New regulations for compounds

Abstract

This invention provides novel compounds for use as inhibitors of NLRP3 inflammasome generation. [Solution] A compound represented by formula (I) is provided. Preferably, R 1 However, C 1~3 Alkyl, -OH, and hydroxyC 1~3 C is optionally substituted with one or two substituents selected from alkyl groups. 3~6 This is a compound representing a cycloalkyl group. JPEG2026097809000192.jpg42170

Description

[Technical Field]

[0001] This invention relates to an inhibitor of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. This invention relates to novel compounds that are useful as such. The present invention also relates to a process for preparing the said compounds. Seth, a pharmaceutical composition containing the compound, and the use of the compound in the treatment of various diseases and disorders. Methods of use, drugs containing them, and diseases mediated by NLRP3 Regarding their use in relation to disabilities. [Background technology]

[0002] The inflammasome, considered a central signaling hub of the innate immune system, is a diverse and multifaceted Intracellular pattern recognition by pathogen or damage-related molecular patterns (PAMP or DAMP) It is a multiprotein complex that is constructed when a specific set of receptors (PRRs) is activated. To date, inflammasomes have been found to be nucleotide-binding oligomeric domains (NODs) Formed by receptors (NLRs) and proteins containing pyrin and HIN200 domains. It has been shown that this is possible (Van Opdenbosch N and Lamkanf i M.Immunity,2019 Jun 18;50(6):1352-1364 ). The NLRP3 inflammasome is composed of environmental crystals, pollutants, host-derived DAMP and tannins. Assembled when detecting protein aggregates (Tartey S and Kannegan) ti TD. Immunology, 2019 Apr;156(4):329-3 38). Clinically relevant DAMPs involved in NLRP3 include gout and atheroma. Uric acid and cholesterol crystals that cause uterine arteriosclerosis, and nerves in Alzheimer's disease. Examples include toxic amyloid-beta fibrils and asbestos particles that cause mesothelioma. (Kelley et al., Int J Mol Sci, 2019 Ju l 6;20(13)). Furthermore, NLRP3 is Vibrio c Infectious pathogens such as holerae; Aspergillus fumigatus Candida lus fumigatus) and Candida albicans Pathogenic fungi such as cans; adenovirus, influenza A virus, and SARS -Activated by CoV-2 (Tartey and Kanneganti, 2019 (see above); Fung et al. Obes Infect, 2020 Mar 14;9(1):558-570).

[0003] The detailed mechanism of NLRP3 activation remains unknown, but in human monocytes, it appears to be a one-step activation process. While one step is sufficient, it has been suggested that there is a two-step mechanism in mice. Considering the existence of various triggers, the NLRP3 inflammasome is at the transcriptional level. Add-on control is required at both the post-transcription and post-transcription levels (Yang Y et al., C ell Death Dis, 2019 Feb 12;10(2):128).

[0004] The NLRP3 protein has a nucleotide binding at the C-terminus following the N-terminal pyrin domain. (Sh) consists of site domains (NBDs) and leucine-rich repeat (LRR) motifs. arif et al.,Nature,2019 Jun;570(7761):33 8-343). After recognition of PAMP or DAMP, NLRP3 is an adapter protein. Apoptosis-related speck-like protein (ASC), and protease caspase-1 They aggregate to form a functional inflammasome. After activation, procaspase-1 automatically Through self-protein degradation, it ultimately cleaves gasdermin D (Gsdmd), and finally... This leads to pore formation in the vesicle membrane and a form of cell lysis called pyroptosis, which is a form of cell death. It generates an N-terminal Gsdmd molecule. Alternatively, caspase-1 produces inflammatory cytokines. Pro-IL-1β and pro-IL-18 are cleaved, and the organism undergoes pyroptosis. This allows for the release of scientifically active forms (see Kelley et al., 2019- above). (Referring to Teru).

[0005] Dysregulation of the NLRP3 inflammasome or its downstream mediators is associated with immunoinflammatory diseases. autoimmune / autoinflammatory diseases (Cryopyrin-associated Peri-inflammatory diseases) odic Syndrome(Miyamae T.Paediatr Drugs,2 012 Apr 1;14(2):109-17); Sickle cell disease; Systemic lupus erythematosus From SLE (Systemic Lupus Erythematosus) to liver damage (e.g., non-alcoholic steatohepatitis (NASH), chronic liver disease) Diseases, viral hepatitis, alcoholic steatohepatitis, and alcoholic liver disease) (Szab o G and Petrasek J.Nat Rev Gastroenterol Hepatol, 2015 Jul;12(7):387-400) and inflammatory bowel disease (For example, Crohn's disease, ulcerative colitis) (Zhen Y and Zhang H.Fr) (ont Immunol, 2019 Feb 28;10:276) and a number of other pathological conditions Related. Also, inflammatory joint disorders (e.g., gout, pseudogout (chondrocalcification), arthropathy, etc.) Arthritis and rheumatoid arthritis (Vande Walle L et al., Natu re,2014 Aug 7;512(7512):69-73) is related to NLRP3. It was added. Furthermore, kidney-related diseases (hyperoxaluria (Knauf et al., Kid ney Int, 2013 Nov;84(5):895-901), lupus nephritis, high Hypertensive nephropathy (Krishnan et al.,Br J Pharmacol,201 6 Feb;173(4):752-65), diabetes (type 1), also known as diabetic nephropathy. Hemodialysis-related inflammation and diabetic nephropathy (S) are kidney-related complications of diabetes mellitus (type 2 and diabetes mellitus). hahzad et al.,Kidney Int,2015 Jan;87(1): 74-84) is associated with NLRP3 inflammasome activation. Reports indicate neuritis Disease-related disorders (e.g., brain infections, acute injuries, multiple sclerosis, Alzheimer's disease) and neurological disorders The onset and progression of degenerative diseases (Parkinson's disease) are related to NLRP3 inflammasome activation. (Sarkar et al., NPJ Parkinsons Dis, (October 17, 2017; 3:30). In addition, recently, cardiovascular or metabolic disorders (e.g., heart Vascular risk reduction (CvRR), atherosclerosis, type 1 and type 2 diabetes and related conditions. Complications (e.g., nephropathy, retinopathy), peripheral artery disease (PAD), acute heart failure, and hypertension. (Ridker et al.,CANTOS Trial Group.N Engl. J Med, 2017 Sep 21;377(12):1119-1131; and T oldo S and Abbate A.Nat Rev Cardiol,2018 Apr;15(4):203-214) is associated with NLRP3. Also, Skin-related diseases were described (e.g., wound healing and scar formation; inflammatory skin diseases, e.g., contusions). Acne, hidradenitis suppurativa (Kelly et al.,Br J Dermatol,2015 Dec;173(6)). In addition, respiratory status is NLRP3 inflammasome activity (For example, asthma, sarcoidosis, severe acute respiratory syndrome (SARS) (Nieto- Torres et al., Virology, 2015 Nov;485:330- 9)) is associated with age-related macular degeneration (Doyle et al., Nat The same is true for several cancer-related cancers. Diseases / disorders described in association with NLRP3 (e.g., myeloproliferative neoplasms, leukemia) Diseases, myelodysplastic syndrome (MOS), myelofibrosis, lung cancer, colon cancer (Ridker et al.) l.,Lancet,2017 Oct 21;390(10105):1833-18 42;Derangere et al.,Cell Death Differ.20 14 Dec;21(12):1914-24;Basiorka et al.,La ncet Haematol,2018 Sep;5(9):e393-e402,Zh ang et al.,Hum Immunol,2018 Jan;79(1):57 -62).

[0006] Several patent application publications describe NLRP3 inhibitors, and those for bacteria, For example, International Patent Application International Publication No. 2020 / 018975 Brochure, and the same No. 2020 Pamphlet No. 037116, Pamphlet No. 2020 / 021447, Pamphlet No. 20 Pamphlet No. 20 / 010143, Pamphlet No. 2019 / 079119, Pamphlet No. 2019 / 0166621 and Pamphlet No. 2019 / 121691 are mentioned, and these disclose a wide range of specific compounds. WO 2019 / 0 07696 pamphlet discloses various compounds for the treatment of fibrosis.

[0007] There is a need for inhibitors of the NLRP3 inflammasome pathway to provide novel and / or alternative treatments for the diseases / disorders mentioned herein. SUMMARY OF THE INVENTION

[0008] The present invention provides a compound that inhibits the NLRP3 inflammasome pathway.

[0009] Thus, in one aspect of the present invention, a compound of formula (I)

Chemical formula

[0010] In some embodiments, the compounds of the present invention that may be referenced are of the formula defined herein. (I) contains the compound or a pharmaceutically acceptable salt thereof, where: R 1 teeth, (i)-OH, -C 1~3 Alkyl and hydroxy C 1~3 Selected independently of alkyl groups C is optionally substituted with one or more substituents. 3~6 Cycloalkyl; (ii) Each is a halo, -CN, =O, -OH, -OC 1~3 Alkyl, -C 1~3 a Lu kill, C 3~6 Cycloalkyl, Halo C 1~3 Alkyl, hydroxy C 1~3 Alkyl , C 1~3 Alkoxy, Halo C 1~3 Alkoxy and -S(O)2C 1~4 Alkyl aryl or aryl compounds, which are optionally substituted with 1 to 3 substituents that are independently selected. Heteroaryl; or (iii) = O, C 1~3 Alkyl and C 3~6 Selected independently from cycloalkyl groups This represents a heterocycline substituted with 1 to 3 substituents by arbitrary selection.

[0011] In another embodiment, the compounds of the present invention are provided for use as drugs. A pharmaceutical composition containing a therapeutically effective amount of the compound of the present invention is provided.

[0012] In a further embodiment, diseases associated with NLRP3 activity (including inflammasome activity) NLRP3 signaling in the treatment of disorders; the pathophysiology of the disease / disorder, and / or In the treatment of the disease or disorder that contributes to the symptoms and / or progression of the symptoms; NLRP3 In inhibition of flammosome activity (including in the target area where it is needed); and / or The compounds of the present invention (and / or such compounds) for use as NLRP3 inhibitors A pharmaceutical composition containing the following is provided. Specific diseases or disorders may be referred to herein. For example, inflammasome-related diseases or disorders, immune diseases, inflammatory diseases, autoimmune diseases, Alternatively, autoinflammatory diseases may be selected.

[0013] In another aspect, diseases associated with NLRP3 activity (including inflammasome activity) NLRP3 signaling in the treatment of disorders; the pathophysiology of the disease / disorder, and / or symptoms In the treatment of diseases or disorders that contribute to the condition and / or progression of the condition; NLRP3 infection In inhibition of ramasomal activity (including in the target area where it is needed); and / or N The compound of the present invention as an LRP3 inhibitor (and / or a pharmaceutical composition comprising such compound) The use of ) is provided.

[0014] In another aspect, diseases associated with NLRP3 activity (including inflammasome activity) Treatment of disorders; NLRP3 signaling is involved in the pathophysiology of disease / disorder and / or symptoms, and / or treatment of diseases or disorders that contribute to progression; and / or NLRP3 Inframa This is the process of manufacturing drugs for inhibiting somal activity (including in the target area where it is needed). The use of the compound of the invention (and / or a pharmaceutical composition containing such compound) is provided.

[0015] In another embodiment, NLRP3 signaling is involved in the pathophysiology and / or symptoms of a disease or disorder, and / or a method for treating a disease or disorder that contributes to its progression, comprising a therapeutically effective amount of the compound of the present invention A method is provided which includes administering a substance to, for example, a subject (who needs it). Further embodiments So, what is a method to inhibit NLRP3 inflammasome activity in the target (required) area? The provided method includes administering a therapeutically effective amount of the compound of the present invention to the target subject in need. It can be done.

[0016] In a further embodiment, in combination with one or more therapeutic agents (e.g., as described herein) The compounds of the present invention, including combination pharmaceuticals, are provided. Furthermore, the compounds of the present invention may be used as described herein, or the compounds of the present invention may be used as described herein. The materials are provided for use in such combinations as described herein. Obtain. Methods as described herein may also be provided with respect to the compounds of the present invention, but The law includes administering such a combination in a therapeutically effective dose. [Modes for carrying out the invention]

[0017] The present invention relates to the compound of formula (I). [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula, R 1 teeth, (i)-OH, -C 1~3 Alkyl and hydroxy C 1~3 Selected independently of alkyl groups C is optionally substituted with one or more substituents. 3~6 Cycloalkyl; (ii) Each is a halo, -O, -OH, -OC 1~3 Alkyl, -C 1~3 Alkyl, Hello C 1~3 Alkyl, hydroxy C 1~3 Alkyl, C 1~3 Alkoxy, Halo C 1~ Alis are optionally substituted with 1 to 3 substituents independently selected from the 3-alkoxy. aryl or heteroaryl; or (iii) = O, C 1~3 Alkyl and C 3~6 Selected independently from cycloalkyl groups This represents a heterocyclyl substituted with 1 to 3 substituents by arbitrary selection; R 2 teeth, (i) Halo, -OH and -OC 1~3 One or more substitutions independently selected from alkyl groups C replaced by arbitrary selection in the base 1~3 alkyl; (ii)C 3~6 Cycloalkyl; or (iii)-OC 1~3 C substituted with alkyl as optional 2~4 Alkenil death; R 3 teeth, (i) Hello; (ii) Halo, -OH and -OC 1~3 One or more positions independently selected from alkyl groups C substituted by arbitrary selection in substitution 1~4 alkyl; (iii)-OC 1~3 C substituted with alkyl as optional 2~4 Alkenil; (iv)C 3~6 Cycloalkyl; or (v)-OC 1~3 Represents alkyl. As shown above, such compounds are referred to herein as “compounds of the present invention.” It is possible.

[0018] Pharmaceutically acceptable salts include acid addition salts and base addition salts. This involves, by conventional means, for example, the compound of the present invention in the form of a free acid or free base and 1 equivalent or more Reactions with appropriate acids or bases, optionally in solvents or in media in which the salt does not dissolve, and The following standard techniques were used (e.g., by freeze-drying in a vacuum or by filtration) The salt may be formed by the removal of the solvent or the medium. By exchanging a counterion with another counterion, for example, using a suitable ion exchange resin... It can be prepared by [method].

[0019] Pharmacologically acceptable acid addition salts can be formed with inorganic and organic acids.

[0020] Examples of inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Some examples include:

[0021] Examples of organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, and sulfate. Malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, man Delic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid These are some examples.

[0022] pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0023] Examples of inorganic bases from which salts can be derived include ammonium salts and bases I through XI of the periodic table. The metals in column I are listed. In certain embodiments, the salts are sodium, potassium, and Derived from monium, calcium, magnesium, iron, silver, zinc, and copper; particularly preferred salts These include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Salt is one example.

[0024] Examples of organic bases from which salts can be derived include primary, secondary, and tertiary amines, and ethereal bases. Examples include naturally occurring substituted amines, substituted amines, cyclic amines, and basic ion exchange resins. It can be given. Certain organic amines include isopropylamine, benzathine, and corinthine. To, diethanolamine, diethylamine, lysine, meglumine, piperazine, and To Metamine is one example.

[0025] For the purposes of the present invention, solvates, prodrugs, N-oxides, and Stereoisomers are also included within the scope of the present invention.

[0026] The term "prodrug" for the related compounds of the present invention refers to the drug that, after oral or parenteral administration, becomes invisible. It is metabolized in the body, and the compound is released within a predetermined time (for example, between 6 and 24 hours (i.e., The drug contains any compound that is formed in an experimentally detectable amount within an interval of 1 to 4 doses per day. Hmm. To avoid any ambiguity, the term "parenteral" administration refers to any administration other than oral administration. Includes a loose dosage form.

[0027] The prodrug of the compound of the present invention has functional groups present on this compound such as The drug is modified in such a way that the modification is cleaved in vivo when administered to mammals. This can be prepared by the following: This modification typically involves prodrug substitution of the parent compound. This is achieved by synthesis using the group. The prodrug contains the hyphen in the compound of the present invention. A droxyl group, an amino group, a sulfhydryl group, a carboxyl group, or a carbonyl group, free hydroxyl group, amino group, sulfhydryl group, carboxyl group or carbonyl group The compounds of the present invention include those bonded to any group that can be cleaved in vivo to regenerate. Born.

[0028] Examples of prodrugs include esters and carbamates of hydroxyl functional groups, and carboxylic acid. Examples include ester groups of syl functional groups, N-acyl derivatives, and N-Mannich bases, however These are not the only examples. General information on prodrugs can be found, for example, at Bundegaa. rd, H. “Design of Prodrugs” p.1-92, Elesevie This can be found in r, New York-Oxford (1985).

[0029] The compounds of the present invention may contain double bonds, and therefore E(e) with respect to each individual double bond. It can exist as a positional isomer of the ntgegen and Z(zusammen) geometric isomers. The compounds of the present invention may also be included in this invention. All such isomers (for example, the compounds of the present invention) (In the case of double bonds or fused rings, this includes both cis and trans forms) and mixtures thereof. The substance is included in the scope of the present invention (for example, a single positional isomer and a mixture of positional isomers, (This may fall within the scope of the present invention.)

[0030] The compounds of the present invention may also exhibit tautomerism. All tautomer forms (or tautomers) and These mixtures are included within the scope of the present invention. The term refers to structural isomers of different energies that are interconvertible across low-energy barriers. It refers to a body. For example, a proton tautomer (also known as a prototropic tautomer). This includes interconversion via proton transfer, such as keto-enols and imine-enamines. Isomerization is involved. Valence tautomers are interconversions resulting from the rearrangement of some bonding electrons. It includes.

[0031] The compounds of the present invention may also contain one or more chiral carbon atoms, and therefore optically distinct They may exhibit sexual and / or diastereoisomerism. Diastereoisomers are prior art, for example, They can be separated using chromatography or fractional crystallization. Various stereoisomers are conventional, For example, fractional crystallization or HPLC techniques can be used to fractionate racemic mixtures or other mixtures of compounds. It can be isolated by separation. Alternatively, the desired optical isomer can be obtained by racemization or epimerization. The appropriate optically active reaction of starting materials under conditions that do not cause chiral reactions (i.e., "chiral" reactions) The "pooling" method allows for the selection of appropriate starting materials and "chiral auxiliaries" that can be removed at appropriate stages. Through reactions with, for example, derivatization using homochiral acids (i.e., cleavage including dynamic cleavage) ) and subsequent diastereomer induction by conventional means (e.g., chromatography) By separation of the conductor, or by a reaction using an appropriate chiral reagent or chiral catalyst, These can all be manufactured under conditions known to those skilled in the art.

[0032] All stereoisomers (including diastereoisomers, enantiomers, and atropisomers) (and not limited to these) and mixtures thereof (e.g., racemic mixtures) are within the scope of the present invention. It is included in.

[0033] In the structures shown herein, the stereochemistry of any particular chiral atom is specified. If none exists, all stereoisomers are intended and are included as compounds of the present invention. When a chemical isomorph is specified by a solid wedge or dashed line representing a specific configuration, its stereoisomers are: It is specified and defined in that way.

[0034] When absolute placement is specified, it follows the Kahn-Ingold-Prelude system. The placement in a child is specified by either R or S. A partition whose absolute placement is unknown. Compounds can be indicated with (+) or (-) depending on the direction in which they rotate plane-polarized light. Cut.

[0035] When a specific stereoisomer is identified, this means that the stereoisomer described above is substantially different from other isomers. It does not contain other isomers, i.e., less than 50%, preferably less than 20%, more preferably less than 50%. Less than 10%, more preferably less than 5%, especially less than 2%, and most preferably less than 1%. It means that it is accompanied by. Therefore, if the compound of formula (I) is identified as, for example, (R), This means that the compound substantially does not contain (S) isomers.

[0036] The compounds of the present invention are available in non-solvated form and in pharmaceutically acceptable solvents (e.g., water, ethanol). It may exist in a solvated form with (such as ru), and the present invention encompasses both solvated and non-solvated forms. It is intended to be done.

