracted with DCM (2×5 mL). The combined organic layers were washed with brine and washed with anhydrous Na 2 SO 4 Dry and filter. Add the filtrate to NH 3 / THF solution (5 mL, 1 M) 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 / PE) to give the title compound (35 mg, 50.7% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ7.88(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) + .

[0322] Intermediate A10: (S)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide

[0323]

[0324] Step 1: 1-Acetyl-1,2-dihydro-pyrazol-3-one

[0325] 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 hour. 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) + .

[0326] Step 2: 1-(3-{[(2S)-oxiran-2-yl]methoxy}-1H-pyrazol-1-yl)ethan-1-one

[0327] At 0°C in N 2 1-Acetyl-2,3-dihydro-1H-pyrazol-3-one (5 g, 39.6 mmol) and PPh 3 To a mixture of 4-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2- + .

[0328] Step 3: 1-{3-[(2R)-3-chloro-2-hydroxypropoxy]-1H-pyrazol-1-yl}ethan-1-one

[0329] 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) were 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 and washed with saturated NaHCO 3 The mixture was washed with aqueous solution and brine, and then with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness to give the title compound as a yellow oil (6 g, 99% yield), which was used directly in the next reaction without purification. LC / MS (ESI) (m / z): 219 (M+H) + .

[0330] Step 4: (6S)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazin-6-ol

[0331] 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 K 2 CO 3(11.4 g, 82.3 mmol), and the mixture was stirred at 100° C. for 3 hours. The mixture was diluted with EtOAc, washed with water and brine, and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-10% DCM / MeOH) to give the title compound (3 g, 78% yield) as a white solid. LC / MS (ESI) (m / z): 141 (M+H) + .

[0332] Step 5: (6S)-6-Methoxy-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine

[0333] 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 hours. MeI (1.99 mL, 32.1 mmol) was added, and the resulting mixture was stirred at 25°C for 4 hours. The mixture was quenched with ice water and extracted with EtOAc (2×10 mL). The combined organic layers were washed with saturated NH 4 The mixture was washed with aqueous Cl solution and brine and then with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-5% DCM / MeOH) to give the title compound (2.9 g, 87.9% yield) as a white solid. LC / MS (ESI) (m / z): 155 (M+H) + .

[0334] Step 6: (6S)-6-Methoxy-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-sulfonic acid

[0335] 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 hours. The mixture was concentrated to dryness to give the title compound as a yellow oil (3 g, 98% yield), which was used directly in the next reaction without purification. LC / MS (ESI) (m / z): 235 (M+H) + .

[0336] Step 7: (6S)-6-Methoxy-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-sulfonyl chloride

[0337] 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 PCl 5 (8.0 g, 38.4 mmol), and the mixture was stirred at room temperature for 4 hours. The mixture was poured into ice water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with saturated NaHCO 3 The mixture was washed with aqueous solution and brine, and then with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-10% EtOAc / PE) to give the title compound (3 g, 92% yield) as a white solid. LC / MS (ESI) (m / z): 253 (M+H) + .

[0338] Step 8: (6S)-6-Methoxy-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine-3-sulfonamide

[0339] 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) at 0 °C was added NH 3 To the mixture was added 4-nitro-1-yl pyridine-2 ... 1 H NMR (400 MHz, DMSO-d 6 )δ7.49(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) + .

[0340] Intermediate B1: 5-(imidazo[1,2-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-amine

[0341]

[0342] Step 1: N-(2,3-dihydro-1H-inden-4-yl)acetamide

[0343] 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 Ac dropwise at 0 °C. 2 O (767 mg, 7.52 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted with DCM (2×10 mL). The combined organic layers were washed with brine and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness to give the title compound as a white solid (1.1 g, 91.8% yield). LC / MS (ESI) m / z: 176 (M+H) + .