[0037] This invention relates to atomic masses or mass numbers (or the most abundant atomic masses) commonly found in nature. (The atom) is replaced by one or more atoms having a different atomic mass or mass number. The isotope-labeled compounds of the present invention are identical to the compounds described herein, except for the fact that they are identical to the compounds described herein. Includes. All isotopes of any particular atom or element as defined herein are included. It is considered to be within the range of compounds of the invention. An exemplary compound that may be incorporated into the compound of the present invention. The isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine. ,for example 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 I is an example of the present invention. Specific isotope-labeled compounds (e.g., 3 H and 14Those labeled with C) are useful in compounds and for substrate tissue distribution assays. Tritium ([ 3 H) and carbon-14 ([ 14 C) isotopes are useful because of their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., [ 2 H) results in certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosing requirements) as a result of greater metabolic stability, and may therefore be preferred in some situations. Positron-emitting isotopes such as [ 13 O, [ 11 N, [ 18 C, and [ 1~q F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following description / Examples, using isotopically labeled reagents instead of non-isotopically labeled reagents. Unless otherwise specified, the C alkyl group (where q is the upper limit of the range) defined herein is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. As used herein (and where q is the upper limit of the range), C alkenyl refers to an alkyl group that is unsaturated, i.e., contains at least one double bond. in compounds and are useful for substrate tissue distribution assays. Tritium ([ 3 H) and carbon-14 ([ 14 C) isotopes are useful because of their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., [ 2 H) results in certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosing requirements) as a result of greater metabolic stability, and may therefore be preferred in some situations. Positron-emitting isotopes such as [ 13 O, [ 11 N, [ 18 C, and [ 1~q F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following description / Examples, using isotopically labeled reagents instead of non-isotopically labeled reagents. Unless otherwise specified, the C alkyl group (where q is the upper limit of the range) defined herein is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. As used herein (and where q is the upper limit of the range), C alkenyl refers to an alkyl group that is unsaturated, i.e., contains at least one double bond. 3 H) and carbon-14 ([ 14 C) isotopes are useful because of their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., [ 2 H) results in certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosing requirements) as a result of greater metabolic stability, and may therefore be preferred in some situations. Positron-emitting isotopes such as [ 13 O, [ 11 N, [ 18 C, and [ 1~q F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following description / Examples, using isotopically labeled reagents instead of non-isotopically labeled reagents. Unless otherwise specified, the C alkyl group (where q is the upper limit of the range) defined herein is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. As used herein (and where q is the upper limit of the range), C alkenyl refers to an alkyl group that is unsaturated, i.e., contains at least one double bond. 14 C) isotopes are useful because of their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., [ 2 H) results in certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosing requirements) as a result of greater metabolic stability, and may therefore be preferred in some situations. Positron-emitting isotopes such as [ 13 O, [ 11 N, [ 18 C, and [ 1~q F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following description / Examples, using isotopically labeled reagents instead of non-isotopically labeled reagents. Unless otherwise specified, the C alkyl group (where q is the upper limit of the range) defined herein is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. As used herein (and where q is the upper limit of the range), C alkenyl refers to an alkyl group that is unsaturated, i.e., contains at least one double bond. i.e., 2 H) results in certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosing requirements) as a result of greater metabolic stability, and may therefore be preferred in some situations. Positron-emitting isotopes such as [ 13 O, [ 11 N, [ 18 C, and [ 1~q F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following description / Examples, using isotopically labeled reagents instead of non-isotopically labeled reagents. Unless otherwise specified, the C alkyl group (where q is the upper limit of the range) defined herein is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. As used herein (and where q is the upper limit of the range), C alkenyl refers to an alkyl group that is unsaturated, i.e., contains at least one double bond. certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosing requirements) as a result of greater metabolic stability, and may therefore be preferred in some situations. Positron-emitting isotopes such as [<000D087>O, [ 11 N, [ 18 C, and [ 1~q F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following description / Examples, using isotopically labeled reagents instead of non-isotopically labeled reagents. Unless otherwise specified, the C alkyl group (where q is the upper limit of the range) defined herein is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. As used herein (and where q is the upper limit of the range), C alkenyl refers to an alkyl group that is unsaturated, i.e., contains at least one double bond. as a result of greater metabolic stability, and may therefore be preferred in some situations. Positron-emitting isotopes such as [ 13 O, [ 11 N, [ 18 C, and [ 1~q F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following description / Examples, using isotopically labeled reagents instead of non-isotopically labeled reagents. Unless otherwise specified, the C alkyl group (where q is the upper limit of the range) defined herein is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. As used herein (and where q is the upper limit of the range), C alkenyl refers to an alkyl group that is unsaturated, i.e., contains at least one double bond. 15 O, 13 N, 11 C and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following description / Examples, using isotopically labeled reagents instead of non-isotopically labeled reagents. Unless otherwise specified, the C alkyl group (where q is the upper limit of the range) defined herein is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. As used herein (and where q is the upper limit of the range), C alkenyl refers to an alkyl group that is unsaturated, i.e., contains at least one double bond. PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following description / Examples, using isotopically labeled reagents instead of non-isotopically labeled reagents. Unless otherwise specified, the C alkyl group (where q is the upper limit of the range) defined herein is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. As used herein (and where q is the upper limit of the range), C alkenyl refers to an alkyl group that is unsaturated, i.e., contains at least one double bond. PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following description / Examples, using isotopically labeled reagents instead of non-isotopically labeled reagents. Unless otherwise specified, the C alkyl group (where q is the upper limit of the range) defined herein is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. As used herein (and where q is the upper limit of the range), C alkenyl refers to an alkyl group that is unsaturated, i.e., contains at least one double bond. PET) studies to examine substrate receptor occupancy. The isotopically labeled compounds of the present invention can generally be prepared by following procedures similar to those disclosed in the following description / Examples, using isotopically labeled reagents instead of non-isotopically labeled reagents. Unless otherwise specified, the C alkyl group (where q is the upper limit of the range) defined herein is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. As used herein (and where q is the upper limit of the range), C alkenyl refers to an alkyl group that is unsaturated, i.e., contains at least one double bond.

[0038] Unless otherwise specified, the C 1~q alkyl group (where q is the upper limit of the range) is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. alkyl group (where q is the upper limit of the range) is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. alkyl group (where q is the upper limit of the range) is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond. alkyl group (where q is the upper limit of the range) is straight-chain or branched-chain if a sufficient number (i.e., at least 2 or 3 as appropriate) of carbon atoms are present. Such a group is attached to the remainder of the molecule by a single bond.

[0039] As used herein (and where q is the upper limit of the range), C 2~q alkenyl refers to an alkyl group that is unsaturated, i.e., contains at least one double bond.

[0040] C 3~qCycloalkyl (where q is the upper limit of the range) is an alkyl group that is cyclic and refers to, for example, a cycloalkyl group that is monocyclic or bicyclic if sufficient atoms are present . In certain embodiments, such a cycloalkyl group is monocyclic. Such cycloalkyl groups are unsaturated. Substituents can be attached at any position on the cycloalkyl group .

[0041] The term "halo" as used herein preferably includes fluoro, chloro, bromo, and iodo.

[0042] C 1~q An alkoxy group (where q is the upper limit of the range) is a group of the formula -OR a (where R a is , a C 1~q alkyl group as defined herein).

[0043] <c A haloC 1~q alkyl (where q is the upper limit of the range) group refers to a C alkyl group as defined herein, such a group being substituted by one or more halos 1~q . HydroxyC alkyl (where q is the upper limit of the range) refers to a C 1~q alkyl group as defined herein, such a group being substituted by one or more (e.g., one) hydroxy (-OH) groups (or one or more, e.g., one of the hydrogen atoms is replaced by -OH 1~q ). Similarly, haloC alkoxy and hydroxyC [[ID=c alkoxy each represent a corresponding -OC alkyl group substituted by one or more halos or by one or more (e.g., one) 1~q hydroxys.​​​​​

[0044] The heterocyclyl group that may be mentioned has at least one atom in the ring system (for example, 1 to 4 atoms are non-carbon (i.e., heteroatoms), and the total number of atoms in the ring system is 3 to 20 items (for example, 3 to 10 items (for example, 3 to 8 items (for example, 5 to 8 items))) This includes non-aromatic monocyclic and bicyclic heterocyclyl groups. Kryl groups can also be crosslinked. Such heterocyclyl groups are saturated. (This can be mentioned.) C 2~q The heterocyclyl groups include 7-azabicyclo[2.2.1]heptanyl and 6-azabicyclo[2.2.1]heptanyl. Bicyclo[3.1.1]heptanil, 6-azabicyclo[3.2.1]-octanil, 8 -Azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropi Ranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), di Oxolanil (including 1,3-dioxolanil), dioxanil (1,3-dioxanil (and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithio Ranyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morphol Nyl, 7-oxabicyclo[2.2.1]heptanil, 6-oxabicyclo[3.2.1 Octanil, oxetanil, oxyranil, piperazinil, piperidinil, non-aromatic pipe Lanyl, pyrazolidinil, pyrrolidinonil, pyrrolidinil, pyrrolidinil, quinuclidinil , sulforanyl, 3-sulforenyl, tetrahydropyranyl, tetrahydrofuranyl, te Trahydropyridyl (e.g., 1,2,3,4-tetrahydropyridyl and 1,2,3, 6-Tetrahydropyridyl), Thietanil, Thiiranil, Thioranil, Thiomorpholinil This includes trithianil (including 1,3,5-trithianil), tropanil, etc. Appropriate In this case, substituents on the heterocyclyl group are located on any atom (including heteroatoms) in the ring system. The bond site of the heterocyclyl group is located at the heteroatom (where appropriate) in the ring system. For example, any fused carbon ring that may exist as part of any atom or ring system containing a nitrogen atom. It can be via the atom above. The heterocyclyl group can also be in an N or S oxidized form. In this context, the heterocyclyl group referred to herein is monocyclic.

[0045] The aryl group that may be mentioned is C 6~12 (For example, C 6~10 ) and other C 6~20 a A reel group is included. Such a group may be monocyclic, bicyclic, or tricyclic, and at least One ring may have 6-12 (e.g., 6-10) ring carbon atoms, each ring being aromatic. 6~ 10 The aryl group includes phenyl, naphthyl, and for example, 1,2,3,4-tetrahydrona Phthyl is present. The bond site of the aryl group can be via any atom in the ring system. For example, aryl When the ole group is polycyclic, the bonding site can be via an atom containing an atom of the non-aromatic ring. However, However, if the aryl group is polycyclic (e.g., bicyclic or tricyclic), they are aromatic rings. It is preferable that the rest of the molecule is linked via a certain aryl group. In some embodiments, each ring is aromatic. In some embodiments, the aryl rings referred to herein are aromatic. The group is monocyclic or bicyclic. In further embodiments, the aryl group referred to herein It is a monoring.

[0046] Unless otherwise specified, the term "heteroaryl" as used herein is preferred Or one or more heteroatoms selected from N, O, and S (for example, 1 to 4 heteroatoms) This refers to an aromatic group containing atoms. Heteroaryl groups have 5 to 20 members (for example, 5 to 1 0) may be included and may be monoring, biring, or triring (however, at least of the rings) Each ring has one aromatic ring (therefore, for example, monocyclic, bicyclic, or tricyclic heteroaromatic rings). (Forms a group group). When the heteroaryl group is polycyclic, the bond site is the atom of the non-aromatic ring. It can be mediated by any atom containing it. However, the heteroaryl group is polycyclic (for example, bicyclic). If they are formula-type or tricyclic, they are preferably linked to the remainder of the molecule via an aromatic ring. In some embodiments, when the heteroaryl group is polycyclic, each ring is aromatic. The heteroaryl groups that may be mentioned include 3,4-dihydro-1H-isoquinolinyl, 1, 3-dihydroisoindolyl, 1,3-dihydroisoindolyl (e.g., 3,4-dihydro) Diro-1H-isoquinoline-2-yl, 1,3-dihydroisoindole-2-yl, 1 ,3-dihydroisoindole-2-yl; that is, linked via a non-aromatic ring Telolaryl group), or preferably acridinyl, benzimidazolyl, benzodioxy Sanyl, benzodioxepinyl, benzodioxolil (containing 1,3-benzodioxolil) (m), benzofuranil, benzoflazanil, benzothiadiazolyl (2,1,3-benzo (Containing thiadiazolyl), benzothiazolyl, benzoxadiazolyl (2,1,3-be) (containing benzooxadiazolyl), benzooxazinyl (3,4-dihydro-2H-1,4 -Containing benzooxazinyl), benzooxazolyl, benzomorpholinyl, benzosele Nadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carba Zolyl, chromanil, sinnorinil, furanil, imidazolyl, imidazo[1,2-a] Pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochrom Nyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiadiolyl, isoth Oclomanil, isoxazolyl, naphthilidinil (1,6-naphthilidinil, or preferred (including 1,5-naphthilidinyl and 1,8-naphthilidinyl), oxadiazolyl (1,2,3-Oxadiazolyl, 1,2,4-Oxadiazolyl, and 1,3,4-O (Containing xadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazine Pteridinyl, Prinyl, Pyrazinyl, Pyrazolyl, Pyridadinyl, Pyrizolyl Zill, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolidinyl, quinoxali Nyl, tetrahydroisoquinolinyl (1,2,3,4-tetrahydroisoquinolinyl and (containing 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (1, Contains 2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl (mu), tetrazolyl, thiadiazolyl (1,2,3-thiadiazolyl, 1,2,4-thia) (Containing diazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanil, thiazolyl Ofenetil, thienyl, triazolyl (1,2,3-triazolyl, 1,2,4-tri This includes azolyl and 1,3,4-triazolyl, etc., where appropriate. Substituents on the aryl group can be located on any atom (including heteroatoms) in the ring system. The bond site of the teloaryl group is a heteroatom (e.g., nitrogen atom) in the ring system, where appropriate. via any atom containing (a child) or any atom on any fused carbon ring that may exist as part of a ring system Obtain. The heteroaryl group can also be in an N or S oxidized form. The heteroaryl group is non-aromatic. If it is a polycyclic compound with a ring, the non-aromatic ring can be substituted by one or more =O groups. In some embodiments, the heteroaryl groups referred to herein are monocyclic or bicyclic. It is possible. In further embodiments, the heteroaryl groups referred to herein are monocyclic. ru.

[0047] Heteroatoms that may be mentioned include phosphorus, silicon, boron, and preferably oxygen and nitrogen. It contains sulfur.

[0048] To avoid any doubt, it should be stated that a group has one or more substituents (for example, C 1~6 Alki Where it is stated herein that it may be substituted with (selected from the group), such The substituents (e.g., alkyl groups) are independent of each other. That is, such groups are identical. A substituent of the same alkyl substituent, or a different substituent (e.g., alkyl) It may be replaced with .

[0049] All individual features mentioned herein (e.g., preferred features) are, in themselves or otherwise, This can be combined with any other features (including preferred features) mentioned herein to solve It can be interpreted that (therefore, a desirable feature can be interpreted in conjunction with other desirable features or independently from them). (This can be interpreted in a certain way.)

[0050] Those skilled in the art will understand that the compounds of the present invention, which are the subject of this invention, include stable compounds. It is likely that the compounds of the present invention, for example, can be purified to a useful degree from the reaction mixture. It contains robust material that can withstand isolation.

[0051] Various embodiments of the present invention, including embodiments of the compound of the present invention, are described herein. ru.

[0052] In one embodiment, the compound of the present invention is R 1 However, (i)C 3~6 Cycloalkyl; (i i) Aryl or heteroaryl; or (iii) heterocyclyl (all are arbitrary) Includes those that represent (which are replaced by selection as defined herein). Specific implementation forms In state, R 1 (i)C 3~6 (ii) cycloalkyl; or (ii) aryl or hetero Represents an aryl (all are optionally replaced as defined herein).

[0053] In one embodiment, R 1 C is replaced by arbitrary selection. 3~6 When representing cycloalkyl That is, C 1~3 Alkyl (e.g., methyl), -OH, and hydroxyC 1~3 Al Optionally selected by one or two substituents chosen from Kill (e.g., -C(CH3)2OH). C replaced by the choice 3~6 Cycloalkyl (or, in some embodiments, C 3~4 Cyclo Represents alkyl. In further embodiments, R 1 is cyclopropyl (e.g., unsubstituted) or represents cyclobutyl. In further embodiments, R 1 This represents cyclohexyl. Further details In terms of application form, R 1 This refers to unsubstituted cyclopropyl or substituted with -OH and methyl (e.g.) For example, it represents cyclobutyl (with the same carbon atom). In further embodiments, R1 represents, for example, - cyclohexyl substituted by OH (for example, one -OH group). Thus, in certain embodiments, R 1 is

Chemical formula

Chemical formula

Chemical formula

[0054] In one embodiment, R 1 A which is optionally replaced as defined herein. When referring to a reel or heteroaryl, it means (i) phenyl; (ii) 5 or 6 (iii) 9- or 10-membered bicyclic heteroaryl group ( All are optionally substituted with 1 to 3 substituents as defined herein. ) can represent. In one embodiment, the aforementioned aryl and heteroaryl groups are halo (for example (Fluoro, iodine), =O, -OH, C 1~3 Alkyl (e.g., methyl), -OC 1~3 Alkyl and -halo C 1~3 One selected from alkyl groups (e.g., -CF3) or It is optionally substituted with two (for example, one) substituents. In one embodiment, R 1 This represents a phenyl or monocyclic 6-membered heteroaryl group, and in another embodiment, it represents a 9-membered group. Alternatively, it may represent a 10-membered (e.g., 9-membered) bicyclic heteroaryl group. Therefore, in some cases, In terms of form, R 1 teeth, [ka] (In the formula, R 1b These are halos (e.g., fluorocarbons, iodine), =O, -OH, and C. 1~3 Alki (For example, methyl), halo C 1~3 A single element selected from alkyl groups (e.g., -CF3) represents two optional substituents, R b , R c , R d , R e and R f at least One may represent a nitrogen heteroatom (and the other may represent CH). In terms of form, R b , R c , R d , R e and R f One or two of them are nitrogen heteroatoms This represents, for example, R d represents nitrogen, and R is optionally selected. b This represents nitrogen, or R c represents nitrogen. In some embodiments, (i)R b and R d (ii)R d (iii)R c (iv)R represents nitrogen; or b and R c is nitrogen It represents a prime element. Therefore, R 1 This is pyridyl (for example, 3-pyridyl or 4-pyridyl). ), pyrimidinyl (e.g., 4-pyrimidinyl) or pyridazinyl (e.g., 3-pyridazinyl) (Dinyl or 6-pyridazinyl) (All of these are as defined herein) (which can be replaced by intentional selection), and therefore, in some embodiments, such a base may represent, Halo (e.g., fluorocarbon, iodine), =O, -OH, C 1~3 Alkyl (for example, methyl ), Hello C 1~3 It may be substituted with an alkyl group (e.g., -CF3), or otherwise The una group may be unsubstituted.

[0055] In another embodiment, R 1 is

Chem.

Chem.

[0056] [[ID=S9]] In one embodiment, R 1 is

Chem.

[0057] In another embodiment, R 1 teeth, [ka] (In the formula, R i and R j One of them represents N and the other represents C, or both represent R i and R j represents N, and in some embodiments, 1 or 2 independent R 1b Substituents are present Or, in another embodiment, R 1b R represents (where no substituent exists). 1b ga = O substitution Considering that it can represent a base, R 1 Also: [ka] It can represent this.

[0058] In one embodiment of the present invention, R 1 is a phenyl or 6-membered heteroaryl group (1 to 3 This may also represent a heteroatom, which is an optional selection as defined herein. It is replaced by selection. In one embodiment, R1 is 1 to 5 heteroatoms (at least 2 It can represent a 6,5-condensed bicyclic ring containing (one of which is nitrogen), and this ring is, for example, , by one or two substituents as defined above, as defined herein , replaced by optional selection (this is halo, C 1~3 Alkyl, C 3~4 Cycloal kill, Hello C 1~3 (Can be selected from alkyl, -CN, and =O).

[0059] In a particular embodiment, R 1 teeth, [ka] (In the formula, R 1b (Preferably does not exist, i.e., the two rings are non-substitutional.)

[0060] R 1 This represents a heterocycline that has been optionally replaced as defined herein. In some embodiments, such groups may be, in further embodiments, for example, at least one nitrogen or acid A 5-membered or 6-membered heterocyclyl group containing an elementary heteroatom; for example, in certain embodiments So, in this case, R 1 This includes one or two substituents as defined herein. Therefore, for example, C 1~3 A 6-membered nitrogen-containing hetase that is optionally substituted with alkyl groups. It may represent a rocyclyl group. In one aspect of this embodiment, the 6-membered heterocyclyl group is as described above. As defined in the details, piperidinil (e.g., 3-piperidine) is optionally substituted. It could be ridinyl.

[0061] In one embodiment, R 2(i) Halo (e.g., fluoro), -OH and -OC 1~ C is optionally substituted with one or more substituents independently selected from 2alkyl groups. 1~ 3 alkyl; (ii) C 3~6 Cycloalkyl; or (iii)-OC 1~2 Alkyl C replaced by more arbitrary selection 2~4 Represents an alkenil. In further embodiments, R 2 teeth , halo, -OH and -OC 1~2 With one or more substituents independently selected from alkyl groups C replaced by intentional selection 1~3 Represents alkyl. In further embodiments, R 2 is non-substituted C 1~3 Represents alkyl.

[0062] In a particular embodiment, R 2 This represents unsubstituted isopropyl or unsubstituted ethyl.

[0063] In another embodiment of the present invention, R 2 is -CH2CH3, isopropyl, -C(H)(C H3)CH2CH3 or cyclopropyl is represented. In certain embodiments, R 2 isopropyl It represents a pill.

[0064] In one embodiment, R 3 (i) Halo (e.g., bromo); (ii) Halo, -OH and Beauty -OC 1~2 Optionally substituted with one or more substituents independently selected from alkyl groups. C 1~4 Alkyl; or (iii) C 3~6 Cycloalkyl (for example, cyclopropyl In further embodiments, R 3 is a halo (for example, a bromo); one or more fluo By choice (and preferred) by an atom (therefore, for example, to form -CF3) (ku) Substituted C 1~3 Alkyl; or C 3~6 (For example, C 3~4 ) Cycloalkyl (For example, it represents cyclopropyl.)

[0065] In one embodiment, R 3 C is replaced by arbitrary selection. 1~4 When representing alkyl, This is a carbon atom optionally substituted with one or more fluoro atoms. 1~3 Represents alkyl In one embodiment, R 3 C 3~6 When referring to cycloalkyl, it is cyclopropyl This represents R 3 ga-OC 1~3 When representing an alkyl group, it is -OC 1~ This represents a 2-alkyl group (for example, -OCH3).

[0066] In a particular embodiment, R 3 These include halo (e.g., bromo), methyl, ethyl, and isopropyl. R represents -CF3, -CHF2, or cyclopropyl. For example, R 3 , bromo, -CF 3 represents cyclopropyl.

[0067] In another embodiment of the present invention, R 3 is a halo (for example, bromo or chloro), one or more Optionally substituted by the fluoro atom above (for example, -CF3, i (Forms socpropyl, -CF2CH3, -CHF2, C(CH3)2F) 1~4 Al Kill (for example, C 1~3 Alkyl) or C 3~6 Cycloalkyl (for example, cyclopropyl R represents (or cyclobutyl). In certain embodiments, R 3 -CF3 or CF2C This represents H3.

[0068] The name of the compound of this invention is Chemical Abstracts Service( According to the naming conventions established by CAS, Advanced Chemical Development, Inc., Software (ACD / Name Product Version) Using 10.01;Build 15494, December 1, 2006), or internationally compliant International Union of Pure and Applied Chemistry Nomenclature rules established by Applied Chemistry (IUPAC) According to Advanced Chemical Development, Inc., Software (ACD / Name Product Version 10.01.0.14105, 2006) (October) was used to generate the tautomer form, the structure of the tautomer shown. The morphological forms have been named. Other tautomer morphologies not shown are also included within the scope of this invention. It can be done.

[0069] Preparation of compounds In one aspect of the present invention, a process for preparing the compound of the present invention is provided, where, References to compounds of formula (I) as defined herein are made.

[0070] The compound of formula (I) is (i) Compound of formula (II), [ka] or its derivatives (for example, its salts or esters, for example, C 1~3 Alkyl ester )(wherein, R 2 and R 3 (as previously defined herein) and formula (III) The compound, H2N-R 1 (III) or its derivatives (wherein R 1 (as defined previously in this specification) and the amide form Under reaction conditions (also called amidation), for example, a suitable coupling reagent (for example, p Ropyruphosphonic anhydride, 1-[bis(dimethylamino)methylene]-1H-1,2,3 -Triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate (O -(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluro Nium hexafluorophosphate), 1,1'-carbonyldiimidazole, N,N' -Dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide (or its hydrochloride), N,N'-disuccinimidyl carbonate, benzotri Zol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphonium 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl Uronium hexafluorophosphate (i.e., O-(1H-benzotriazole) -1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (t) Benzotriazole-1-yloxytris-pyrrolidinophosphonium hexa-f Luorophosphate, bromo-tris-pyrrolidinophosphonium hexafluorophosphate tetra-fluorocarbonate 2-(1H-benzotriazol-1-yl)-1,1,3 ,3-tetramethyluronium,1-cyclohexylcarbodiimide-3-propyl oxy Methylpolystyrene, O-benzotriazol-1-yl-N,N,N',N'-teto In the presence of methyluronium tetrafluoroborate, a suitable base can be optionally selected. For example, sodium hydride, sodium bicarbonate, potassium carbonate, pyridine, triethyl Amine, dimethylaminopyridine, diisopropylamine, sodium hydroxide, potassium tert-butoxide and / or lithium diisopropylamide (or its variant) and suitable A suitable solvent (e.g., tetrahydrofuran, pyridine, toluene, dichloromethane, chloro Form, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxin The reaction occurs in the presence of 1-hydroxybenzolamine (or triethylamine). This may be carried out in the presence of further additives such as zotriazole hydrate. Alternatively, the process may be carried out in the presence of carbo The acidic group can first be converted to the corresponding acyl chloride under standard conditions (for example, S (In the presence of OCl2 or oxalyl chloride), the acyl chloride is then converted into the compound of formula (II). For example, the reaction is carried out under the same conditions as described above; (ii) Compound of formula (IV), [ka] or its derivatives (e.g., salts) (wherein R 1 and R 3 As defined previously in this specification (and so on) and the compound of formula (V), R 2 -LG a (V) (In the formula, LG a R represents a suitable leaving group (e.g., iodine, chloro or other halos), 2 teeth Under suitable reaction conditions, for example, with a suitable base (as defined herein), For example, in the presence of Cs2CO3, K2CO3, or LiHMDS, or alternative alkyl Reaction under fermentation reaction conditions (typically, such a reaction involves the derivative of the compound of formula (IV) or with a derivative of the compound of formula (II) (or other intermediates described herein) However, in this case, the carboxylic acid group can be protected. (iii) Conversion of a particular compound of formula (I) to another (such conversion process is intermediate (This can also be done on interstellar bodies), for example: - Regarding compounds of formula (I) containing alkenes, the corresponding compounds of formula ( I) A suitable reaction to the compound under reducing conditions, such as ethanol or methanol. In an inert solvent, for example, in the presence of a suitable catalyst such as palladium on carbon, For example, reduction by hydrogen; - For example, a suitable coupling reagent (for example, the reagent is -B(OH)2, -B(OR wx )2, zincate (e.g., -Zn(R wx )2,-ZnBrR wx (including) or -S n(R wx )3(each R wx Independently, C 1~6 Suitable groups such as alkyl groups It contains a suitable alkyl, alkenyl, or aryl / heteroaryl group attached, or -B(OR wx )In the case of 2, each R wx The bases are joined together to form a 4-6 membered annular base ( Forms (such as the 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group) Halo Alternatively, the triflate group can be converted to, for example, an alkyl, alkenyl, or cycloalkyl group. The reaction is carried out using a suitable catalyst system, for example, Pd, CuI, Pd / C , PdCl2, Pd(OAc)2, Pd(Ph3P)2Cl2, Pd(Ph3P)4(S) That is, palladium tetraxtriphenylphosphine, Pd2(dba)3 and / or The catalyst is a metal such as NiCl2 (or its salt or complex) (a preferred catalyst is RuPhos Pd G3, XPhos Pd and bis(tri-tert-butylphosphine) paradiulose (0) and optional selections include Na2CO3, K3PO4, Cs2CO3, NaOH, KOH, K2CO3, CsF, Et3N, (i-Pr)2NEt, t-BuONa or t -BuOK (or a mixture thereof; preferred bases include Na2CO3 and K2CO3) PdCl2(dppf).DCM, t-Bu3P, combined with suitable bases such as (which can be used), (C6H 11 )3P, Ph3P, AsPh3, P(o-Tol)3, 1,2-bis(diph phenylphosphino)ethane, 2,2'-bis(di-tert-butylphosphino)-1, 1'-biphenyl, 2,2'-bis(diphenylphosphin)-1,1'-bi-naphthyl , 1,1'-bis(diphenyl-phosphino-ferrocene), 1,3-bis(diphenyl In the presence of ligands such as phosphinopropane, xantphos, or mixtures thereof, Dioxane, Toluene, Ethanol, Dimethylformamide, Dimethoxyethane, Ethylene Dimethyl glycol ether, water, dimethyl sulfoxide, acetonitrile, dimethyl Acetamide, N-methylpyrrolidinone, tetrahydrofuran, or a mixture thereof (preferred) Suitable solvents include dimethylformamide and dimethoxyethane. This can be carried out in a solvent - for example, R 3However, the compound that represents the halo is R 3 However, previously defined As specified, the compounds were converted to the corresponding compounds representing alkyl, alkenyl, or cycloalkyl groups. It is acceptable; - Reduction of ketones to alcohols under suitable reduction conditions, e.g., in the presence of NaBH4. ; - A suitable Grignard reagent, e.g., reaction of alkyl MgBr with -C(O) Conversion of the kill moiety to the -C(OH)(alkyl)(alkyl) moiety; - For example, in the presence of AD-mix-Alpha and methane-sulfonamide, alke Conversion of the -CH2 portion to the carbonyl=O portion, for example, the -CH=CH2 portion becomes -C( The O)H portion may also be converted (for example, by reaction with osmium tetroxide), followed by D It may be converted to a -CHF2 group by reaction with AST; - Conversion of ketones to the alcohol-OH moiety; - Alkylation of the -OH moiety (to -O-alkyl) under appropriate reaction conditions It can be prepared by [method].

[0071] The compound of formula (II) is the corresponding compound of formula (VI), [ka] or its derivatives (wherein R 2 and R 3 (as defined herein), Under appropriate oxidation reaction conditions as described in the manual, for example, acid using Jones reagent It can be prepared by chemical reaction. Alternatively, the compound of formula (II) can be prepared by the corresponding compound of formula (VII). thing, [ka] or its derivatives (wherein R 2and R 3 (as previously defined herein) Under appropriate oxidation reaction conditions as described herein, for example, monona in a suitable solvent system Reaction in a mixture of thorium phosphate, 2-methyl-2-butene, and sodium chlorite It may also be prepared by oxidation.

[0072] The compound of formula (VII) undergoes oxidation, such as in the reaction with Dess-Martin periodinane. It can be prepared by oxidation of the compound of formula (VI) under certain conditions.

[0073] The compound of formula (VI) may need to be protected (then deprotected at an appropriate point in the synthesis). (Protected). For example, protected with a silyl protecting group (e.g., tri-isopropyl-silyl) The compound of formula (VI) can be deprotected, for example, by reaction with TBAF.

[0074] Protected (for example, by a silyl protecting group such as a triisopropylsilyl group) The compound of formula (VI) is the corresponding compound of formula (VIII), [ka] or its derivatives (wherein PG is a suitable protecting group (if necessary, e.g., tri-isopropyl alcohol) (representing a silyl protecting group such as pyr-silyl), and the compound of formula (IX), R 2 -LG (IX) (In the formula, R 2 This is as previously defined herein, and LG is a suitable leaving group, for example , with halos (e.g., iodine, chloroform), for example, under reaction conditions and as specified herein. Using reagents such as those listed, for example, K2CO3, NaH or similar substances. It can be prepared by a reaction in the presence of a suitable base.

[0075] The compound of formula (VIII) is the compound of formula (X), [ka] (In the formula, R 3 (as previously defined herein), for example, standard protective clauses For example, in the case of a silyl protecting group, a suitable silyl chloride (e.g., triisopropyl silyl) It can be prepared by protecting the reaction in the presence of a chlorolide.

[0076] The compound of formula (X) is the corresponding compound of formula (XI). [ka] or its derivatives (wherein R 3 (as previously defined herein), for example, Cyclization in the presence of an acid (e.g., H2SO4) in deionized water, followed by sodium nitrite. It can be prepared by adding (in deionized water).

[0077] The compound of formula (XI) is the corresponding compound of formula (XII). [ka] or its derivatives (wherein R 3 This is as previously defined in this specification, and LG 1 , (For example, a suitable leaving group such as iodine), and the compound of formula (XIII), HC≡C-CH2CH2-OH (XIII) It can be prepared by reaction with a suitable coupling reagent and formula (I The preparation of compounds (halo or triflate groups of alkyl, alke) is described. Reaction conditions such as process step (iii)) in which conversion to nyl or cycloalkyl groups takes place. It can be carried out in the presence of, for example, Pd, CuI, Pd / C, PdCl2, Pd( OAc)2, Pd(Ph3P)2Cl2, Pd(Ph3P)4 (i.e., palladium tetra Traxtriphenylphosphine), Pd2(dba)3 and / or NiCl2 (preferably) Examples of catalysts include RuPhosPd G3, XPhosPd, and bis(tri-ter). Examples include metals (or so) such as t-butylphosphine (palladium(0)) In the presence of a salt or complex of (and optionally a suitable base (e.g., Et3N) It can be implemented under the current circumstances.

[0078] A particular intermediate compound may be commercially available or known from the literature. Alternatively, it may be used with the processes described herein, or with appropriate reagents and reaction conditions. It may also be obtained from possible starting materials, in the same manner as conventional synthesis procedures following standard techniques.

[0079] Certain substituents in the final compound or related intermediates of the present invention are as described by those skilled in the art. The above process may be modified one or more times after or during the process by a well-known method. Examples of such methods include substitution, reduction, oxidation, alkylation, acylation, hydrolysis, etc. Examples include sterling, etherification, halogenation, nitration, or coupling.

[0080] The compounds of the present invention are derived from conventional techniques (e.g., recrystallization under standard conditions where possible). They can be isolated from those reaction mixtures using this method.

[0081] In the processes described above and below, the functional groups of the intermediate compound must be protected by protecting groups. Those skilled in the art will understand that this may be necessary.

[0082] The need for such protection varies depending on the nature of the detached sensory properties and the conditions of the preparation method. This will result (the necessity of which can be easily determined by those skilled in the art). Suitable amino protecting groups are For example, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyl Oxycarbonyl (CBz), 9-Fluorenylmethyleneoxycarbonyl (Fmoc) and 2,4,4-trimethylpentan-2-yl (acid, e.g., water / alcohol (e.g., Examples include deprotection by reaction in the presence of HCl in MeOH. The need for such protection is easily determined by those skilled in the art. For example, -C(O)Ot When the ert-butyl ester moiety functions as a protecting group for the -C(O)OH moiety Therefore, the former is, for example, the reaction in the presence of a mild acid (e.g., TFA). Depending on the situation, it can be converted to the latter.

[0083] Protection and deprotection of functional groups may be carried out before or after the reaction in the above scheme.

[0084] The protective group is removed in accordance with the art well known to those skilled in the art and as described below. For example, the protected compounds / intermediates described herein may be subject to standard deprotection techniques. It can be chemically converted to an unprotected compound using techniques.

[0085] The type of chemical reaction involved, the necessity and type of protecting group, and the sequence for achieving the synthesis. This will result in giving instructions.

[0086] The use of protecting groups is permitted under the “Protective Groups in Organic S” category. Synthesis, 3 rd edition, TWGreene&P.GMW This is well described in utz, Wiley, and Interscience (1999). .

[0087] The compounds of the present invention, prepared by the process described above, are a racemic mixture of enantiomers. They may be synthesized in various forms, and they may be synthesized with respect to each other according to division procedures known in the art. They can be separated. The compounds of the present invention obtained in racemic form are suitable chiral It can be converted to the form of the corresponding diastereomer salt through reaction with an acid. Subsequently, the di The astereomer salt forms can be separated, for example, by selective crystallization or fractional crystallization, and The enantiomers are released by alkali. An alternative method involves liquid chromatography using a chiral stationary phase. Chemical isomers can also be derived from the corresponding pure stereochemical isomers of appropriate starting materials. However, this reaction must occur stereospecifically. If a specific stereoisomer is desired... In such cases, it would be preferable that the compound be synthesized by a stereospecific preparation method. These methods advantageously involve using enantiomerically pure starting materials.

[0088] Pharmacology NLRP in inflammatory responses associated with or resulting from numerous different disorders 3. Evidence exists regarding the roles of inducible IL-1 and IL-18 (Menu et al.) .,Clinical and Experimental Immunology,2 011,166,1-15;Strowig et al.,Nature,2012, 481,278-286). NLRP3 mutations are a series of rare autoimmune disorders known as CAPS. It has been found to be involved in autoinflammatory diseases (Ozaki et al., J. Infl. ammation Research,2015,8,15-27;Schroder et al.,Cell,2010,140:821-832;Menu et al. ,Clinical and Experimental Immunology,20 11,166,1-15). CAPS is characterized by recurrent fever and inflammation. It is a genetic disorder and consists of three autoinflammatory disorders that form a clinical continuum. The diseases, in order of severity, are Familial Cold Autoinflammatory Syndrome (FCAS), Mackle Werner's Disease. Luz syndrome (MWS) and chronic childhood cutaneous neuroarthritis syndrome (CINCA; neonatal onset) It is a multi-organ inflammatory disease (also called NOMID), and all of them involve IL-1 beta It has been shown that this is due to gain-of-function mutations in the NLRP3 gene that lead to increased secretion. NLRP3 is also used for septic arthritis, pyoderma gangrenosum and pyoderma pallidum (PAPA), and sweet's disease. It is used in several autoinflammatory diseases, including syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris. Related in (Cook et al., Eur.J.lmmunol., (2010, 40, 595-653).

[0089] In particular, multiple sclerosis, type 1 diabetes (T1D), psoriasis, rheumatoid arthritis (RA), and Behce's disease. Several autoimmune diseases, including scotch disease, Schnitzler syndrome, and macrophage activation syndrome. The disease has been shown to be associated with NLRP3 (Braddock et al., Na t.Rev.Drug Disc.2004,3,1-10;Inoue et al. ,Immunology,2013,139,11-18;Coll et al.,N at.Med.2015,21(3),248-55;Scott et al.,Cl in.Exp.Rheumatol.2016,34(1),88-93), systemic lupus Thematosus and its complications such as lupus nephritis (Lu et al., J. lmmun) ol.,2017,198(3),1119-29), systemic sclerosis (Artlett et al.,Arthritis Rheum.2011,63(11),3563- 74). NLRP3 is also used for chronic obstructive pulmonary disease (COPD) and asthma (steroid-resistant asthma). It has been shown to play a role in several lung diseases, including asbestosis (including respiratory illness), silicosis, and other lung diseases. (De Nardo et al., Am.J.Pathol., 2014, 184:42-54;Kim et al.,Am.J.Respir.Crit.Ca re Med, 2017, 196(3), 283-97). NLRP3 is also associated with multiple rigidity. MS (Multiple Sclerosis), Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease Brain injury from Ton's disease, cerebral malaria, and pneumococcal meningitis (Walsh et al., N Academic Reviews, 2014, 15, 84-97; and Dempsey et al. al.,Brain.Behav.lmmun.2017,61,306-16), head Intramural aneurysm (Zhang et al., J. Stroke and Cerebrov Ascular Dis., 2015, 24, 5, 972-9), and traumatic brain injury (I smael et al.,J.Neurotrauma.,2018,35(11), It is suggested that it plays a role in several central nervous system conditions, including (1294-1303). NLRP3 activity is also associated with type 2 diabetes (T2D) and its organ-specific complications. Atherosclerosis, obesity, gout, pseudogout, metabolic syndrome (Wen et al., N ature Immunology,2012,13,352-357;Duewell et al.,Nature,2010,464,1357-1361;Strowi g et al., Nature, 2014, 481, 278-286), and non-alcoholic steatohepatitis (Mridha et al.,J.Hepatol.2017,66 It has been shown to be involved in various metabolic diseases, including (5), 1037-46). IL- The role of NLRP3 via 1-beta is also related to atherosclerosis, myocardial infarction. van Hout et al.,Eur.Heart J.2017,38(11), 828-36), heart failure (Sano et al., J.Am.Coll.Cardio l.2018,71(8),875-66), Aortic aneurysm and dissection (Wu et al., Arteriosc / er.Thromb.Vase.Biol.,2017,37(4 ), 694-706), and other cardiovascular events (Ridker et al., NE As suggested in ngl.J.Med.,2017,377(12),1119-31) It is.