[0344] Step 2: N-(5-bromo-2,3-dihydro-1H-inden-4-yl)acetamide

[0345] N-(2,3-dihydro-1H-inden-4-yl)acetamide (780 mg, 4.50 mmol), PTSA (460 mg, 2.44 mmol) and Pd(OAc) were mixed. 2 A mixture of 4-nitropropene (38 mg, 0.17 mmol) in toluene (10 mL) was stirred at room temperature under 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 and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-30% EtOAc / PE) to give the title compound (700 mg, 61.9% yield) as a white solid. LC / MS (ESI) m / z: 255 (M+H) + .

[0346] Step 3: 5-Bromo-2,3-dihydro-1H-inden-4-amine

[0347] 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 saturated with NaHCO 3The aqueous solution was basified to pH about 8. The mixture was extracted with EtOAc (3 x 10 mL), and the combined organic layers were washed with Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-16% EtOAc / PE) to give the title compound (300 mg, 55.3% yield) as a grey solid. LC / MS (ESI) m / z: 212 (M+H) + .

[0348] Step 4: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-4-amine

[0349] In N 2 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'-di(1,3,2-dioxaborolane) (780 mg, 3.07 mmol) in 1,4-dioxane (8 mL) was added KOAc (463 mg, 4.72 mmol) and Pd(dppf)Cl under atmospheric pressure. 2 (173 mg, 0.24 mmol). The mixture was stirred at N 2 The mixture was degassed three times under a 3% CO atmosphere and stirred at 100 °C for 3 h. The mixture was diluted with EtOAc and washed with saturated NH 4 The mixture was washed with aqueous Cl solution and brine and then with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-5% EtOAc / PE) to give the title compound (200 mg, 32.7% yield) as a yellow solid. LC / MS (ESI) (m / z): 260 (M+H) + .

[0350] Step 5: 5-(Imidazolo[1,2-a]pyridin-7-yl)-2,3-dihydro-1H-inden-4-amine

[0351] In N 2 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) were dissolved in 1,4-dioxane (5 mL) and H 2 O under atmosphere. 2 O (1 mL) was added to the mixture 2 CO 3(333 mg, 2.41 mmol), followed by the addition of Pd(dppf)Cl 2 (71 mg, 0.09 mmol). The mixture was stirred under N 2 Degassed three times under a 4% CO atmosphere and stirred at 100° C. for 2 hours. The mixture was diluted with EtOAc (20 mL), washed with water and brine, and purified by Na 2 SO 4 Dried, filtered and concentrated to dryness.The residue was purified by flash chromatography (silica gel, 0-5% MeOH / DCM) to give the title compound (150 mg, 62.4% yield) as a yellow solid. 1 HNMR (400MHz, CDCl 3 )δ8.16(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), 6.77 (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) + .

[0352] Intermediate B7: 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine

[0353]

[0354] Step 1: N-(2,3-dihydro-1H-inden-5-yl)acetamide

[0355] 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 hour. The mixture was quenched with water and extracted with DCM (3×30 mL). The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness to give the title compound as a yellow solid (5.9 g, 89.7% yield). 1 HNMR (400MHz, CDCl 3)δ7.44(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) + .

[0356] Step 2: N-(6-bromo-2,3-dihydro-1H-inden-5-yl)acetamide

[0357] To a solution of N-(2,3-dihydro-1H-inden-5-yl)acetamide (5.9 g, 33.7 mmol) in AcOH (90 mL) was added Br dropwise over a period of 1 h at 10 °C. 2 (2.08 mL, 40.4 mmol). After stirring for another 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 with brine, saturated NaHCO 3 Aqueous solution and saturated NaHSO 3 Wash with aqueous solution and 2 SO 4 Dry, filter and concentrate to dryness to give the title compound as a white solid (7 g, 81.8% yield). 1 H NMR (400 MHz, CDCl 3 )δ7.44(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) + .