[0090] Other diseases in which NLRP3 has been shown to be involved include exudative and dry keratoconjunctivitis. Ocular diseases such as age-related macular degeneration (Doyle et al., Nature Medi) cine,2012,18,791-798;Tarallo et al.,Cell 2012, 149(4), 847-59), diabetic retinopathy (Loukovaara et al.,Acta Ophthalmol.,2017,95(8),803-8 ), non-infectious uveitis and optic nerve injury (Puyang et al., Sci. Rep .2016,6,20998); Non-alcoholic steatohepatitis (NASH) and acute alcoholic Liver diseases including pulmonary hepatitis (Henao-Meija et al., Nature, 20 12,482,179-185); Contact hypersensitivity (bullous pemphigoid, etc. (Fang et al.) al.,J Dermatol Sci.2016,83(2),116-23)), Topical dermatitis (Niebuhr et al., Allergy, 2014, 69(8) ), 1058-67), hidradenitis suppurativa (Alikhan et al., J.Am.Ac ad. Dermatol., 2009, 60(4), 539-61), and sarcoid Cis (Jager et al., Am.J.Respir. Crit.Care M) Inflammatory reactions in the lungs and skin, including (Prim ed., 2015, 191, A5816) iano et al.,J.lmmunol.2016,197(6),2421-3 3); Inflammatory response in the joints (Braddock et al., Nat. Rev. Dr. ug Disc,2004,3,1-10);Amyotrophic lateral sclerosis(Gugliando lo et al.,Int.J.Mo / .Sci.,2018,19(7),E199 2); Cystic fibrosis (lannitti et al., Nat. Commun., 20 16,7,10791); Stroke (Walsh et al., Nature Review) ws,2014,15,84-97);Chronic kidney disease (Granata et al.,P LoS One 2015, 10(3), eoi22272); and ulcerative colitis and Crohn's disease (Braddock et al., Nat. Rev. Drug Disc, 2004,3,1-10;Neudecker et a / .,J.Exp.Med.2 017,214(6),1737-52;Lazaridis et al.,Dig. Inflammatory bowel disease, including Dis.Sci.2017,62(9),2348-56), is cited as an example. The NLRP3 inflammasome has been found to be activated in response to oxidative stress. It has been shown that NLRP3 is also involved in inflammatory hyperalgesia (Dol unay et al.,Inflammation,2017,40,366-86) .

[0091] Activation of the NLRP3 inflammasome is associated with influenza and leishmaniasis, among other diseases. It has been shown to enhance several pathogenic infections (Tate et al., Sci Rep.,2016,10(6),27912-20;Novias et al., PLOS Pathogens 2017,13(2),e1006196).

[0092] NLRP3 has also been linked to the pathogenesis of many cancers (Menu et al.). al.,Clinical and Experimental Immunolog y, 2011, 166, 1-15). For example, some previous studies have shown that cancer is invasive, increasing This suggests a role for IL-1 beta in proliferation and metastasis, and canakinumab is responsible for IL-1 Beta inhibition reduced the incidence and overall incidence of lung cancer in a randomized, double-blind, placebo-controlled clinical trial. It has been shown to reduce cancer mortality (Ridker et al., Lance t., 2017, 390(10105), 1833-42). NLRP3 Inframasor Inhibition of IL-1 beta or IL-1 beta also inhibits the proliferation and migration of lung cancer cells in vitro. This has been shown (Wang et al., Onco / Rep., 2016, 35( 4), 2053-64). The role of the NLRP3 inflammasome is related to myelodysplastic syndrome. Myelofibrosis and other myeloproliferative neoplasms, as well as acute myeloid leukemia (AML) (BAS orka et al.,Blood,2016,128(25),2960-75.) Furthermore, glioma (Li et al., Am.J. Cancer Res. 2015, 5 (1), 442-9), Inflammation-induced tumors (Allen et al., J.Exp.Me d.2010,207(5),1045-56;Hu et al.,PNAS.,20 10,107(50),21635-40), Multiple Myeloma (Li et al.,He Matology, 2016 21(3), 144-51), and squamous cell carcinoma of the head and neck ( Huang et al.,J.Exp.Clin.Cancer Res.,2017 It has also been suggested in the carcinogenesis of various other cancers, including 36(1),116). NLRP Activation of the 3-inflammasome is also a chemotherapy target for 5-fluorouracil in tumor cells. It has also been shown to mediate resistance (Feng et al., J.Exp.Clin Cancer Res., 2017, 36(1), 81), NLRP in peripheral nerves Activation of the 3-inflammasome contributes to chemotherapy-induced neuropathic pain (Jia et al.) al., Mol. Pain., 2017, 13, 1-11). NLRP3 is also known as Wi It has also been shown to be necessary for the efficient control of rus, bacteria, and fungi.

[0093] Activation of NLRP3 causes cellular pyroptosis, and this characteristic is the manifestation of clinical disease. Plays an important role in chemical transformation (Yan-gang et al., Cell Death h and Disease,2017,8(2),2579;Alexander e t al.,Hepatology,2014,59(3),898-910;Bald win et al.,J.Med.Chem.,2016,59(5),1691-1 710;Ozaki et a / ., J. Inflammation Research ,2015,8,15-27;Zhen et a / .,Neuroimmunolog y Neuroinflammation,2014,1(2),60-65;Matt ia et a / ., J.Med.Chem.,2014,57(24),10366- 82;Satoh et al.,Cell Death and Disease,2 (013,4,644). Therefore, inhibitors of NLRP3 are pyroptosis, and cells This is predicted to block the release of inflammatory cytokines (e.g., IL-1 beta). It will be done.

[0094] Therefore, (for example, those according to the examples and / or forms described herein) Any of the embodiments described herein, including, for example, a salt form or a free form. The compounds of the present invention as described herein (in which case) are provided, for example, herein. Useful pharmacological properties as demonstrated in in vitro studies, e.g., NLR It exhibits NLRP3 inhibitory properties against the P3 inflammasome pathway, and therefore its application is , for example, use as a tool compound, as a therapeutic or research chemical. This invention These compounds are used in inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, and The indications selected from autoinflammatory diseases include, for example, NLRP3 signaling, pathology, and / or contributing to symptoms and / or progression, and responsive to NLRP3 inhibition and the present specification Use or administration of the compound of the present invention, for example, in accordance with any of the methods / uses described in this document. Useful in the treatment of diseases, disorders, or conditions that can be treated or prevented by In some cases, and therefore in certain embodiments, such indications may include: I. Inflammatory disorders, for example, inflammation resulting from autoinflammatory diseases, as a symptom of non-inflammatory disorders Inflammation resulting from the occurrence of an infection, or secondary inflammation from trauma, injury, or autoimmunity Inflammation, including inflammation occurring in the following areas. Examples of inflammation that can be treated or prevented include: a. Contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, Allergic contact dermatitis, seborrheic dermatitis (is) Skin conditions such as lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia. skin condition; b. Osteoarthritis, systemic juvenile rheumatoid arthritis, adult-onset Still's disease, relapsing polychondritis Inflammation, rheumatoid arthritis, juvenile rheumatoid arthritis, crystal-induced arthropathy (e.g., pseudogout, gout), or seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis, or Reiter's disease) Joint condition; c. Muscle conditions such as polymyositis or myasthenia gravis; d. Inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcer, celiac disease, urinary tract infection Enteritis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid antibody syndrome, or diseases away from the intestines. Stomach problems such as food-related allergies (e.g., migraines, rhinitis, or eczema) that may be affected. Intestinal condition; e. Chronic obstructive pulmonary disease (COPD), asthma (bronchial, allergic, endogenous, exogenous or Dust asthma, and in particular chronic or refractory asthma, including delayed-onset asthma and airway hyperresponsiveness. ), bronchitis, rhinitis (acute rhinitis, allergic rhinitis, atopic rhinitis, chronic rhinitis, caseous rhinitis) Rhinitis, hypertrophic rhinitis, purulent rhinitis (rhinitis pumlenta), dry rhinitis, Drug-induced rhinitis, membranous rhinitis, seasonal rhinitis (including, for example, hay fever and vasomotor rhinitis), side effects Sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, adult Respiratory conditions such as respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; f. Atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis, etc. The vascular condition; g. Systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic sclerosis, Hashimoto's disease Immunological conditions such as adenitis, type 1 diabetes, idiopathic thrombocytopenic purpura, or Graves' disease, for example. For example, an autoimmune state; h. Ocular conditions such as uveitis, allergic conjunctivitis, or vernal keratoconjunctivitis; i. Neurological conditions such as multiple sclerosis or encephalomyelitis; j. Acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic Sexually transmitted parasitic infections, acute or chronic viral infections, acute or chronic fungal infections, meningitis, liver Hepatitis (A, B, or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria Dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberclaw Mycobacterium tuberculosis Mycobacterium avium intr acellulare, Pneumocystis carinii pneumonia, orchitis / epididymitis, Legionnaires' disease Lyme disease, influenza A, Epstein-Barr virus, viral encephalitis / Infection or infection-related conditions such as aseptic meningitis or pelvic inflammatory disease; k. Mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure Kidney conditions such as total kidney disease, uremia, or nephritis syndrome; l. Lymphatic conditions such as Castleman disease; m. High IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or transmissible Immune system conditions or conditions related to the immune system, such as graft-versus-host disease; n. Chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis Non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD) D) Liver conditions such as alcoholic steatohepatitis (ASH) or primary biliary cirrhosis; o. Cancers including those listed below in this specification; p. Burns, wounds, injuries, bleeding, or stroke; q. Radiation exposure; r. Obesity; and / or s. Pain such as inflammatory hyperalgesia This includes inflammatory responses associated with or resulting from the same condition; II. Inflammatory disorders, e.g., cryopyrin-associated periodic syndromes (CAPS), Maclewyn Luz syndrome (MWS), Familial cold autoinflammatory syndrome (FCAS), Familial Mediterranean fever (F MF, neonatal-onset multi-system inflammatory disease (NOMID), Magid syndrome, suppurative joints Inflammation, pyoderma gangrenosum / acne syndrome (PAPA), adult-onset Still's disease (AOSD), A20 Haploinsufficiency (HA2O), childhood granulomatous arthritis (PGA), PLCG2-related antibody deficiency • Immune disorders (PLAID), PLCG2-related autoinflammatory antibody deficiency • Immune disorders (APL AID, or sideroblastic anemia (SIFD) with B-cell immune deficiency, periodic fever, and developmental delay. Inflammatory diseases, including inflammation resulting from autoinflammatory diseases such as those mentioned above; III. Immune diseases, e.g., acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibodies systemic syndrome (APS), antisynthetic enzyme syndrome, aplastic anemia, autoimmune adrenalitis, autoimmunity Hepatitis, autoimmune oophoritis, autoimmune polyendocrine insufficiency, autoimmune thyroiditis, celiac disease Crohn's disease, type 1 diabetes (T1D), Goodpasture syndrome, Graves' disease, G Lahn-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, systemic erythema Lupus erythematosus (SLE), including primary progressive multiple sclerosis (PPM) S) Secondary progressive multiple sclerosis (SPMS) and relapsing-remitting multiple sclerosis (RRMS) Multiple sclerosis (MS), myasthenia gravis, opsoclonus-myoclonus syndrome (including ) Group (OMS), optic neuritis, oad thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary tract Cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis, or Still's disease , refractory gouty arthritis, Reiter's disease, Sjögren's syndrome, systemic sclerosis, systemic connective tissue Disorders, Takayasu's arthritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granuloma, systemic Alopecia, Behçet's disease, Chagas disease, autonomic nervous system disorder, endometriosis, hidradenitis suppurativa (H S) Interstitial cystitis, neurogenic myotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis , autoimmune diseases such as vitiligo or vulvar pain; IV. Lung cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), Langerhans cell histiocytosis (L CH), myeloproliferative neoplams (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndrome (MOS), acute lymphoblastic leukemia (AL) Leukemia including L) and acute myeloid leukemia (AML), promyelocytic leukemia (APML), or APL), adrenal cancer, anal cancer, basal cell and squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and Spinal tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CLL) ML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, tumors Ewing family, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (G IST), gestational trophoblastic disease, glioma, Hodgkin lymphoma, Kaposi's sarcoma, renal cancer, larynx and lymphomas including hypopharyngeal cancer, liver cancer, pulmonary carcinoid tumors, cutaneous T-cell lymphoma, malignant Mesothelioma, melanoma skin cancer, Merkel cell carcinoma, multiple myeloma, nasal cavity and sinus cancer, nasopharyngeal cancer Cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer Testicular cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small-scale cancer Alveolar lung cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymic cancer, thyroid cancer including undifferentiated thyroid cancer, Uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, and Wilms Cancer, including tumors; V. Viral infections (e.g., influenza virus, human immunodeficiency virus (HIV)) , alphaviruses (such as chikungunya and Ross River virus), flaviviruses (de (e.g., staghorn virus and Zika virus), herpesvirus (Epstein-Barr virus) (e.g., cytomegalovirus, islet herpes zoster virus, and KSHV), poxvirus Rus (Vaccinia virus (modified Vaccinia virus Ankara) and Myxoma virus) (etc.), adenovirus (such as adenovirus 5), papillomavirus, or SARS -CoV-2-derived) bacterial infection (e.g., Staphylococcus aureus (Staphy Helicobacter pylori (H. lococcus aureus) Bacillus anthracis ), Bordatella pertussis, Burgh Burkholderia pseudomallei Corynebacterium diphtheria ae), Clostridium tetani, Cross Clostridium botulinum, Strepto Coccus pneumoniae (Streptococcus pneumoniae), St Leptococcus pyogenes, squirrel Listeria monocytogenes, Hemoph Hemophilus influenzae, Pasteur Pasteurella multicida, Sigella dicente Rie (Shigella dysenteriae), Mycobacterium tuberculaco Mycobacterium tuberculosis Mycobacterium leprae, Mycoplasma nucleus Monier (Mycoplasma pneumoniae), Mycoplasma hominis ( Mycoplasma hominis, Neisseria meningitidis (Neis Neisseria meningitidis, Neisseria gonorea (Gonorrhoeae), Rickettsia ric Legionella pneumophylla (kettsii) Phila, Klebsiella pneumoni ae), Pseudomonas aeruginos a) Propionibacterium acnes nes), Treponema pallidum, Chlamydia Chlamydia trachomatis, Bibliothus Lera (Vibrio cholerae), Salmonella typhimurium (Salmo Salmonella typhimurium typhi), Borrelia burgdorfe (derived from Yersinia pestis), fungal infection Infection (for example, Candida or Aspergillus) (of species origin), protozoan infection (e.g., Plasmodium, Babesia) Babesia, Giardia, Entamoe ba), Leishmania or Trypanosome Some originate from helminth infections (e.g., schistosomiasis, roundworms, tapeworms, or trematodes), and pre- Infections including on-infection; VI. Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease Diseases, cerebral malaria, brain injury resulting from pneumococcal meningitis, intracranial aneurysm, traumatic brain injury, multiple Central nervous system diseases such as lateral sclerosis and amyotrophic lateral sclerosis; VII. Type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudogout, etc. metabolic diseases; VIII. Hypertension, ischemia, reperfusion injury including ischemic-reperfusion injury after MI, and ischemic stroke. This includes stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, congestive heart failure and ejection. Heart failure including heart failure with maintained heart rate, embolism, aneurysms including abdominal aortic aneurysm, and low cardiovascular risk. Cardiovascular diseases such as reduced cardiovascular rate (CvRR) and pericarditis, including Dressler syndrome; IX. Chronic obstructive pulmonary disease (COPD), allergic asthma, and steroid-resistant asthma, etc. This includes asthma, asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis. respiratory diseases; X. Non-alcoholic fatty liver disease (NAFL), including advanced fibrosis stages F3 and F4. D) Non-alcoholic steatohepatitis (NASH), alcoholic fatty liver disease (AFLD) ), and liver diseases including alcoholic steatohepatitis (ASH); XI. Acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcification, glomerulonephropathy Kidney diseases, including inflammation and diabetic nephropathy; XII. Epithelial lesions of the eyeball, age-related macular degeneration (AMO) (dry and exudative types), uveitis ophthalmic diseases including corneal infections, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma; XIII. Contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, suppurative Skin conditions including hidradenitis (HS), other cystic skin diseases, and dermatitis such as acne clusters. skin diseases; XIV. Lymphangitis and lymphatic conditions such as Castleman disease; XV. Psychological disorders such as depression and psychological stress; XVI. Graft-versus-host disease; XVII. Bone diseases, including osteoporosis and osteopetrosis; XVIII. Blood disorders, including sickle cell disease; XIX. Allodynia including mechanical allodynia; and XX. The individual was determined to have a non-silent mutation in germline or somatic cell NLRP3. Any disease that is being treated.

[0095] More specifically, the compounds of the present invention are used for inflammasome-related diseases / disorders, immune disorders, and inflammation. Diseases, autoimmune diseases, or autoinflammatory diseases, such as autoinflammatory fever syndrome (e.g., crippled inflammatory disease). Opirin-associated periodic syndromes, sickle cell disease, systemic lupus erythematosus (SLE), liver Related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (N) ASH, alcoholic steatohepatitis, and alcoholic liver disease, inflammatory arthritis-related disorders (For example, gout, pseudogout (chondrocalcification), osteoarthritis, rheumatoid arthritis, arthritis, for example) (e.g., acute, chronic), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II) Type 1 diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases) Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR)) ), hypertension, atherosclerosis, type 1 and type 2 diabetes and related complications, peripheral Arterial disease (PAD), acute heart failure, inflammatory skin diseases (e.g., hidradenitis suppurativa, acne), Wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases / Disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MOS), It may be useful in the treatment of indications selected from myelofibrosis, particularly autoinflammatory fever. Syndromes (e.g., CAPS), sickle cell disease, type 1 / type 2 diabetes and related complications ( For example, nephropathy, retinopathy, hyperoxaluria, gout, pseudogout (chondrocalcification), chronic liver disease NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infections, acute injury, neurodegeneration) Diseases (e.g., Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., cardiovascular Risk reduction (CvRR), hypertension, hidradenitis suppurativa, wound healing and scar formation, and cancer ( For example, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MOS), bone marrow fibrosis).

[0096] In particular, the compounds of the present invention are effective in treating autoinflammatory fever syndrome (e.g., CAPS), sickle cell disease, Type 1 / Type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, pain Cold, pseudogout (chondrocalcification), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple (Sex sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis Sclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), purulent sweating Adenitis, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasm, leukemia) In the treatment of diseases or disorders selected from among myelodysplastic syndrome (MOS) and myelofibrosis. Therefore, it may be useful. In a further embodiment, the present invention may be useful in therapy. Compound (and therefore defined by any of the embodiments / forms / examples specified herein) The use of compounds (including the same compound) is provided. In further embodiments, the therapy is NLRP3 A disease is selected from among those that can be treated by inhibiting the phramosome. In another embodiment, the disease The disease is defined in any of the lists herein. Therefore, Diseases or disorders described in the details (for example, as described in the list above) The compounds of the present invention described herein for use in any of the treatments (Embodiments / One of the following is provided (including either a form or an embodiment).