[0358] Step 3: N-(6-bromo-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide

[0359] 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) was added a pre-cooled mixture of sulfuric acid (20 mL) and nitric acid (24.8 mL, 275.5 mmol) dropwise below 20 °C for 1 hour, and the resulting mixture was stirred at room temperature for an additional 1 hour. The mixture was poured into ice water and stirred at 0 °C for 2 hours. The mixture was filtered, and the filter cake was washed with water and purified by Na 2 SO 4 Dry, filter and concentrate to dryness to give the title compound as a brown solid (7.3 g, 88.6% yield). 1 H NMR (400 MHz, CDCl 3)δ7.65(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) + .

[0360] Step 4: N-(6-methyl-4-nitro-2,3-dihydro-1H-inden-5-yl)acetamide

[0361] In N 2 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-trioxatriborane (11.7 mL, 46.8 mmol) and K were added under atmosphere. 2 CO 3 (34.7 g, 251 mmol) was dissolved in 1,4-dioxane (70 mL) and H 2 O (15 mL) was added to the mixture with Pd(dppf)Cl 2 (1.71 g, 2.34 mmol), the mixture was stirred under N 2 Degassed three times under a 4% CO atmosphere and stirred at 100° C. for 16 h. The mixture was diluted with EtOAc, washed with water and brine, and washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to dryness.The residue was purified by flash chromatography (0-20% EtOAc / PE) to give the title compound (2.9 g, 52.9% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 )δ7.74(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) + .

[0362] Step 5: 6-Methyl-4-nitro-2,3-dihydro-1H-inden-5-amine

[0363] 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 2M NaOH aqueous solution. The mixture was extracted with DCM (2×20 mL), and the combined organic layers were washed with water and brine, washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness to give the title compound as a yellow solid (2.1 g, 88.3% yield). 1 H NMR (400 MHz, CDCl 3 )δ7.15(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) + .

[0364] Step 6: 5-Bromo-6-methyl-4-nitro-2,3-dihydro-1H-indene

[0365] 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) were dissolved in CH 3 The mixture in CN (30 mL) was heated to 55 °C and stirred under N 2 Add CuBr under atmosphere 2 (2.44 g, 10.9 mmol), and the mixture was stirred at 70 ° C for 1 hour. The reaction mixture was cooled to room temperature and 1M HCl aqueous solution (20 mL) was added. The reaction mixture was extracted with DCM (3×20 mL), and the combined organic layers were washed with brine and purified by Na 2 SO 4 Dried, filtered and concentrated to dryness.The residue was purified by flash chromatography (silica gel, 0-10% EtOAc / PE) to give the title compound (1.7 g, 60.8% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ7.49(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) + .

[0366] Step 7: 5-Bromo-6-methyl-2,3-dihydro-1H-inden-4-amine

[0367] 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 NH 4 Cl aqueous solution (4 mL) and Fe (3.7 g, 66.4 mmol) were added and the mixture was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction was diluted with EtOAc (30 mL) and filtered through a celite pad. The filtrate was washed with water and brine and purified by anhydrous MgSO 4 Dry, filter and concentrate to dryness.The residue was purified by flash chromatography (silica gel, 0-10% EtOAc / PE) to give the title compound (1.4 g, 93.3% yield) as a pink solid. 1 H NMR (400 MHz, DMSO-d 6 )δ6.47(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) + .

[0368] Step 8: 6-methyl-5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine

[0369] In N 2 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 K 2 CO 3 (260 mg, 1.9 mmol), followed by the addition of Pd(dppf)Cl 2 (50 mg, 0.07 mmol). The mixture was stirred under N 2 The mixture was degassed three times under a 4% CO atmosphere and stirred at 90° C. for 16 hours. After cooling, the reaction was diluted with EtOAc and filtered through a celite pad. The filtrate was washed with water and brine and purified by anhydrous Na 2 SO 4Dried, filtered and concentrated to dryness.The residue was purified by flash chromatography (silica gel, 0-40% EtOAc / PE) to give the title compound (110 mg, 67.7% yield) as a white solid. 1 HNMR (400MHz, CDCl 3 )δ8.55(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) + .

[0370] The intermediates in Table 1 below were prepared by using methods and starting materials similar to those used to prepare the intermediates as described herein.

[0371] Table 1

[0372]

[0373]

[0374]

[0375] 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

[0376]

[0377] At 0°C in N 2 Under atmosphere, 5-(pyrazolo[1,5-a]pyridin-5-yl)-2,3-dihydro-1H-inden-4-amine (Intermediate B5, 30 mg, 0.12 mmol) and Et 3To a mixture of N (36 mg, 0.36 mmol) in THF (3 mL) was added triphosgene (21 mg, 0.07 mmol) in batches. After stirring at 0 ° C for 0.5 hours, 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) was added NaH (22 mg, 0.54 mmol, 60% dispersed in mineral oil) in batches at 0 ° C, and after stirring at 0 ° C for 0.5 hours, the above filtrate was added dropwise to the mixture. The resulting mixture was stirred at room temperature for 0.5 hours. The mixture was poured into ice water and acidified to pH about 4 with 1N HCl aqueous solution. The mixture was extracted with EtOAc (3×10 mL), and the combined organic layers were washed with brine and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by preparative HPLC (C 18 , 10-80% acetonitrile / H 2 (0) to give the title compound (10 mg, 10.7% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.56(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,1H),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) + .

[0378] 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

[0379]

[0380] 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. 1 H NMR (400 MHz, DMSO-d 6 )δ8.54(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) + .

[0381] 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

[0382]

[0383] 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. 1 H NMR (400 MHz, DMSO-d 6)δ8.97(d,J=6.8Hz,1H),8.17(s,1H),7.83(s,1H),7.21(s,2H),7.08(d,J =6.7Hz,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) + .

[0384] 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

[0385]

[0386] 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. 1 H NMR (400 MHz, DMSO-d 6 )δ8.80(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),1.1 4-1.06(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) + .

[0387] 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

[0388]

[0389] 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. 1 H NMR (400 MHz, DMSO-d 6 )δ8.57(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 =7.4Hz,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) + .

[0390] 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

[0391]

[0392] 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. 1 H NMR (400 MHz, DMSO-d 6 )δ8.55(s,1H),8.00(d,J=2.1Hz,1H),7.64(d,J=9.2Hz,1H),7.15(d,J=9.9Hz,3H),6.6 2(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=13.8,6.7Hz,1H),2.92(t,J=7.4Hz,2H),2.73(t,J=7.2Hz,2H),2.04-1.94(m,2H) ,1.15(t,J=7.3Hz,1H),0.66(d,J=8.0Hz,1H),0.57(d,J=4.4Hz,1H),0.52-0.42(m,2H). LC / MS(ESI)m / z:519(M+H) + .

[0393] 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

[0394]

[0395] 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. 1 H NMR (400 MHz, DMSO-d 6)δ8.80(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),1.1 4-1.06(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) + .

[0396] 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

[0397]

[0398] 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. 1 H NMR (400 MHz, DMSO-d 6 )δ8.81(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,1H),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) + .

[0399] 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

[0400]

[0401] 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. 1 H NMR (400 MHz, DMSO-d 6 )δ8.58(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,3 H), 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) + .

[0402] 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

[0403]

[0404] 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. 1 H NMR (400 MHz, DMSO-d 6 )δ8.38(s,1H),8.29(d,J=7.3Hz,1H),7.43(s,1H),7.34(s,1H),7.15(q,J=8.0Hz,2 H),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) + .

[0405] 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

[0406]

[0407] 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. 1 H NMR (400 MHz, DMSO-d 6)δ8.53(d,J=6.9Hz,1H),7.98(s,1H),7.61(s,1H),7.44(s,1H),7.21(q,J=7.6Hz,2 H),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) + .

[0408] 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

[0409]

[0410] 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. 1 H NMR (400 MHz, DMSO-d 6)δ8.35(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) + .

[0411] 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

[0412]

[0413] 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. 1 H NMR (400 MHz, DMSO-d 6)δ8.86(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) + .