[0097] Pharmaceutical compositions and combinations In some embodiments, the present invention also provides a pharmaceutically acceptable carrier and an active ingredient for therapeutic purposes. The present invention relates to a composition containing an effective amount of the compound of the present invention. The compound of the present invention is intended for administration purposes. It can be formulated into various pharmaceutical forms. As a suitable composition, it is commonly used in systemically administered drugs. All compositions may be listed. To prepare the pharmaceutical composition of the present invention, an effective amount of a specific The compound, as an active ingredient, is optionally used in salt form and a pharmaceutically acceptable carrier. These are combined to form a homogeneous mixture, and this carrier is used in various forms depending on the desired preparation for administration. These pharmaceutical compositions can take various forms. They are particularly administered orally or by parenteral injection. A suitable unit dosage form is desirable. For example, in the preparation of an oral dosage form composition, a suspension In the case of oral liquid preparations such as syrups, elixirs, emulsions, and liquids, the usual pharmaceutical medium Any of the following can be used (e.g., water, glycol, oil, alcohol, etc.), or a powder. In the case of pills, capsules and tablets, a solid carrier (e.g., starch, sugar, kaolin, diluent) is used. Disintegrants (such as lubricants, binders, and disintegrants) may be used. Tablets and capsules are easy to administer. Therefore, it is the most advantageous oral dosage form, and in that case, a solid drug carrier is naturally used. In the case of parenteral compositions, the carrier will typically contain at least a large amount of sterile water. However, other components may be included, such as components to promote solubility. For example, the carrier may contain physiological food Injectable solutions containing saline solution, glucose solution, or a mixture of physiological saline and glucose solution. A suitable liquid carrier may be prepared. An injection suspension may also be prepared, in which case a suitable liquid carrier may be used. Suspensions may be used. It is intended to be converted into a liquid preparation immediately before use. This also includes solid-form preparations.

[0098] In one embodiment, depending on the administration method, the pharmaceutical composition is preferably 0.05 to 99 grams by weight. %, more preferably 0.1 to 70% by weight, and even more preferably 0.1 to 50% by weight of activity Contains ingredients, 1 to 99.95% by weight, more preferably 30 to 99.9% by weight, even more preferably This will include 50-99.9% by weight of pharmaceutically acceptable carriers (percentage) All measurements are based on the total weight of the composition.

[0099] The pharmaceutical composition may also contain various other components known in the art (e.g., lubricants). Contains stabilizers, buffers, emulsifiers, viscosity modifiers, surfactants, preservatives, fragrances, or colorants. It is possible to have.

[0100] To facilitate administration and ensure uniformity of the dosage, the aforementioned pharmaceutical composition is formulated into a unit dosage form. It is particularly advantageous to convert it. When used herein, the unit dosage form is as a unit dose. This refers to a suitable physically separated unit, each unit working in conjunction with the necessary pharmaceutical carrier to produce the desired therapeutic effect. It contains a predetermined amount of the active ingredient calculated to produce a therapeutic effect. Examples of such unit dosage forms are: Tablets (including split tablets or coated tablets), capsules, pills, powder packets, This includes lath preparations, suppositories, injectable solutions or suspensions, and separation and compound preparations thereof.

[0101] The daily dose of the compound according to the present invention naturally depends on the compound used, the method of administration, and desired The treatment and the mycobacterial disease will vary. Generally, satisfactory results are obtained when the compound according to the present invention does not exceed 1 gram, for example, 1 This effect is likely to be obtained when administered at a daily dose within the range of 0-50 mg / kg body weight.

[0102] In one embodiment, the therapeutically effective amount of any one of the embodiments described herein A combination comprising the compound of the present invention and another therapeutic agent (containing one or more therapeutic agents) is provided. In further embodiments, other therapeutic agents are used to target farnesoid X receptor (FXR) agonists. Anti-fatty liver; anti-fibrosis; JAK inhibitors; anti-PD1 inhibitors, anti-LAG-3 inhibitors, anti-TI Checkpoint inhibitors including M-3 inhibitors or anti-POL1 inhibitors; chemotherapy, radiation Therapies and surgical procedures; uric acid-lowering therapy; anabolic and cartilage regeneration therapies; IL-17 blockers; complement inhibitors. Harmful agents; Bruton's tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors (TL R7 / 8 inhibitors; CAR-T therapy; antihypertensive drugs; cholesterol lowering agents; leukotriene A 4-hydrolase (LTAH4) inhibitor; SGLT2 inhibitor; 132-agonist; anti-inflammatory Drugs; non-steroidal anti-inflammatory drugs ("NSAIDs"); acetylsalicylic acid including aspirin Agent (ASA); paracetamol; regenerative therapy; treatment of cystic fibrosis; or atherosclerosis A treatment is selected from sexual therapy (and there are two or more treatments that are independently selected from these). Such combinations are provided. In further embodiments, the compounds of the present invention are For use as described herein, for example, NLRP3 signaling , the pathophysiology of a disease / disorder, and / or symptoms, and / or diseases or disorders that contribute to its progression, This includes inhibiting NLRP3 inflammasome activity (NLRP3 activity). For use in the treatment of diseases or disorders associated with (including phramosome activity), Furthermore, in this regard, the same applies to the specific diseases / disorders mentioned herein. Other combinations are also provided. With respect to the compounds of the present invention, as described herein. The law, but the method, includes administering such a combination in a therapeutically effective amount (and In one embodiment, such a method inhibits NLRP3 inflammasome activity. (In this context, it may also be possible to treat the diseases or disorders referred to herein.) The combinations referred to herein may be present in a single preparation, or they may be present in a single preparation. They may be formulated in separate preparations so that they can be administered simultaneously, separately, or sequentially. Therefore, in one embodiment, the present invention also inhibits NLRP3 inflammasome activity. A disease or disorder associated with (that disease or disorder is any one of those described herein) Combination preparations for simultaneous, separate, or sequential use in the treatment of (possibly) As a substance, (a) a compound according to the present invention according to any one of the embodiments described herein (b) substances, and (b) one or more other therapeutic agents (such therapeutic agents as described herein) Regarding combination products containing ), for example, in one embodiment, the combination It can be a kit of parts. Such combinations are called "combination medicines" and It may be called. The administration route for the compound of the present invention as a component of the combination is that It may be the same as or different from one or more other therapeutic agents that can be combined with it. The therapeutic agent is therapeutically active when administered to a patient in combination with the compound of the present invention. or enhances therapeutic activity, for example, chemical compounds, peptides, antibodies, antibody fragments or nuclei It is an acid.

[0103] (a) the compound according to the present invention and (b) other therapeutic agents when given as a combination The weight ratio can be determined by those skilled in the art. The ratio, as well as the exact dosage and frequency of administration, can be determined by those skilled in the art. As is well known to those who use the specific compounds and other antimicrobial agents of the present invention, The specific condition being treated, the severity of the condition being treated, the age, weight, sex, and diet of the specific patient. The timing of administration, the individual's overall health, the method of administration, and any other substances the individual may be taking. It depends on the medicine. Furthermore, the effective daily dose is determined according to the response of the subject being treated and / or according to the present invention. It is clear that the dosage of the compound may be reduced or increased depending on the assessment of the prescribing physician. Yes. The specific weight ratio of the compound of this invention to another antibacterial agent is in the range of 1 / 10 to 1 / 10. It can take the range of 1 / 5 to 1 / 5, and even more specifically, the range of 1 / 3 to 1 / 3.

[0104] The pharmaceutical composition or combination of the present invention provides approximately 1 to 100 units for a subject weighing approximately 50 to 70 kg. 0 mg of active ingredient, or approximately 1-500 mg, or approximately 1-250 mg, or approximately 1- A unit dose of the active ingredient of 150 mg, or 1 to 100 mg, or approximately 1 to 50 mg. It is possible. The therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the target species and body. It depends on the severity, age, and individual condition, the disability or disease being treated, or the degree of their severity. A physician, clinician, or veterinarian with ordinary skills can prevent or treat the progression of a disability or disease. The effective amount of each active ingredient needed to either or inhibit the activity can be easily determined. ru.

[0105] The dosage characteristics cited above are advantageous for mammals, such as mice, rats, and dogs. Using monkeys, or their isolated organs, tissues, and preparations, in vitro and in vitro This can be verified by a biochemical test. The compounds of the present invention are available in the form of a solution, for example, an aqueous solution. In vitro, and either enterally, parenterally, or preferably intravenously, for example, suspension It can be administered in vivo as a turbidity or in an aqueous solution. The in vitro dose is approximately 10 -3 Molar concentration ~10 -9 It can be within a range of molar concentrations. Therapeutic effectiveness in vivo. The dosage varies depending on the route of administration, ranging from approximately 0.1 to 500 mg / kg, or approximately 1 to 100 mg / kg. It could be within the range of g.

[0106] As used herein, the term "pharmaceutical composition" refers to a form suitable for oral or parenteral administration. In this, the compound of the present invention combined with at least one pharmaceutically acceptable carrier, or the This refers to pharmaceutically acceptable salts.

[0107] As used herein, the term “pharmaceutically acceptable carrier” means the preparation of a pharmaceutical composition or This refers to a substance useful in use, as is known to those skilled in the art, such as a suitable diluent or solvent. Dispersion medium, surfactant, antioxidant, preservative, isotonic agent, buffer, emulsifier, absorption retarder, salt, Drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, colorants, and so on. This includes combinations of (for example, Remington The Science and Practice of Pharmacy,22nd Ed.Pharmaceuti (See Cal Press, 2013, pp. 1049-1070).

[0108] As used herein, the term "subject" refers to an object that is the subject of treatment, observation, or experimentation, or an object that is the subject of an experiment. This refers to animals that have become mammals, most preferably humans.

[0109] As used herein, the term “therapeutic dose” means the biological or medical response of the subject, e.g. For example, it induces a reduction or inhibition of enzyme or protein activity, or relieves symptoms. To alleviate the condition, slow or delay the progression of the disease, or prevent the disease, etc. The compounds of the present invention (where applicable, forms, compositions, and combinations comprising such compounds of the present invention) This refers to the amount (including combinations). In one non-limiting embodiment, the term “therapeutic effective dose” When administered to a subject, (1)(i) it is mediated by NLRP3, or (ii (iii) related to NLRP3 activity, or (iii) depending on NLRP3 activity (normal or abnormal) To at least partially alleviate or inhibit a condition, disorder, or disease characterized by the above, (2) To prevent and / or induce remission; or to reduce the activity of NLRP3 or (3) Inhibit; or (4) This product is effective in reducing or inhibiting NLRP3 expression. This refers to the amount of the compound. In another non-limiting embodiment, the term “therapeutic effective dose” means the amount of cells, or When administered to tissue, noncellular biological material, or culture medium, it reduces the activity of NLRP3. Either partially reduce or inhibit NLRP3 expression; or at least partially reduce NLRP3 expression This refers to the amount of the compound of the present invention that is effective in reducing or inhibiting [a certain factor].

[0110] As used herein, the terms “inhibit,” “inhibit,” or “inhibit” are given Reduction or suppression of a condition, symptom, or disorder, or disease, or biological activity or process This refers to a significant decrease in baseline activity. Specifically, it involves inhibiting NLRP3 or Inhibiting the NLRP3 inflammasome pathway is effective in controlling IL-1 and / or IL-18 To reduce the ability of NLRP3 or the NLRP3 inflammasome pathway to induce production. This includes inactivating, destabilizing, and / or altering the distribution of NLRP3. This can be achieved by mechanisms including, but not limited to, the following:

[0111] As used herein, the term "NLRP3" means, but is not limited to, nucleic acids, polynucleotides. Rheotides, oligonucleotides, sense and antisense polynucleotide chains, complementary combinations Rows, peptides, polypeptides, proteins, homologs and / or orthologs of NLRP molecules isoform, precursor, mutant, variant, derivative, splice variant, all This means that it contains different species, as well as their active fragments.

[0112] As used herein, the terms “to treat” and “to treat” any disease or disorder "To do" or "treatment" means to alleviate or reduce a disease or disability (that is, (i) delaying or stopping the onset of a disease or at least one of its clinical symptoms; or At least one disease or disorder associated with a patient, including one that may not be identifiable to the patient. This refers to reducing or eliminating physical parameters or biomarkers.

[0113] As used herein, the terms “prevent” and “prevent” any disease or disorder "To do" or "prevention" means preventive treatment of a disease or disorder; or the onset of a disease or disorder. Alternatively, it refers to slowing down the process.

[0114] When used herein, the subject means that such subject is biologically free from such treatment. Treatment is "needed" if it provides medical or quality-of-life benefits.

[0115] "Combination" refers to a fixed combination of a single unit dosage form, or a combination of dosage forms. This refers to either of the compounds and combination partners of the present invention (for example, as described below). Another drug, also called a "therapeutic agent" or "adjunct," can simultaneously and independently... Alternatively, they may be administered separately within a time interval. A single component may be packaged in a kit. They may be packaged separately. Reconstitute one or both of the components (e.g., powder or liquid). Alternatively, it may be diluted to the desired dose before administration. (Term: "simultaneous administration" or "combination") When used herein, terms such as "administration" refer to the selection of a single target (e.g., a patient) as required. This means that the administration of the combination partner is included, and that the administration route is the same. It is intended to include treatment regimens in which drugs are not necessarily administered simultaneously or in combination.

[0116] As used herein, the term “combination drug” means a mixture of two or more active ingredients or This refers to the products resulting from a combination, including both fixed and non-fixed combinations of active ingredients. This includes both combinations. As used herein, the term “combination drug” refers to a single unit agent. Fixed combinations in form, or non-fixed combinations for combination administration or Refers to any of the kit of parts, where two or more therapeutic agents are used simultaneously, independently, or at the same time. They can be administered separately within an interval. The term “fixed combination” refers to therapeutic agents, for example, in this invention. Both the compound and its combination partner are available to patients simultaneously in the form of a single entity or dosage. It is administered to [the patient]. The term "non-fixed combination" refers to therapeutic agents, for example, the compounds and combinations of the present invention. Both matching partners, as separate entities, simultaneously, in parallel, or for a specific time limit This means that the drug is administered to the patient sequentially, and such administration will take place in the patient's body for 2 This brings therapeutically effective levels of various compounds. The latter also includes cocktail therapies, for example, three types. This also applies to the administration of the above-mentioned therapeutic agents.

[0117] The term "combination therapy" refers to the treatment of any therapeutic condition or disorder described in this disclosure. This refers to the administration of two or more therapeutic agents. Such administration involves a single agent having a fixed ratio of active ingredients. This includes the simultaneous administration of these therapeutic agents in substantially simultaneous manner, such as in capsules. Such administration involves distributing each active ingredient in multiple or separate containers (e.g., tablets, capsules). This includes simultaneous administration in powder and / or liquid form. Powder and / or liquid form may be administered before administration as desired. It can be reconstituted or diluted to the dose. In addition, such administrations may be administered at approximately the same time or at different times. This also includes the use of each type of therapeutic agent in a continuous manner in any of the following: In this case as well, the treatment regimen is a combination of drugs used to treat the condition or disorder described herein. This will provide beneficial effects from the combination.

[0118] Overview of pharmacology, use, compositions, and combinations In one embodiment, the therapeutically effective amount of any one of the embodiments described herein The present invention comprises a compound and a pharmaceutically acceptable carrier (containing one or more pharmaceutically acceptable carriers). A pharmaceutical composition containing (mu) is provided.

[0119] In some embodiments, any of the embodiments described herein for use as a drug The present invention provides a compound comprising one of the following.

[0120] In one embodiment, NLRP3 activity (including inflammasome activity) is associated with disease development In the treatment of the disorder, NLRP3 signaling is involved in the pathophysiology of the disease / disorder, and / or In the treatment of the disease or disorder that contributes to the symptoms and / or progression; NLRP3 In inhibition of phramosome activity (including in the target area where it is needed); and / or This is any one of the embodiments described herein for use as an NLRP3 inhibitor. The compound of the present invention (and / or any one of the embodiments described herein) A pharmaceutical composition containing such a compound of the present invention is provided.

[0121] In one embodiment, NLRP3 activity (including inflammasome activity) is associated with disease development In the treatment of the disorder, NLRP3 signaling is involved in the pathophysiology of the disease / disorder, and / or In the treatment of the disease or disorder that contributes to the symptoms and / or progression; NLRP3 In inhibition of phramosome activity (including in the target area where it is needed); and / or The present invention is based on any one of the embodiments described herein as an NLRP3 inhibitor. The compound (and / or the present invention as described herein in any one of the embodiments) The use of pharmaceutical compositions containing such compounds is provided.

[0122] In one embodiment, NLRP3 activity (including inflammasome activity) is associated with disease development Treatment of the disorder; NLRP3 signaling is involved in the pathophysiology and / or symptoms of the disease / disorder. Treatment of diseases or disorders that contribute to the progression of the disease; and / or NLRP3 infection In the manufacture of drugs for inhibiting ramosome activity (including in the target area where it is needed) The compound of the present invention (and / or the present invention) according to any one of the embodiments described herein. Pharmaceutical combination comprising such compound according to any one of the embodiments described in the details The use of the finished product is provided.

[0123] In one embodiment, NLRP3 signaling is involved in the pathophysiology of a disease or disorder, and / or symptoms. A method for treating a disease or disorder that contributes to the progression of and / or a therapeutically effective amount specified herein The compound of the present invention according to any one of the embodiments described herein (and / or described herein) A pharmaceutical composition comprising such a compound according to any one of the embodiments of the present invention, For example, a method is provided which includes administering to a subject (who needs it). In further embodiments... This was a method of inhibiting NLRP3 inflammasome activity in the target (required) area. And, to the target that requires a therapeutically effective amount, by any one of the embodiments described herein The compound of the present invention (and / or any one of the embodiments described herein) A method is provided which involves administering a pharmaceutical composition containing such a compound.

[0124] In all relevant embodiments of the present invention, a disease or disorder, for example, NLRP3 signal In diseases or disorders where transmission contributes to the pathophysiology, and / or symptoms, and / or progression of the disease / disorder Impairment of NLRP3 activity, or inhibition of NLRP3 inflammasome activity (NLRP3 activity) When diseases or disorders associated with (including RP3 inflammasome activity) are mentioned (e.g.) For example, as stated above in this specification, such diseases are inflammasome-related diseases or disorders. This may include immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases. In further embodiments, Such diseases or disorders include autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic disorders). Symptoms), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic lipid disorders) Fatty liver disease (NASH, alcoholic steatohepatitis, and alcoholic liver disease), inflammatory lividity Arthritis-related disorders (e.g., gout, pseudogout (chondrocalcification), osteoarthritis, rheumatoid arthritis, Arthritis (e.g., acute, chronic), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis) Type 1 / Type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hematological conditions (Dialysis-related inflammation), neuroinflammation-related diseases (e.g., multiple sclerosis, brain infections, acute injury, neuropathy) (Degenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., low cardiovascular risk) Reduced cerebrospinal fluid ratio (CvRR), hypertension, atherosclerosis, type 1 and type 2 diabetes and related conditions. Complications, peripheral artery disease (PAD), acute heart failure, inflammatory skin diseases (e.g., suppurative sweat gland disease) Inflammation, sores), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and Cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome) (MOS, myelofibrosis) may be included. In certain embodiments, such diseases or disorders may be self Inflammatory fever syndrome (e.g., CAPS), sickle cell disease, type 1 / type 2 diabetes and related conditions Complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcification), Chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infections, acute injury) (Neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (for example) For example, cardiovascular risk reduction (CvRR), hypertension, hidradenitis suppurativa, wound healing and scar formation, Furthermore, cancer (for example, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MOS)) Selected from ), myelofibrosis). In certain embodiments, NLRP3 inflammasome activity Diseases or disorders associated with sexual dysfunction include inflammasome-related disorders and disorders, immune disorders, and inflammation. Diseases, autoimmune diseases, autoinflammatory fever syndromes, cryopyrin-associated periodic syndromes, chronic liver disease Diseases, viral hepatitis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, alcohol Liver disease, inflammatory arthritis-related disorders, gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis, Chronic arthritis, acute arthritis, kidney-related diseases, hyperoxaluria, lupus nephritis, type I and type II. Type 1 diabetes, nephropathy, retinopathy, hypertensive nephropathy, hemodialysis-related inflammation, neuroinflammatory disorders, multiple Sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease, cardiovascular diseases, metabolic diseases Patients, reduced cardiovascular risk, hypertension, atherosclerosis, peripheral vascular disease, acute heart failure, Inflammatory skin diseases, acne, wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration. Select from sex, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, and myelofibrosis. It will be selected.