[0414] 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

[0415]

[0416] 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. 1 H NMR (400 MHz, DMSO-d 6)δ9.21(d,J=9.4Hz,1H),8.48(d,J=14.7Hz,1H),7.63(d,J=9.6Hz,1H),7.3 5(d,J=8.8Hz,1H),7.12(s,2H),6.29(s,1H),4.26(s,1H),4.04(s,1H),3.9 4(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) + .

[0417] 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

[0418]

[0419] 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. 1 H NMR (400 MHz, DMSO-d 6 )δ8.55(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) + .

[0420] 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

[0421]

[0422] 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. 1 HNMR (400MHz, CDCl 3 )δ8.34(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) + .

[0423] 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

[0424]

[0425] 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. 1 H NMR (400 MHz, DMSO-d 6 )δ8.59(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=28.8 Hz,2H),2.87-2.88(m,2H),2.68-2.69(m,2H),2.35(d,J=8.3Hz,4H),2.0 5(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) + .

[0426] 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

[0427]

[0428] 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. 1 H NMR (400 MHz, DMSO-d 6)δ8.61(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=8.0Hz,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) + .

[0429] 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

[0430]

[0431] 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

[0432] 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 hours. The mixture was poured into ice water and acidified to pH about 4 with 1N HCl aqueous solution. The mixture was extracted with EtOAc (3×10 mL), and the combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness. The residue was purified by flash chromatography (silica gel, 0-8% MeOH / PE) to give the title compound (100 mg, 64% yield) as a white solid. LC / MS (ESI) m / z: 633 (M+H) + .

[0433] 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

[0434] 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 hour. The reaction was poured into NaHCO 3 The combined organic layers were washed with brine and purified by Na 2 SO 4 Dried, filtered and concentrated to dryness.The residue was purified by preparative HPLC to give the title compound as a white solid (15 mg, 18% yield). 1H NMR (400 MHz, DMSO-d 6 )δ11.69(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,2 H), 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) + .

[0435] 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

[0436]

[0437] 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 (400 MHz, DMSO-d 6)δ11.67(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,1 H), 4.05 (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) + .

[0438] 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

[0439]

[0440] 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. 1 H NMR (400MHz, CD 3 OD)δ8.13(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) + .

[0441] 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

[0442]

[0443] 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, CD 3 OD)δ8.50(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,1H),4.15-4.09(m,4H),2.93(t,J=7.4Hz,2H),2.68(dd,J=16.6,8.0Hz,2H),2.10(s,3H),2.06-2.00(m,2H),1.53(s,6H). LC / MS(ESI)m / z:521(M+H) + .

[0444] 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

[0445]

[0446] 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, CD 3OD)δ8.47(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) + .

[0447] 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

[0448]

[0449] 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. 1 HNMR (400 MHz, DMSO-d 6 )δ8.51-8.43(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,1H),4.40(s,3H),2.92(s,2H),2.70-2.66(m,2H),2.37-2.23(m,2 H), 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) + .

[0450] 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

[0451]

[0452] 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. 1 H NMR (400 MHz, DMSO-d 6 )δ8.51(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) + .

[0453] 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

[0454]

[0455] 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. 1H NMR (400MHz, CD 3 OD)δ8.45(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) + .

[0456] 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

[0457]

[0458] 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 (400 MHz, DMSO-d 6 )δ8.62(d,J=19.4Hz,1H),8.03(s,1H),7.47(s,1H),7.40(s,1H),7.07(s ,1H),6.59(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,3 H),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) + .

[0459] 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

[0460]

[0461] 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) + .

[0462] 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

[0463]

[0464] 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 (400 MHz, DMSO-d 6)δ8.41(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),4.5 6(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) + .

[0465] 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

[0466]

[0467] 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 (400 MHz, DMSO-d 6 )δ8.30(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),3.38(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) + .

[0468] Biological Research

[0469] The following method was used for compound screening.

[0470] 1. THP-1 cells (5.56*10^5 cells / mL) containing 1.0ug / mL LPS (Sigma, L6529) in 45uL RPMI 1640 medium (without FBS) were seeded into a 384-well plate (Thermo Scientific, 164688).

[0471] 2. Add 5uL of compound (10 doses, starting at 5uM, 1:3 dilution) or vehicle (0.05% DMSO in culture medium) to appropriate wells.

[0472] 3. Centrifuge the plate at 1000 rpm for 2 minutes and incubate at 37°C, 5% CO 2 Incubate for 3 hours.

[0473] 4. Add 5uL of nigericin (MEC, HY-100381) (final concentration 5uM) to the sample wells and positive control wells; add 5uL of RPMI 1640 medium to the negative control wells.

[0474] 5. Centrifuge the plate at 1000 rpm for 2 minutes and incubate at 37°C, 5% CO2 for 1 hour.

[0475] 6. At the end of the incubation period, the plate was centrifuged at 1000 rpm for 6 minutes and 8 uL of the supernatant was transferred to a 384-well assay plate (PerkinElmer, 6008280).

[0476] 7. Add 8ul RPMI 1640 medium to each well and spin down for 10 seconds.

[0477] 8. Prepare the standard solution and premixed IL1β antibody solution of the human IL1β kit (PerkinElmer, 62HIL1BPEH) according to the instructions.

[0478] 9. Add 16uL of standard solution to the clear wells of the 384-well assay plate.

[0479] 10. Add 4uL of premixed IL1β antibody solution to all wells, including sample wells, positive control wells, negative control wells, and standard solution wells.

[0480] 11. Seal the plate, spin down for 10 seconds, incubate overnight at room temperature, and The data were read on a compatible reader (BMG LABTECH, PHERAstar FS).

[0481] 12. Calculate the IL1β concentration of the treated wells using the standard curve.

[0482] 13. Place IC 50 Data were fitted to a nonlinear regression equation (log inhibitor vs. response - variable slope with four parameters). The results of the pyroptosis assay were used as THP IC 50 They are summarized in Table 2 below. *

[0483] Table 2

[0484] Instance Number <![CDATA[THP IC 50 ]]> Instance Number <![CDATA[THP IC 50 ]]> 1 A 16 B 2 B 17 A 3 A 18 A 4 B 19 C 5 A 20 B 6 B 21 B 7 B 22 A 8 B 23 A 9 A 24 A 10 B 25 A 11 B 26 B 12 B 27 A 13 B 28 A 14 C 29 A 15 A 30 A

[0485] *NLRP3 inhibitory activity-THP IC 50 :A: ≤100nM; B: >100nM and ≤500nM; C: >500nM and ≤1uM.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, in: Ring A is a fused 6,5-bicyclic aryl or heteroaryl ring system, wherein the heteroaryl ring system includes 1, 2, 3 or 4 nitrogen atoms as ring members, and the ring A carries R 5 and R 6 substituent, and in the group selected from R 7 or R 9 The ring carbon of the present invention carries 1, 2 or 3 substituents, and / or is selected from R 8 and R 10 The ring nitrogen of the compound carries 1 or 2 substituents; Ring Q is a fused 6,5-bicyclic heteroaryl or fused 6,6-bicyclic heteroaryl ring system, which includes 1, 2 or 3 nitrogen atoms as ring members, and optionally includes 1 or 2 ring members selected from O, S or S(═O2), wherein the ring Q carries R as indicated by formula (I): 1 and R 2 substituent, and optionally carrying 1 or 2 R 12 Substituents; R 1 is independently hydrogen, C 1-4 Alkyl, halogenated C 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 NR b C(=O)R a 、C(=O)NHC(=O)R a or a 4-6 membered heterocyclic group, each of which is optionally substituted by one to three R 11 replace; R 2 C independently at each occurrence 1-4 Alkyl, halogenated C 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 a 4-6 membered heterocyclic group, each of which is optionally substituted by one to two R 11 Substitution, or two R in geminal position 2 The group can optionally form a spiro C 3-5 Cycloalkyl; R 3 and R 4 are independently hydrogen, halogen, CN, C 1-4 Alkyl or halogenated C 1-4 alkyl; R 7 is independently hydrogen or C 1-4 alkyl; R 8 is independently hydrogen or C 1-4 alkyl; R 9 is independently hydrogen, C 1-4 Alkyl or C 1-4 Alkoxy; R 10 is independently hydrogen, C 1-4 Alkyl, C 3-7 Cycloalkyl or optionally C 1-4 Alkyl-substituted 4-6 membered heterocyclic group; R 11 C independently at each occurrence 1-4 Alkyl, halogenated C 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 NR b C(=O)R a 、C(=O)NHC(=O)R a or a 4-6 membered heterocyclic group; R 12 is independently hydrogen, C 1-4 Alkyl, halogenated C 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 a 4-6 membered heterocyclic group optionally substituted by one to three groups selected from the following: C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-7 Cycloalkyl, halogen, CN, OH, C 1-4 Alkoxy, C 3-7 Cycloalkoxy or NR a R b ; R a and R b is independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl, or R a and R b Together with the nitrogen atom to which it is attached, it forms a saturated or unsaturated heterocyclic ring containing three to seven ring atoms, which ring may optionally contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by one to three groups which may be the same or different and are selected from C 1-4 the group consisting of alkyl, phenyl and benzyl; and n is independently 0, 1 or 2 at each occurrence.