[0125] In one embodiment, the therapeutically effective amount of any one of the embodiments described herein A combination comprising the compound of the present invention and another therapeutic agent (containing one or more therapeutic agents) is provided. In further embodiments, other therapeutic agents are used to target farnesoid X receptor (FXR) agonists. Anti-fatty liver; anti-fibrosis; JAK inhibitors; anti-PD1 inhibitors, anti-LAG-3 inhibitors, anti-TI Checkpoint inhibitors including M-3 inhibitors or anti-POL1 inhibitors; chemotherapy, radiation Therapies and surgical procedures; uric acid-lowering therapy; anabolic and cartilage regeneration therapies; IL-17 blockers; complement inhibitors. Harmful agents; Bruton's tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors (TL R7 / 8 inhibitors; CAR-T therapy; antihypertensive drugs; cholesterol lowering agents; leukotriene A 4-hydrolase (LTAH4) inhibitor; SGLT2 inhibitor; 132-agonist; anti-inflammatory Drugs; non-steroidal anti-inflammatory drugs ("NSAIDs"); acetylsalicylic acid including aspirin Agent (ASA); paracetamol; regenerative therapy; treatment of cystic fibrosis; or atherosclerosis A treatment is selected from sexual therapy (and there are two or more treatments that are independently selected from these). Such combinations are provided. In further embodiments, the compounds of the present invention are For use as described herein, for example, NLRP3 signaling , the pathophysiology of a disease / disorder, and / or symptoms, and / or diseases or disorders that contribute to its progression, This includes inhibiting NLRP3 inflammasome activity (NLRP3 activity). For use in the treatment of diseases or disorders associated with (including phramosome activity), Furthermore, in this regard, the same applies to the specific diseases / disorders mentioned herein. Other combinations are also provided. With respect to the compounds of the present invention, as described herein. The law, but the method, includes administering such a combination in a therapeutically effective amount (and In one embodiment, such a method inhibits NLRP3 inflammasome activity. (In this context, it may also be possible to treat the diseases or disorders referred to herein.) The combinations referred to herein may be present in a single preparation, or they may be present in a single preparation. They may be formulated in separate preparations so that they can be administered simultaneously, separately, or sequentially. Therefore, in one embodiment, the present invention also inhibits NLRP3 inflammasome activity. A disease or disorder associated with (that disease or disorder is any one of those described herein) Combination preparations for simultaneous, separate, or sequential use in the treatment of (possibly) As a substance, (a) a compound according to the present invention according to any one of the embodiments described herein (b) substances, and (b) one or more other therapeutic agents (such therapeutic agents as described herein) This relates to combination products containing ( ).

[0126] The compound of the present invention (including forms and compositions / combinations containing the compound of the present invention) is as described above. Regardless of whether they are used for the indications, compared to compounds known in the prior art High efficacy, low toxicity, long duration of action, high potency, few side effects, Easily absorbed and / or with excellent pharmacokinetic properties (e.g., high oral bioavailability) (Having ability and / or low clearance) and / or other useful pharmacological, physical It may have the advantage of possessing specific or chemical properties.

[0127] For example, the compounds of the present invention have good or improved thermodynamic solubility (e.g., Compared to compounds known in the prior art; and, for example, known methods and / or as specified herein The compounds of the present invention may have the advantage of having (when measured by the method described). This blocks pyroptosis and the release of inflammatory cytokines (e.g., IL-1β) from cells. The compounds of the present invention may have the advantage of being able to make a decision. Compared to compounds of the same type, this may have the advantage of avoiding side effects, which is NL This may be due to the selectivity of RP3 inhibition. The compounds of the present invention may also be good or improved It may also have the advantage of possessing in vivo pharmacokinetics and oral bioavailability. They also have the advantage of having good or improved in vivo efficacy. Specifically, the compounds of the present invention are also outlined later in this specification (for example, (In Examples C and D) When compared in tests, the compounds offer advantages over the prior art compounds. It may have.

[0128] General preparation and analysis processes The compounds of the present invention are generally known to those skilled in the art, or are described herein. It can be prepared by a series of possible steps.

[0129] In the reactions described above and below, the reaction products are isolated from the reaction medium, if necessary. , methods generally known in the art (e.g., extraction, crystallization, and chromatography) It is clear that it can be further purified according to the (graph) method. Furthermore, two or more mirror images The reaction products exist in a sexual form, and are produced using known techniques, particularly preparative chromatography (for example) They can be isolated from the mixture by preparative HPLC or chiral chromatography. It is clear that each diastereoisomer or each enantiomer is a supercritical fluid. It can also be obtained by chromatography (SFC).

[0130] The starting materials and intermediates are either commercially available or generally known in the art. It is a compound that can be prepared according to conventional reaction procedures.

[0131] Analysis section LC-MS (Liquid Chromatography / Mass Spectrometry) General procedure Perform high-performance liquid chromatography (HPLC) measurements as specified for each method. Using an LC pump, diode array detector (DAD) or UV detector, and column This was carried out. Additional detectors were included as needed (see the table of methods below).

[0132] The flow from the column was introduced into a mass spectrometer (MS) equipped with an atmospheric pressure ion source. To obtain ions that can identify the nominal monoisotopic molecular weight (MW) of the compound Setting adjustment parameters (e.g., scanning range, dwell time, etc.) is a matter of knowledge to those skilled in the art. It falls within the scope of knowledge. Data collection was performed using appropriate software. The compounds have different experimental retention times (R t ) and are listed for each ion. Separately in the data table. Unless otherwise specified, the reported molecular ion is [M+H] + (Protonated molecules and bi / or [MH] - (Deprotonation molecules) In that case, specify the type of adduct (i.e., [M+NH4]). + [M+HCOO] - etc.) For molecules with multiple isotopic patterns (such as Br and Cl), the reported value is the most These values ​​were obtained for low isotopic masses. All results are typically associated with the methods used. It was obtained with experimental uncertainty.

[0133] From this point forward, "SQD" refers to a single quadrupole detector, and "MSD" refers to mass selectivity. It means detector, "RT" means room temperature, and "BEH" is cross-linked ethylsiloxane. It stands for Sun / Silica Hybrid, and "DAD" stands for Diode Array Detector. "HSS" stands for high-strength silica.

[0134] [Table 1]

[0135] [Table 2]

[0136] NMR For some compounds, Bruker Ava operates at 300 or 400 MHz. The Bruker Avance III spectrometer operates at 400 MHz. -HD, Bruker NEO spectrometer operating at 400MHz, operating at 500MHz With a Bruker Avance Neo spectrometer, or a Bru operating at 600 MHz Using a Ker Avance 600 spectrometer, chloroform-d(deuterated chloroform) was used as the solvent. Formaldehyde (CDCl3), DMSO-d6 (deuterated DMSO, dimethyl-d6 sulfoxy) D), methanol-d4 (deuterated methanol), benzene-d6 (deuterated benzene, Using C6D6) or acetone-d6 (deuterated acetone, (CD3)2CO), 1 The 1H NMR spectrum was recorded. The chemical shift (δ) was used as an internal standard for tetra Report the methylsilane (TMS) concentration in parts per million (ppm).

[0137] melting point The values ​​represent peak values ​​or melting ranges and are subject to the experimental uncertainties typically associated with this analytical method. And you can get that.

[0138] Method A: For some compounds, determine the melting point of DSC823e (Mettler-To The melting point was determined using a LedO (Ledo) instrument. The melting point was measured with a temperature gradient of 10°C / min. Standard maximum temperature The temperature was 300℃.

[0139] Method B: For some compounds, the melting point was determined by placing them in an open capillary tube and measuring the Mettler T The melting point was determined using an Oledo MP50. The melting point was measured with a temperature gradient of 10°C / min. Maximum temperature The temperature was 300°C. The melting point data was read from a digital display device and recorded on video. I checked it on the stem.

[0140] Experiment Section In the following, the term "mp" means melting point, "aq." means aqueous, and "rm" means aqueous. " means reaction mixture, "rt" means room temperature, and "DIPEA" means N,N-diiso- "DIPE" means diisopropyl ether, and "T" means propylethylamine. "HF" stands for tetrahydrofuran, and "DMF" stands for dimethylformamide. "DCM" stands for dichloromethane, and "EtOH" stands for ethanol. " means ethyl acetate, "AcOH" means acetic acid, and "iPrOH" means isopropano It means "ru", "iPrNH2" means isopropylamine, and "MeCN" or "A "CN" stands for acetonitrile, "MeOH" stands for methanol, and "Pd(OAc )2" means palladium(II) diacetate, and "rac" means racemic, and "s "at." means saturation, and "SFC" means supercritical fluid chromatography. "C-MS" stands for supercritical fluid chromatography / mass spectrometry, while "LC-MS" stands for liquid GCMS stands for Gas Chromatography / Mass Analysis. "HPLC" means high-performance liquid chromatography, and "RP" means reversed phase. It means that "UPLC" stands for ultra-high performance liquid chromatography, and "R t (or "RT '') means holding time (in minutes), and "[M+H] + " is the protonation of the free base of a compound. "DAST" means mass, and "DMTM" means diethylaminosulfur trifluoride. "M" stands for 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmethyl It means rufolium chloride, and "HATU" is O-(7-azabenzotriazole-1- (1)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1 -[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] Xantphos (meaning pyridinium 3-oxide hexafluorophosphate) " is (9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenylphosphine "TBAT" means tetrabutylammonium triphenyldifluorosilicone "TFA" means trifluoroacetic acid, and "Et2O" means diethyl acetate. "Tel" means "methyl sulfoxide," "DMSO" means dimethyl sulfoxide, and "SiO2" means silica. This means that "XPhos Pd G3" is (2-dicyclohexylphosphino-2',4' ,6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- Biphenyl refers to palladium(II) ethanesulfonate, and "CDCl3" is heavy water. It means chloroform, "MW" means microwave or molecular weight, and "min" means minute It means that "h" means time, "rt" means room temperature, and "quant" means quantitative. In this context, "nt" means untested, and "Cpd" means compound. "POCl3" stands for phosphorus(V) oxychloride.

[0141] For important intermediates and some final compounds, the absolute configuration of the chiral center (R and / (or shown as S) is compared with a sample having a known configuration, or VCD (vibrating circular polarization) By using analytical methods suitable for determining absolute configuration, such as dichroism or X-ray crystallography, Confirmed. If the absolute configuration at the chiral center is unknown, it is arbitrarily denoted as R*. [Examples]

[0142] Example - Example A Preparation of intermediates Synthesis of 4-(2-amino-4-bromophenyl)buta-3-in-1-ol(I-1) [ka] 5-bromo-2-iodoaniline [64085-52- 5] (11.5g, 38.6mmol), copper(I) iodide (147.0mg, 0.77mg) mol) and tetrakis(triphenylphosphine)palladium(0)(446.1mg) In a solution of 0.39 mmol, under nitrogen, 3-buty-1-ol (3.07 mL, 4 (0.5 mmol) and triethylamine (8.05 mL, 57.9 mmol) in a syringe. It was added simultaneously via [method / method]. This mixture was vigorously stirred at room temperature for 18 hours. Reaction mixture E Extraction was performed using tOAc (4 x 80 mL). The combined organic layers were dried with Na2SO4 and filtered. The solution was then concentrated in a vacuum. The resulting brown residue was heptane / toluene (4:1~0:1). Purified by column chromatography using gradient elution, 4-(2-amino-4 - Bromophenyl)buta-3-in-1-ol I-1, dark brown oily substance (9.35g (This was obtained as a quantitative result.) ¹H NMR (400 MHz, chloroform-d) δ ppm 1.99 (t, J=5) .7Hz,1H),2.72(t,J=6.2Hz,2H),3.82(q,J=6.0 Hz,2H),4.27(br s,2H),6.78(dd,J=8.2,1.9Hz ,1H),6.84(d,J=1.9Hz,1H),7.09(d,J=8.3Hz,1 H). LCMS (Rt=1.63 min, 96%(UV), m / z(ES+)=240.1;m / z (ES-)=ND method 1.

[0143] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0144] [Table 3]

[0145] 7-Bromo-3-(2-hydroxyethyl)sinnoline-4(1H)-one(I-4) synthesis [ka] 4-(2-amino-4-bromophenyl)buta-3-in-1-ol I-1(9.3 5g, 38.9 mmol) to which a solution of H2SO4 in DI water (75 mL) (8.3 mL, 155.8 mmol) was added. The mixture was cooled to 0°C for 10 minutes, and then DI water (1 A 12 mL solution of sodium nitrite (4.03 g, 58.4 mmol) is heated at 0°C for 45 minutes. It was added dropwise over several minutes. After adding, the mixture was slowly warmed to room temperature (remove the ice from the ice bath). (Keep the water at 0°C and slowly heat it to room temperature), and stir for a total of 6 hours. Pale brown Filter off the resulting suspension, wash with DI water (2 x 10 mL), and then place the moist paste under vacuum. Then, dry at 50°C for 16 hours, and 7-bromo-3-(2-hydroxyethyl) sinnoli N-4(1H)-ONE I-4 was obtained as a light brown solid (9.35 g, yield 89%). 1H NMR(400MHz,DMSO-d6)δ ppm 2.85(t,J=6.9 Hz,2H),3.71(t,J=6.9Hz,2H),7.50(dd,J=8.6, 1.8Hz,1H),7.72(d,J=1.8Hz,1H),7.95(d,J=8. 6Hz, 1H), 13.23(s, 1H). LCMS Rt=1.22 min, 100%(UV), m / z(ES+)=269.0 / 27 1.0;m / z(ES-)=267.0 / 269.0, method 1.

[0146] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0147] [Table 4]

[0148] 7-Bromo-3-(2-((triisopropylsilyl)oxy)ethyl)sinnoline-4 (1H)-on (I-7) synthesis [ka] 7-bromo-3-(2-hydroxyethyl) cinnamon in dried DMF (80.7 mL) N-4(1H)-ONE I-4 (9.35g, 34.7mmol) and imidazole (2. In a suspension of 84 g (41.7 mmol), triisopropyl siliceous chloride was added under nitrogen and at 0°C. Add 7.8 mL (36.5 mmol) dropwise. After addition, remove the ice bath and the mixture The mixture was heated to room temperature and stirred for 16 hours. The mixture was concentrated to a solution of approximately 10-15 mL and then brewed. The mixture was poured into a line (100 mL) and extracted with an ethyl acetate filter (5 × 100 mL). The organic extract was concentrated in a vacuum, and the resulting residue was redissolved in DCM to obtain Na2SO4. The solution was filtered on a pad. The solution was concentrated and 7-bromo-3-(2-((triisopropyl sulfate) (15.9) g, with a purity of 92% by weight and a yield of 99%, was obtained and used without further purification. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 0.96-1.08 m,21H),3.13(t,J=6.9Hz,2H),4.10(t,J=6.9Hz ,2H),7.42(dd,J=8.8,1.7Hz,1H),7.77(d,J=1. 6Hz, 1H), 8.13(d,J=8.8Hz, 1H). LCMS Rt=2.59 min, 98%(UV), m / z(ES+)=425.2 / 427 .2;m / z(ES-)=423.3 / 425.3, method 1.

[0149] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0150] [Table 5]

[0151] 7-Cyclopropyl-3-(2-((triisopropylsilyl)oxy)ethyl)cinno Synthesis of phosphorus-4(1H)-one (I-10) [ka] I-7 (5.012g, 11.781mmol), cyclopropylboronic acid [4112 35-57-9](3.106g, 36.159mmol), Cesium Carbonate [534-1 7-8] (12.9g, 39.592 mmol) and Pd(dppf)Cl2·CH2C l2[95464-05-4](1.46g, 1.788 mmol) in a 250mL round-bottom container. It was placed in a flask and left under nitrogen (3 cycles of vacuum / nitrogen). 1,4-Dioxy Sun (60 mL) and DI water (20 mL) were added to the solid, and the resulting reaction mixture was nitrogen-12. Stirred overnight at -90°C. Then, add toluene (approx. 100 mL) and brine (approx. 3 mL). The liquid-liquid was separated between (00 mL). The organic layer was collected, and the aqueous layer was further separated into HCl (3 × approximately 100 mL). Extracted using L). The combined organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure at 40°C. The crude substance was subjected to flash column chromatography (heptane / toluene 1:0 Purified by a ratio of approximately 3:2, I-10 (2.885g, yield 61%) was obtained as a white solid. I obtained it. 1 H NMR(400MHz,DMSO-d6)δ ppm 0.76-0.84(m, 2H),0.89-1.04(m,22H),1.04-1.11(m,2H),2.0 4-2.14(m,1H),2.91(t,J=7.04Hz,2H),3.98(t, J=6.93Hz,2H),7.04(dd,J=8.58,1.54Hz,1H),7 .19(d,J=1.54Hz,1H),7.90(d,J=8.58Hz,1H). LCMS Rt=2.57 min, 96%(UV), m / z(ES+)=387;m / z(E S-)=385, method 1.

[0152] 1-Isopropyl-7-(trifluoromethyl)-3-(2-((triisopropyl silicone Synthesis of hydroxyethyl-sinnoline-4(1H)-one (I-11) [ka] 7-(trifluoromethyl) in dried acetonitrile [75-05-8] (98 mL) -3-(2-((triisopropylsilyl)oxy)ethyl)sinnoline-4(1H)- ON I-8 (15.8g, 37.73 mmol), 2-iodopropane [75-30-9 ](4.52mL, 45.28 mmol) and K2CO3[584-08-7](10. Stir the mixture of 43g (75.47 mmol) and heat it in a pressure tube at 90°C for 18 hours. The solvent was evaporated, the residue was placed in water, and extracted with HCl. The organic layer was separated. Washed with brine, dried over MgSO4, and filtered. The solvent was evaporated, and the residue was heptane. For column chromatography that uses gradient elution of / ¼(1:0~85:15) Further purification yields 1-isopropyl-7-(trifluoromethyl)-3-(2-((tri Sopropylsilyl(oxy)ethyl(sinoline-4(1H)-one I-11 is yellow It was obtained as an oily substance (10.99 g, yield 63%). 1 H NMR(300MHz,DMSO-d6)δ ppm 0.91-1.00(m, 21H),1.43(d,J=6.4Hz,6H),2.98(t,J=6.6Hz,2 H),4.05(t,J=6.6Hz,2H),5.30-5.46(m,1H),7. 66-7.73(m,1H),8.30-8.37(m,2H). LCMS Rt=1.62 min, 99%(UV), m / z(ES+)=457;m / z(E S-)=-, method 6.

[0153] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0154] [Table 6]

[0155] 1-Cyclopropyl-7-(trifluoromethyl)-3-(2-((triisopropyl methyl Synthesis of lyl(oxy)ethyl)sinnoline-4(1H)-one(I-18) [ka] Pyridine [110-86-1] (3.5 mL, 43.451 mmol) in 100 mL I-8 (5.02 g, 12.1) in 1,4-dioxane (40 mL) in a round-bottom flask. 1 mmol) and copper(II) acetate [142-71-2] (6.67 g, 36.722 mm) The mixture was added to a suspension of (ol) and stirred at 110°C for 15 minutes. The mixture was then left to cool to room temperature. Cool to the desired temperature, then add cyclopropylboronic acid [411235-57-9] (2.75g, 32 0.015 mmol) was added. The reaction mixture was then stirred overnight at 110°C. Propylboronic acid [411235-57-9] (3.02 g, 35.158 mmol) and Further part of copper(II) acetate [142-71-2] (1.1 g, 6.056 mmol) The reaction mixture was stirred at 110°C for 4 hours. Cyclopropylboronic acid [411235 -57-9] (908 mg, 10.571 mmol) and copper(II) acetate [142-71 -2] (3.08g, 16.957 mmol) was added, and the reaction mixture was incubated at 120°C for 1 hour. Then, stir at room temperature overnight. Allow the reaction mixture to cool to room temperature, rinse with oxygen for 5 minutes, and then... Clopropylboronic acid [411235-57-9] (1.26g, 14.668mmol) ) and the final result of copper(II) acetate [142-71-2] (2.5g, 13.764 mmol) The mixture was added and the reaction was stirred at 110°C for 3 hours. The reaction mixture was then mixed with water (approximately 150 mL) and Quench with a mixture of ا (approximately 50 mL), and the product is divided into ا (3 × 50 mL). Extraction was performed. The combined organic extracts were dried with MgSO4, filtered, and concentrated under reduced pressure at 40°C. It shrunk. The crude substance was subjected to flash column chromatography (heptane / ¼ 1: Purification was performed using a 0-7:3 ratio to obtain I-18 (4.2g, 76% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm 0.86-1.06(m, 21H),1.08-1.16(m,2H),1.20-1.29(m,2H),2.9 3(t,J=6.7Hz,2H),3.92(tt,J=7.1,3.6Hz,1H), 4.00(t,J=6.6Hz,2H),7.74(dd,J=8.5,1.4Hz,1 H),8.30(d,J=8.5Hz,1H),8.32(s,1H). LCMS Rt=2.89 min, 100%(UV), m / z(ES+)=455.4;m / z(ES-)=-, method 1.

[0156] 7-Bromo-1-cyclopropyl-3-(2-((triisopropylsilyl)oxy) Synthesis of thirlin-4(1H)-one(I-19) [ka] Copper(II) acetate [142-71-2] (4.7g, 25.81 mmol) and cyclop Ropyruvoronic acid [411235-57-9] (1.8g, 21.51 mmol) is used in 1, 7-bromo-3-(2-((triisopropyl silicone in 4-dioxane (36.7 mL) (Lu)oxy)ethyl)sinnoline-4(1H)-one I-7 (3.7g, 8.60mmo) l) was added to a solution of pyridine (2.1 mL) in an open-air system. Condenser Then, secure the oxygen balloon to the reaction setup, vacuum the system, and fill it with oxygen three times. I refracted the greenish reaction mixture. I heated it under reflux for 10.5 hours (110°C) and left it over the weekend. The mixture was then stirred at room temperature. Next, the reaction mixture was added to water and 1 mL of 25% aqueous ammonia solution. Quenched and extracted three times with DCM. The combined organic layer was dried with MgSO4 and filtered. The product was concentrated in a vacuum. The brown crude product was subjected to flash column chromatography (DCM). Purified by 7-bromo-1-cyclopropyl-3-(2-((triisopropyl s (Lyl)oxy)ethyl)sinnoline-4(1H)-one I-19 (3.5g, yield 87%) ) was obtained as an orange solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 0.96-1.11(m) ,22H),1.24(d,J=5.3Hz,5H),3.05(t,J=6.7Hz, 2H),3.48-3.54(m,1H),4.06(t,J=6.7Hz,2H),7 .47(dd,J=8.7,1.7Hz,1H),8.04(d,J=1.5Hz,1H ), 8.16(d,J=8.6Hz,1H). LCMS Rt=2.98 min, 100%(UV), m / z(ES+)=465.3 / 46 7.3;m / z(ES-)=-, method 2.

[0157] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0158] [Table 7]

[0159] 7-Cyclopropyl-1-ethyl-3-(2-((triisopropylsilyl)oxy) Synthesis of thirlin-4(1H)-one(I-21) [ka] Degassed solution of I-12 (2g, 4.41 mmol) in dried THF (24.05 mL) Under nitrogen, Pd( t Bu3P)2[53199-31-8](225.4mg, 0.4 (4 mmol), followed by a commercially available cPr-ZnBr solution in Me-THF [126403- [68-7] (22.05 mL, 0.5 M, 11.03 mmol) was added. Reaction mixture The mixture was stirred at room temperature under an inert atmosphere for 3 hours. Then, DI water (20 mL) was added, followed by N Quench by adding a saturated aqueous solution of H4Cl (200 mL), then add brine (100 mL) The mixture was poured into a container and extracted with ELISA (3 x 80 mL). The combined organic extract was then treated with Na2S Dry with O4, filter, concentrate, and extract the residue from FCC (heptane / toluene 7:3~ The mixture is purified using a 0:1 ratio to obtain I-21 as a white solid, which is then used directly in the next step. Used in the following conditions: LCMS Rt=1.61 min, 100% (UV), m / z (ES+)=41 5.4;m / z(ES-)=-, method 5.

[0160] 7-Cyclopropyl-1-isopropyl-3-(2-((triisopropylsilyl)oxy Synthesis of ethyl sinnoline-4(1H)-one (I-22) [ka] I-13 (8g, 17.11 mmol) with 1,4-dioxane and DI water (80mL) It was dissolved in a 3:1 mixture. The solution was sparged with N2 in a sealed tube for 5 minutes. Then, Cyclopropylboronic acid [411235-57-9] (1.76g, 20.53mmol) ), cesium carbonate [534-17-8] (12.27 g, 37.65 mmol) and Pd (dppf)Cl2·CH2Cl2[95464-05-4](2.096g, 2.57 mmol) was added sequentially. The resulting mixture was sparged with N2 for 5 minutes, and then 90°C. The mixture was stirred at °C for 16 hours. Then, the mixture was diluted with DI water and extracted with ethyl acetate. The prepared organic layer was dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. The crude product was then processed. Purification by Rush column chromatography (heptane / toluene 1:0~4:1) The mixture was prepared to obtain I-22 (5.25 g, yield 72%) as a pale yellow oily substance. 1 H NMR(400MHz,DMSO-d6)δ ppm 0.90(dd,J=4. 8,2.1Hz,2H),0.91-1.02(m,21H),1.06-1.12(m ,2H),1.41(d,J=6.4Hz,6H),2.02-2.27(m,1H), 2.92(t,J=6.7Hz,2H),4.01(t,J=6.7Hz,2H),5. 23(dt,J=12.8,6.4Hz,1H),7.05(dd,J=8.5,0.9 Hz,1H),7.59(s,1H),8.00(d,J=8.5Hz,1H). LCMS Rt=1.79 min, 99%(UV), m / z(ES+)=429.3;m / z (ES-)=-, method 8.

[0161] 7-(1-ethoxyvinyl)-1-ethyl-3-(2-((triisopropylsilyl)o Synthesis of xy)ethyl)sinnoline-4(1H)-one(I-23) [ka] I-12 (7.1 g, 15.66 mmol) in 1,4-dioxane (125 mL) and dichlorobis(triphenylphosphine)palladium(II)[13965-03-2 The mixture of ](1.1g, 1.57 mmol) was sparged with N2 for 10 minutes. Then, Tributyl(1-ethoxyvinyl)tin [97674-02-7] (7.93 mL, 23 Add 0.48 mmol) and heat the mixture at 100°C for 4 hours. Cool the crude mixture to room temperature. It was rinsed and concentrated under vacuum. The obtained substance was treated with a saturated aqueous solution of NaHCO3 and EtO3 was obtained. Extraction was performed using Ac (2 x 200 ml). The combined organic layer was evaporated under vacuum and flashed. Purified by ram chromatography (heptane / dimethyl 1:0~4:1), I -23 (6.01 g, yield 86%) was obtained as a yellow oily substance. LCMS Rt=1.68 min, 99%(UV), m / z(ES+)=445;m / z(E S-)=-, method 4.

[0162] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0163] [Table 8]

[0164] 1-Ethyl-7-(prop-1-en-2-yl)-3-(2-((triisopropyl ethyl Synthesis of lyl(oxy)ethyl)sinnoline-4(1H)-one(I-26) [ka] I-12 (4g, 8.82 mmol) is mixed with 1,4-dioxane (72mL) and DI water. It was dissolved in (24 mL) of the mixture. The solution was sparged with N2 in a sealed tube for 5 minutes. Next And, potassium isopropenyltrifluoroborate [395083-14-4] (1.5 7g, 10.58 mmol), cesium carbonate [534-17-8] (6.32g, 19. 4 mmol) and Pd(dppf)Cl2·CH2Cl2[95464-05-4](1 (0.08g, 1.32 mmol) was added sequentially. Further treatment was performed in N2. After sparging for 5 minutes, the mixture was stirred at 90°C for 16 hours. Then, it was mixed with DI water. Diluted and extracted with carboxymethylcellulose. The combined organic layers were washed with brine and dried (MgSO4). The mixture was filtered, and the solvent was evaporated under vacuum. The crude product was then chromatographed using a flash column chromatograph. Purified by (heptane / ethylammonium 1:0~4:1), I-26 (2.8g, A yield of 77% was obtained as a colorless oily substance. LCMS Rt=1.64 min, 95%(UV), m / z(ES+)=415;m / z(E S-)=-, method 5.

[0165] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0166] [Table 9]

[0167] 1-Ethyl-7-isopropyl-3-(2-((triisopropylsilyl)oxy)eth Synthesis of cinnoline-4(1H)-one(I-29) [ka] Pd / C (10% by weight, 718.6 mg, 0.68 mmol) was hydrogenated in 250 mL of water. Solution of I-26 (2.8 g, 6.75 mmol) in EtOH (40 mL) in a flask. It was added to the reaction vessel. The reaction vessel was purged with hydrogen (3 hydrogen / vacuum cycles) and placed under a hydrogen atmosphere. The reactants were placed in a cool place. The reactants were stirred at room temperature until the completion of the reaction was observed by LC-MS. Next... Then, the solid material is filtered on a Decalite pad, the filtrate is concentrated, and the resulting residue is purified. Used without preparation. Note: Partial deprotection of TIPS was observed. LCMS Rt=1.66 min, 37%(UV), m / z(ES+)=417.4;m / z (ES-)=-&Rt=0.82min m53%(UV), m / z(ES+)=261.2; m / z(ES-)=-, method 5.

[0168] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0169] [Table 10]

[0170] 1-Ethyl-7-(2-hydroxypropan-2-yl)-3-(2-((triisopropyl Synthesis of pyrsilyl(oxy)ethyl(sinnoline-4(1H)-one(I-32) [ka] I-26 (1.9g, 4.6mmol), 4-nitrobenzenesulfonyl chloride [98- 74-8](1.3g, 5.9mmol), NaHCO3[144-55-8](770 mg, 9.2 mmol) and Fe(acac)3[14024-18-1](40 mg, 0.1 mmol) was dissolved / suspended in dry MeOH (35 mL) in a sealed tube. Mixing The material was sparged with N2 for 5 minutes and cooled to 0°C. Then, phenylsilane [694-53 Add -1] (1.7 mL, 13.7 mmol) at 0°C and slowly allow the mixture to rise to room temperature. The mixture was heated and stirred at room temperature for 16 hours. The solvent was removed under vacuum to obtain a yellow solid, which was then processed. Purification by Rush column chromatography (heptane / acetone 1:0~0:1) Prepared, I-32 (373 mg, approximately 80% purity, 15% yield) was obtained as a yellow oily substance. Ta. 1 H NMR(300MHz,DMSO-d6)δ ppm 0.95-1.00(m, 21H),1.39(t,J=7.1Hz,3H),1.50(s,6H),2.92( t,J=6.6Hz,2H),3.96-4.07(m,2H),4.47(q,J=7 .1Hz,2H),5.37(s,1H),7.53(dd,J=8.6,1.3Hz, 1H),7.73(s,1H),8.06(d,J=8.5Hz,1H). LCMS Rt=1.27 min, 80%(UV), m / z(ES+)=433.2;m / z (ES-)=-, method 6.

[0171] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0172] [Table 11]

[0173] 7-Bromo-3-(2-hydroxyethyl)-1-isopropylcinnoline-4(1H) - ON (I-34) synthesis [ka] 7-bromo-1-isopropyl-3-(2-((triiso in dried THF (16 mL) Propylsilyl(oxy)ethyl(sinnoline-4(1H)-one I-13(5.1g, In a 10.91 mmol solution, TBAF (1 M in THF) (16 ml) was added under nitrogen and at 0°C. (L, 16 mmol) was added dropwise over 5 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. Remove the liquid and dissolve the crude substance by gradient elution with heptane / toluene (1:0~1:1). The following was purified by column chromatography: 7-bromo-3-(2-hydroxyethyl (Lu)-1-isopropylcinnoline-4(1H)-one I-34 (2.78g, yield 82 The %) was obtained as a white powder. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.41(d,J=6.4 Hz,6H),2.88(t,J=7.0Hz,2H),3.67-3.79(m,2H ),4.56(t,J=5.6Hz,1H),5.14-5.29(m,1H),7.5 6(dd,J=8.7,1.7Hz,1H),8.04(d,J=8.6Hz,1H), 8.22 (d, J=1.5Hz, 1H). LCMS Rt=1.67 min, 100%(UV), m / z(ES+)=311;m / z( ES-)=-, method 1.

[0174] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0175] [Table 12]

[0176] [Table 13]

[0177] [Table 14]

[0178] [Table 15]

[0179] 7-Acetyl-1-ethyl-3-(2-hydroxyethyl)sinnoline-4(1H)-O Synthesis of n (I-51) [ka] A 2M aqueous solution of HCl (67.6 mL, 135.2 mmol) is used to dissolve 1,4-dioxane ( It was added to a solution of I-23 (6.01 g, 13.52 mmol) in 67 mL. Reaction mixture The mixture was stirred at room temperature for 16 hours. Then, it was treated with a saturated aqueous solution of NaHCO3, and E Extracted with tOAc. The combined organic layers were washed with brine, dried on MgSO4, and filtered. The mixture was then evaporated in a vacuum. The resulting residue was stirred in 150 ml of DIPE, and the solids were removed. Filter and dry under vacuum to obtain I-51 (3.3g, yield 94%) as a pale yellow solid. I obtained it by doing so. LCMS Rt=0.57 min, 92%(UV), m / z(ES+)=261;m / z(E S-)=-, method 4.

[0180] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0181] [Table 16]

[0182] 7-Bromo-3-(2-hydroxyethyl)-1-isopropylcinnoline-4(1H) - ON (I-54) synthesis [ka] Commercially available Jones reagent 2M solution [65272-70-0] (42 mL, 84 mmol) ) in acetone [67-64-1] (514.6 mL) I-35 (8.32 g, 28 The solution of mmol was added dropwise at 0°C. After the addition was complete, the mixture was allowed to rise to room temperature for 30 minutes. Stirring was continued. Then, it was poured into DI water (1.5 L), and the resulting solution / suspension was divided into 3 Stirred for 0-60 minutes. Filter out the solids and wash with water (twice) and heptane (twice). Dry at -50°C, and I-54 (9.17g, 95% purity, 82% yield) is white. It was obtained as a solid. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.36(t,J=7.1 Hz,3H),3.61(s,2H),4.49(q,J=7.1Hz,2H),7.6 2(dd,J=8.7,1.6Hz,1H),8.03(d,J=8.7Hz,1H), 8.15(d,J=1.5Hz,1H),12.45(s,1H). LCMS Rt=0.84 min, 95%(UV), m / z(ES+)=311.1;m / z (ES-)=-, method 6.

[0183] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0184] [Table 17]

[0185] [Table 18]

[0186] [Table 19]

[0187] [Table 20]

[0188] Ethyl 2-(7-bromo-1-isopropyl-4-oxy-1,4-dihydrosinnoline) Synthesis of -3-yl acetate (I-74) [ka] 1-Propanephosphonic anhydride [68957-94-8] (50% by weight in toluene) 1.2 mL, 2.016 mmol) in EtOH (4.5 mL) I-55 (300 ml) (g, 0.793 mmol) and Et3N[121-44-8](0.4 mL, 2.878 The reaction was added to a solution of mmol. The reaction mixture was stirred overnight at room temperature. The crude mixture was then heated under reduced pressure at 40°C. The product is concentrated and the product is subjected to flash column chromatography (heptane / I1 1). Purified by (0~0:1), I-74 (229 mg, yield 82%) is obtained as a colorless oil. I obtained it by doing so. LCMS Rt=2.03 min, 100%(UV), m / z(ES+)=353;m / z( ES-)=-, method 1.

[0189] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0190] [Table 21]

[0191] [Table 22]

[0192] [Table 23]

[0193] Methyl 2-(7-bromo-1-isopropyl-4-oxo-1,4-dihydrosinnoline) Synthesis of -3-yl acetate (I-87) [ka] Iodomethane [74-88-4] (1.74 mL, 27.94 mmol) in DMF I-54 (7.56g, 24.3 mmol) and cesium carbonate [534-17-8]( The mixture was added to a stirred solution (10.29 g, 31.59 mmol) at room temperature. The mixture was stirred. The mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with toluene. The organic layer was dried with MgSO4, filtered, and concentrated in vacuum. The crude material was flash-treated. Purified by ram chromatography (heptane / dimethyl 1:0~4:1), I -87 (6.32g, yield 79%) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.36(t,J=7.1 Hz,3H),3.61(s,3H),3.71(s,3H),4.49(q,J=7. 1Hz,2H),7.63(dd,J=8.7,1.6Hz,1H),8.03(d,J =8.7Hz,1H),8.16(d,J=1.6Hz,1H). LCMS Rt=2.96 min, 99%(UV), m / z(ES+)=311.1;m / z (ES-)=-, method 7.

[0194] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0195] [Table 24]

[0196] [Table 25]

[0197] Ethyl 2-(7-(1,1-difluoroethyl)-1-ethyl-4-oxo-1,4-di Synthesis of hydrosinnoline-3-yl)acetate (I-95) [ka] DAST[38078-09-0](5.9mL, 44.65 mmol) and (HF) 3·Et3N[73602-61-6] (4.37 mL, 26.79 mmol), dried Add to a solution of I-84 (2.7g, 8.93 mmol) in DCM (20 ml) at room temperature. After adding, the mixture was stirred at 47°C for 24 hours. Then, it was cooled in an ice bath, and Na was added. The organic layer was quenched with a saturated aqueous solution of HCO3 (added dropwise). The organic layer was separated and dried with Na2SO4. The crude substance was concentrated in a vacuum. The crude substance was then subjected to flash column chromatography (heptane / E). Purified by tOAc (1:0~3:2), I-95 (2.7g, yield 93%) was obtained from ash It was obtained as a white solid. LCMS Rt=0.96 min, 100%(UV), m / z(ES+)=325;m / z( ES-)=-, method 5.

[0198] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0199] [Table 26]

[0200] Methyl 2-(1-ethyl-7-(2-fluoropropan-2-yl)-4-oxo-1, Synthesis of 4-dihydrosinnolin-3-yl)acetate (I-98) [ka] DAST[38078-09-0](220uL, 1.7 mmol) and (HF)3· Et3N[73602-61-6] (102 μL, 0.6 mmol) was dried in DCM (4 A mixture of I-93 (127 mg, 0.4 mmol) in mL is placed in a sealed plastic tube. The mixture was added at room temperature. The mixture was stirred at 50°C for 16 hours. The crude reaction mixture was cooled to 0°C. Then, it was quenched with a saturated aqueous solution of NaHCO3. Next, it was extracted with DCM and combined. The organic layer was dried with MgSO4, filtered, and concentrated under vacuum. The crude product was flash-coated. Purified by ram chromatography (heptane / dimethyl 1:0~1:1), I -98 (109 mg, yield 84%) was obtained as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.39(t,J=7.1 Hz,3H),1.72(s,3H),1.79(s,3H),3.61(s,3H), 3.72(s,2H),4.54(q,J=7.2Hz,2H),7.55(dd,J= 8.6,1.3Hz,1H),7.71(s,1H),8.14(d,J=8.5Hz, 1H). LCMS Rt=0.81 min, 99%(UV), m / z(ES+)=307.2;m / z (ES-)=-, method 6.

[0201] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0202] [Table 27]

[0203] Methyl 2-(7-cyclobutyl-1-ethyl-4-oxo-1,4-dihydrosinnoline) Synthesis of -3-yl acetate (I-100) [ka] CataCXium(registered trademark) A [321921-71-5] (57.3 mg, 0. 16 mmol) is used in a mixture of toluene (6.4 mL) and DI water (0.6 mL) with I- 87 (520 mg, 1.6 mmol), potassium cyclobutyltrifluoroborate [10 65010-88-9] (285 mg, 1.76 mmol), Cesium Carbonate [534-1 7-8](1.56g, 4.8mmol) and Pd(OAc)2[3375-31-3] Add N2 to a stirred solution of (35.9 mg, 0.16 mmol) while sparging. The mixture obtained was heated at 100°C for 16 hours. The reaction mixture was diluted with DI water, and two The phase mixture was extracted with DCM. The combined organic extract was dried over MgSO4 and filtered. The product was concentrated in a vacuum. The crude product was subjected to flash column chromatography (heptane / Et). Purified by OAc (1:0~7:3), I-100 (209 mg, 95% purity, yield) A 41% yield was obtained as a white solid. LCMS Rt=1.21 min, 95%(UV), m / z(ES+)=301.1;m / z (ES-)=-, method 6.