2. The compound according to claim 1, which has formula (II)-(IV): or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, in: Ring Q is independently Q 1 is independently N or CH at each occurrence, provided that at least one Q 1 is N; Q 2 is independently at each occurrence O, S, S(=O2), CH2 or NR 12 , X 1 and X 5 are each independently N or C; and X 2 , X 3 and X 4 Each independently is N or CR 7 , and the dotted circle represents the bond forming the five-membered aromatic ring; provided that X 1 , X 2 , X 3 , X 4 and X 5 At least two but no more than three of them are N; Y 1 N or CH, Y 2 Yes N, NR 8 or CH, and Y 3 Yes N, NR 8 or CH, and in formula (III) express Z 1 N or CH, Z 2 Is N or CR 9 , and Z 3 is N or CH; and R 1 –R 12 and R a and R b As defined in claim 1.

3. The compound according to claim 1, which has the structure of formula (II):

4. The compound according to claim 1 or 2, wherein yes 5. The compound according to claim 1, which has the structure of formula (III):

6. The compound according to claim 1 or 4, wherein yes 7. The compound according to claim 1, which has the structure of formula (IV):

8. The compound according to claim 1 or 6, wherein yes 9. A compound according to any one of claims 1 to 7, wherein ring Q is independently at each occurrence 10. A compound according to any one of claims 1 to 7, wherein ring Q is independently at each occurrence 11. A compound according to any one of claims 1 to 7, wherein ring Q is independently at each occurrence 12. A compound according to any one of claims 1 to 7, wherein ring Q is independently at each occurrence 13. A compound according to any one of claims 1 to 7, wherein ring Q is independently at each occurrence 14. A compound according to any one of claims 1 to 7, wherein ring Q is independently at each occurrence 15. A compound according to any one of claims 1 to 7, wherein ring Q is independently at each occurrence 16. A compound according to any one of claims 1 to 7, wherein ring Q is associated with R at each occurrence. 1 and R 2 Together and independently 17. A compound according to any one of claims 1 to 7, wherein ring Q is bound to R at each occurrence. 1 and R 2 Together and independently 18. A compound according to any one of claims 1 to 7, wherein ring Q is associated with R at each occurrence. 1 and R 2 Together and independently 19. A compound according to any one of claims 1 to 7, wherein ring Q is bound to R at each occurrence. 1 and R2 Together 20. A compound according to any one of claims 1 to 7, wherein ring Q is bound to R at each occurrence. 1 and R 2 Together 21. A compound according to any one of claims 1 to 7, wherein ring Q is associated with R at each occurrence. 1 and R 2 Together 22. A compound according to any one of claims 1 to 7, wherein ring Q is associated with R at each occurrence. 1 and R 2 Together 23. A compound according to any one of claims 1 to 21, wherein Q 1 is independently N or CH at each occurrence, provided that there is only one Q in each ring 1 It is N.

24. A compound according to any one of claims 1 to 22, wherein R 1 C independently at each occurrence 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-5 Cycloalkyl, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, NR a R b or a 4-6 membered heterocyclic group, each of which is optionally substituted by one to three R 11 replace.

25. A compound according to any one of claims 1 to 22, wherein R 1 C independently at each occurrence 1-4 Alkyl, cyclopropyl, cyclobutyl, C 1-4 Alkoxy, cyclopropyloxy, cyclobutyloxy, C 3-5 Cycloalkoxy, NR a R b or a 4-6 membered heterocyclic group, each of which is optionally substituted by one to three R 11 replace.

26. A compound according to any one of claims 1 to 24, wherein R 2 is independently hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-5 Cycloalkyl, halogen, CN, OH, C 1-4 Alkoxy, NR a R bor a 4-6 membered heterocyclic group, each of which is optionally substituted by one to two R 11 replace.

27. A compound according to any one of claims 1 to 25, wherein R 3 is independently at each occurrence hydrogen, methyl, F or Cl.

28. A compound according to any one of claims 1 to 26, wherein R 4 is independently at each occurrence hydrogen, methyl or halogen.

29. A compound according to any one of claims 1 to 27, wherein R 5 is independently at each occurrence hydrogen or methyl.

30. A compound according to any one of claims 1 to 28, wherein R 6 is independently at each occurrence hydrogen or methyl.

31. A compound according to any one of claims 1 to 29, wherein R 7 is independently at each occurrence hydrogen or methyl.

32. A compound according to any one of claims 1 to 30, wherein R 8 is independently at each occurrence hydrogen or methyl.

33. A compound according to any one of claims 1 to 31, wherein R 9 is independently at each occurrence hydrogen, methyl or methoxy.

34. A compound according to any one of claims 1 to 32, wherein R 10 is independently hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl or optionally C 1-4 The 4-6 membered heterocyclic group substituted by an alkyl group, wherein the 4-6 membered heterocyclic group contains one to two heteroatoms selected from N, O and S.

35. A compound according to any one of claims 1 to 33, wherein R 11 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 4-6 membered heterocyclic group, wherein the 4-6 membered heterocyclic group contains one to two heteroatoms selected from N, O and S.

36. A compound according to any one of claims 1 to 34, wherein R 12 is independently hydrogen, C 1-4 Alkyl, halogenated C 1-4Alkyl, 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 a 4-6 membered heterocyclic group optionally substituted by one to three groups selected from the following: C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 3-5 Cycloalkyl, halogen, CN, OH, C 1-4 Alkoxy, C 3-5 Cycloalkoxy or NR a R b , wherein the 4-6 membered heterocyclic group contains one to two heteroatoms selected from N, O and S.

37. The compound according to claim 1, selected from:

38. The compound according to claim 1, selected from:

39. A pharmaceutical composition comprising a compound according to any one of claims 1 to 37 and a pharmaceutically acceptable carrier.

40. A method for treating or preventing a disease or condition responsive to inhibition of NLRP3 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 37 or a pharmaceutical composition according to claim 38.

41. A method for treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 37 or a pharmaceutical composition according to claim 38, wherein the disease or condition is a genetic disease, a neurodegenerative disorder, a metabolic disease, an inflammatory syndrome, or cancer.

42. The method of claim 40, wherein the inherited disease is cryptopyrin-associated periodic syndrome; the neurodegenerative disorder is multiple sclerosis, Alzheimer's disease, or Parkinson's disease; the metabolic disease is atherosclerosis or type 2 diabetes; and the inflammatory syndrome is a gout attack or osteoarthritis.

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