[0204] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0205] [Table 28]

[0206] 2-(7-cyclobutyl-1-ethyl-4-oxo-1,4-dihydrosinnoline-3- Synthesis of yl(I-102) acetate [ka] LiOH·H2O[1310-66-3] (33.9 mg, 0.81 mmol) I-100 (202 mg) in a mixture of HF (6.84 mL) and DI water (1.69 mL) It was added to a 0.67 mmol solution at room temperature. The reaction mixture was stirred at 30°C for 16 hours. A 1M aqueous solution of HCl was added until the pH reached 4. The mixture was diluted with DI water, and Et Extracted with OAc. The combined organic extract was dried with MgSO4, filtered, and concentrated in a vacuum. By reducing the solution, I-102 (195 mg, 98% purity, 99% yield) was obtained as a yellow solid. The crude product was used in the next step without further purification. 1 H NMR(300MHz,DMSO-d6)δ ppm 1.38(t,J=7.1 Hz,3H),1.86(dd,J=10.8,9.3Hz,1H),1.99-2.1 3(m,1H),2.15-2.30(m,2H),2.32-2.45(m,2H), 3.60(s,2H),3.64-3.85(m,1H),4.51(q,J=7.1H z,2H),7.40(dd,J=8.4,1.0Hz,1H),7.54(s,1H) ,8.06(d,J=8.4Hz,1H),12.17(s,1H). LCMS Rt=0.97min, 98%(UV), m / z(ES+)=287.2;m / z (ES-)=-, method 6.

[0207] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0208] [Table 29]

[0209] 2-(7-(1,1-difluoroethyl)-1-ethyl-4-oxo-1,4-dihydro Synthesis of cinnoline-3-yl)acetic acid (I-106) [ka] A 1M aqueous solution of NaOH [1310-73-2] (11.1 mL, 11.1 mmol) , I-95 (1.8g, 5) in 1:1 THF / DI water (11.1mL:11.1mL) It was added to a 0.55 mmol) stirred solution. The resulting mixture was stirred at room temperature for 2 hours. Next... Then, it was neutralized with a 1M aqueous solution of HCl (11.1 ml) to concentrate the volatile substances. The residue was diluted with DI water (20 mL) and extracted with ethyl acetate (twice). Combined organic extracts Wash with brine, dry with MgSO4, filter, concentrate under vacuum, and obtain I-106( 1.6 g, with a yield of 97%, was obtained as a grayish-white solid. LCMS Rt=0.52 min, 100%(UV), m / z(ES+)=297;m / z( ES-)=-, method 5.

[0210] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0211] [Table 30]

[0212] Ethyl 6-iodoimidazo[1,5-a]pyridine-1-carboxylate (I-109 ) synthesis [ka] Anhydrous DMF (50 mL) is mixed with NaH (60% dispersion in mineral oil) [7646-69-7] ( The mixture was added under N2 conditions to a vial filled with 2.24 g (56.06 mmol). Cooled to °C. Isocyanoethyl acetate [2999-46-4] (6.13 mL, 56.0 Add 6 mmol) dropwise, and after 30 minutes, 2-fluoro-5-iodopyridine [17119 [7-80-1] (10.0 g, 44.85 mmol) was added in three separate additions. The reaction products The mixture was heated to room temperature, then heated at 60°C for 16 hours. The reaction mixture was cooled to room temperature and EtOA was added. Diluted with c (500 mL) and DI water (300 mL). The organic layer was separated and rinsed with saline solution (2 × 1 Washed with 00 mL. The combined aqueous layer was extracted with alkyl (200 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was then subjected to FCC (Hepto). Purified by tan / siRNA (1:0~3:7), I-109 (2.94g, yield 2 1% was obtained as a grayish-white solid. LCMS Rt=0.84 min, 97%(UV), m / z(ES+)=317.0;m / z (ES-)=-, method 4.

[0213] Synthesis of 6-iodoimidazo[1,5-a]pyridine-1-carboxylic acid (I-110) [ka] A 1M aqueous solution of NaOH [1310-73-2] (36 mL, 36 mmol) is used in THF It was added to a solution of I-109 (3.75 g, 11.86 mmol) in (35 mL). The solution was stirred at 60°C for 2 hours. Then it was concentrated under reduced pressure, and then the pH was slightly The solution was treated with a 1M HCl aqueous solution until it became acidic. The solid precipitate was filtered off, washed with water, and then... Then, it was dried under vacuum at 50°C to obtain I-110 (3.25g, yield 95%), which was a grayish-white solid. It was obtained as a physical object.

[0214] 6-iodoimidazo[1,5-a]pyridine-1-carbonyl chloride (I-111) synthesis [ka] SOCl2[7719-09-7] (4.1 mL, 56.5 mmol) is dried into MeC It was added dropwise to a suspension of I-110 (3.25 g, 11.28 mmol) in N (30 mL). The reaction mixture was stirred at 60°C for 1 hour. Volatile substances were removed under reduced pressure to obtain crude product I-111. (3.45g, quantitative) was used in subsequent processes without further processing.

[0215] Synthesis of 6-iodoimidazo[1,5-a]pyridine-1-carboxylic acid (I-112) [ka] In DCM (50 mL), the suspension of crude substance I-111 (3.45 g, 11.26 mmol) The turbid liquid was cooled to 0°C. 28 wt% aqueous solution of NH3 [7664-41-7] (50 mL, Gradually add 740 mmol of the solution, warm the mixture to room temperature, and stir for 1 hour. The mixture is filtered, the solid cake is washed with water, and then dried under vacuum at 50°C for 16 hours. I-112 (2.29 g, yield 71%) was obtained as a brown solid. LCMS Rt=0.60 min, 100%(UV), m / z(ES+)=288.0;m / z(ES-)=-, method 4.

[0216] Synthesis of 6-iodoimidazo[1,5-a]pyridine-1-carbonitrile (I-113) [ka] POCl3[10025-87-3] (815 μL, 8.77 mmol) was prepared using anhydrous DM. A solution of I-112 (2.29 g, 7.98 mmol) in F (23 mL) was stirred at 0°C. The reaction mixture was added dropwise while stirring. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was then cooled with ice (approximately 50°C). Quenched with (mL), then diluted with alkyl (400mL) and DI water (150mL). The organic layer was separated, and the aqueous layer was extracted again with HCl (100 mL). The combined organic layers were M Dry with gSO4, filter, and concentrate under reduced pressure to obtain the desired I-113 (2.09 g, yield) 97% was obtained as a brown solid. LCMS Rt=0.76 min, 99%(UV), m / z(ES+)=270.1;m / z (ES-)=-, method 4.

[0217] 6-((diphenylmethylene)amino)imidazo[1,5-a]pyridine-1-carbon Synthesis of trills (I-114) [ka] I-113 (695 mg, 2.58 mmol) in anhydrous 1,4-dioxane (28 mL) ), benzophenone imine [1013-88-3] (0.65 mL, 3.875 mmol) ), BINAP[98327-87-8](322mg, 0.517mmol) and sodium Rium tert-butoxide [865-48-5] (397 mg, 4.133 mmol) The mixture was sparged with N2 for several minutes. Pd2(dba)3[51364-51-3] (237 mg, 0.258 mmol) was added, and the reaction mixture was heated at 60°C for 2 hours. The mixture was cooled to room temperature and filtered through Celite® (washed with ԅ). (While purifying). The filtrate was concentrated under reduced pressure to obtain a brown paste. The crude product was processed using FCC (Hepto). Purified using tan / acetaldehyde (1:0-3:2), I-114 (360 mg, yield 4 3% was obtained as a yellow solid. LCMS Rt=1.08 min, 99%(UV), m / z(ES+)=323.2;m / z (ES-)=-, method 4.

[0218] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0219] [Table 31]

[0220] Synthesis of 6-aminoimidazo[1,5-a]pyridine-1-carbonitrile (I-115) [ka] A 1M aqueous solution of HCl (5.6 mL, 5.6 mmol) is added to I-1 in THF (5 mL). It was added to a solution of 14 (360 mg, 1.12 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM (10 ml), the organic layer was collected, and the aqueous layer was diluted with solid potassium until saturated. The mixture was treated with 2CO3 and extracted using DCM (5 × 20 mL). The combined organic layer was then treated with MgSO4. After drying, filtering, and concentrating, I-115 (130 mg, 74% yield) was obtained as a light brown solid. It was obtained as such. LCMS Rt=0.96 min, 100%(UV), m / z(ES+)=159.1;m / z(ES-)=157.1, method 2.

[0221] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0222] [Table 32]

[0223] N'-((5-bromopyridine-2-yl)-4-methylbenzenesulfonohydrazide( Synthesis of I-116) [ka] 4-Methylbenzenesulfone hydrazide [1576-35-8] (1.0g, 5.38 mmol) in DCM (10 mL) and MeOH (10 mL) 5-bromopyridine- In a solution of 2-carbaldehyde [31181-90-5] (1.0 g, 5.38 mmol) The mixture was added. The reaction was stirred at room temperature for 1 hour. The volatile substances were removed under reduced pressure, and the resulting solid was obtained. Substance I-116 was used in subsequent processes without purification. LCMS Rt=0.90 min, 100%(UV), m / z(ES+)=354.0 / 35 6.0;m / z(ES-)=-, method 4.

[0224] Synthesis of 6-bromo-[1,2,3]triazolo[1,5-a]pyridine (I-117) [ka] I-116 (Previous process crude material estimated to be quantitative, 5.71g, 16.12m) A mixture of (mol) and morpholine [110-91-8] (25 mL, 289.8 mmol) The mixture was stirred at 90°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Crude product. It is purified by FCC (heptane / alkyl 1:0~2:3) and then I-117(3 0.08 g, with a yield of 96%, was obtained as a white solid. LCMS Rt=0.61 min, 100%(UV), m / z(ES+)=198.0 / 20 0.0;m / z(ES-)=-, method 4.

[0225] 3-Chloro-1-(difluoromethyl)-5-nitropyridine-2(1H)-one(I- 120) Synthesis [ka] NaH (60% dispersion in mineral oil) [7646-69-7] (0.5g, 12.5mmo l) 3-chloro-2-hydroxy-5-nitropyridine in DMSO (20 mL) [ Add to a solution of [22353-38-4] (2g, 11.46 mmol) under nitrogen at room temperature. The mixture was reacted at room temperature for 15 minutes, and sodium chlorodifluoroacetate [1895- [39-2] (2g, 13.12 mmol) was added. Then, the resulting solution was heated at 60°C. It was heated for 16 hours. It was then cooled to room temperature and quenched by adding DI water. The resulting solution was extracted with SiO3 (3 times), and the combined organic layers were dried with MgSO4. The product was filtered and concentrated under vacuum. The crude product was then treated with FCC (heptane / toluene 1:0-3). :2) Purification was performed to obtain I-120 (390 mg, yield 15%) as a white solid. Ta. LCMS Rt=1.50 min, 100%(UV), m / z(ES+)=-;m / z(ES -)=223.0, method 2.

[0226] 5-amino-3-chloro-1-(difluoromethyl)pyridine-2(1H)-one(I- 121) Synthesis [ka] I-120 (290 mg, 1.29 mmol) and iron powder in EtOH (5 mL) [74 39-89-6] (214 mg, 3.83 mmol) and a 7.2 M aqueous solution of NH4Cl [ A mixture of [12125-02-9] (1.21 mL, 8.73 mmol) under a nitrogen atmosphere. The reaction mixture was heated in a sealed MW vial at 80°C for 16 hours. The reaction mixture was cooled to room temperature and then D The filtrate was filtered on icalite® and thoroughly washed with EtOH. The filtrate was then steamed under reduced pressure. The mixture was allowed to ferment, suspended in DCM, and filtered again. The filtrate was concentrated and FCC(DCM / MeOH) Purified by 1:0~95:5, I-121 (110 mg, yield 44%) is obtained in green It was obtained as a solid. LCMS Rt=1.02 min, 100%(UV), m / z(ES+)=194.9;m / z(ES-)=-, method 2.

[0227] Synthesis of 9-methyl-9H-purine-2-amine (I-122) [ka] 6-chloro-9-methyl-9H-p in MeOH (30 mL) and THF (50 mL) Phosphorus-2-amine [3035-73-2] (500 mg, 2.72 mmol) and Pd / A mixture of C (10% by weight, 289.8 mg, 0.27 mmol) was prepared under a hydrogen atmosphere (1 gas). The mixture was placed under pressure and stirred at room temperature for 16 hours. The catalyst was filtered off on Decalite®. The filtrate was concentrated to obtain I-122 (780 mg, yield 85%) as a red solid. LCMS Rt=0.75 min, 79%(UV), m / z(ES+)=150.0;m / z (ES-)=-, method 2.

[0228] 5-Chloro-3-methyl-3H-imidazo[4,5-b]pyridine (I-123) and 5 Synthesis of chloro-1-methyl-1H-imidazo[4,5-b]pyridine (I-124) [ka] NaH (60% dispersion in mineral oil, 1.5g, 37.5 mmol) is mixed with anhydrous DMF (70 5-chloro-3H-imidazo[4,5-b]pyridine[52090-89-8 mL] It was gradually added at 0°C to a stirred mixture of ](5g, 32.56 mmol). The resulting mixture After warming the mixture to room temperature and stirring for 30 minutes, add MeI[74-88-4](2.3 mL, 36 (0.95 mmol) was added dropwise. After 2 hours, the mixture was quenched with DI water and extracted with pharmaceutically acceptable ammonium compounds. The combined organic extracts were washed with brine (5 times), dried with MgSO4, and filtered. The product was then concentrated under reduced pressure. The crude product was converted to FCC (DCM / MeOH 1:0~97:3). Further purification yields I-123 (3.7g, 68% yield) as a pale orange solid, and I-124 (880 mg, yield 16%) was obtained as a white solid. I-123: LCMS Rt=0.68 min, 100%(UV), m / z(ES+)=168.1;m / z(ES-)=-, method 3. 1 ¹H NMR (400 MHz, chloroform-d) δ pp m 3.93(s,3H),7.29(d,J=0.9Hz,1H),8.00-8.0 6 (m, 2H). I-124: LCMS Rt=0.58 min, 82%(UV), m / z(ES+)=168.1;m / z (ES-)=-, method 3. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 3.91(s,3H),7.29(d,J=0.9Hz,1H),7.71(d,J= 8.4Hz, 1H), 8.08(s, 1H).

[0229] N-(3-methyl-3H-imidazo[4,5-b]pyridine-5-yl)-1,1-diph Synthesis of phenylmethaneimine (I-125) [ka] Degassed 1,4-dioxane (15 mL) is mixed with I-123 (500 mg, 2.98 mm ol), Pd(OAc)2[3375-31-3] (33.5mg, 0.15mmol) , XantPhos[161265-03-8] (172.6mg, 0.3mmol), Benzophenonimine [1013-88-3] (648.8mg, 3.58mmol) and A mixture of cesium carbonate [534-17-8] (1.94 g, 5.97 mmol) is subjected to pressure The mixture was added under nitrogen in a pressure tube and heated at 100°C for 3 hours. The reaction mixture was allowed to cool to room temperature. The filtrate was cooled, the solids were filtered out, and the filter case was washed with HCl. The filtrate was concentrated in a vacuum. Shrinkage is performed, and the crude product is purified by FCC (heptane / siRNA 1:0~0:1). I-125 (730 mg, 78% yield) was obtained as a gray solid. LCMS Rt=0.94 min, 100%(UV), m / z(ES+)=313.2;m / z(ES-)=-, method 5.

[0230] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0231] [Table 33]

[0232] tert-butyl(RS)-cis-3-(((benzyloxy)carbonyl)amino)- Synthesis of 4-methylpiperidine-1-carboxylate (I-129) [ka] Benzyl chloroformate [501-53-1] (0.83 mL, 5.9 mmol), Et tert-butyl3-amine in a mixture of OAc (2.5 mL) and DI water (2.5 mL) No-4-methylpiperidine-1-carboxylate hydrochloride [1312810-2 0-0](1.3g, 4.92 mmol) and K2CO3[584-08-7](2.7 It was added dropwise to a 2g (20 mmol) stirred suspension. The mixture was stirred at room temperature for 2 hours. The solution was diluted with DI water and extracted with pharmaceutically acceptable phosphate. The combined organic extract was dried on MgSO4. The crude product was filtered and concentrated in a vacuum. The crude product was then treated with FCC (heptane / toluene 1:0-4). By purification according to :1), I-129 (1.71 g, yield 93%) is obtained as a colorless oil. Ta. LCMS Rt=1.30 min, 93%(UV), m / z(ES+)=249.2(MB oc);m / z(ES-)=-, method 6. 1 H NMR (300 MHz, chloroform- d)δ ppm 0.94(d,J=6.8Hz,3H),1.26(t,J=10.7 Hz,2H),1.43(d,J=12.4Hz,9H),1.79(s,1H),2. 69(d,J=12.8Hz,1H),2.87(dd,J=13.4,2.1Hz,1 H),3.81(s,1H),4.11(d,J=13.2Hz,2H),4.85(d ,J=9.2Hz,1H),5.11(s,2H),7.30-7.40(m,5H).

[0233] Benzyl(RS)-cis-(4-methylpiperidine-3-yl)carbamate(I-13 0) Synthesis [ka] CF3CO2H[76-05-1](12.5mL) in DCM(41.5mL) The reaction mixture was added to a stirred solution of I-129 (1.71 g, 4.91 mmol). The reaction mixture was stored at room temperature. Stirring for 1 hour, the volatile substances were concentrated in a vacuum to obtain I-130 (1.89g, yield 93%). The product was obtained as a colorless oil. The crude product was used in the next step without further purification. LCMS Rt=0.72 min, 93%(UV), m / z(ES+)=249.2;m / z (ES-)=-, method 6.

[0234] Benzyl(RS)-cis-(1-ethyl-4-methylpiperidine-3-yl)carbame Synthesis of (I-131) [ka] Bromoethane [74-96-4] (1.95 mL, 26.1 mmol) and DIPEA [7087-68-5] (10.9 mL, 62.6 mmol) is mixed with MeCN (13.6 mL). It was added to a solution of I-130 (1.89 g, 5.22 mmol) in (L). The mixture was stirred. The mixture was then heated at 85°C for 16 hours. The reaction mixture was diluted with DI water and extracted with carboxyl. The combined organic extracts were dried with MgSO4, filtered, and concentrated under reduced pressure. The crude product was then prepared. Purified by FCC (heptane / toluene 10-4:1), I-131 (1.19 g, yielding 78%, was obtained as a brown oily substance. LCMS Rt=1.02 min, no UV, m / z(ES+)=277.2;m / z(ES -)=-, method 6.

[0235] Synthesis of (RS)-cis-1-ethyl-4-methylpiperidine-3-amine (I-132) [ka] Pd / C (10% by weight, 137.5 mg, 3 mol%) in MeOH (20 mL) Add to a stirred solution of I-131 (1.19 g, 4.31 mmol), and the reaction mixture contains hydrogen. The mixture was placed under atmospheric pressure and stirred at room temperature for 16 hours. The mixture was then placed on a Celite® pad. Filter through (washing with MeOH), concentrate the filtrate under vacuum, and obtain I-132(5 50 mg was obtained as a yellow solid with a yield of 87%. LCMS Rt=0.27 min, no UV, m / z(ES+)=143.2;m / z(ES -)=-, method 7. 1 H NMR(400MHz,DMSO-d6)δ ppm 0.8 8(t,J=9.8Hz,3H),0.98(q,J=7.1Hz,3H),1.38- 1.53(m,2H),1.61-1.77(m,1H),1.90-2.03(m,1 H),2.11(d,J=10.3Hz,1H),2.25-2.43(m,2H),2 .67-2.84(m,2H),3.08(d,J=2.6Hz,1H),6.49(s ,2H).

[0236] Synthesis of 7-bromosinnoline-4(1H)-one (I-133) [ka] NaNO2[7632-00-0](1.44g, 20) in DI water (6mL) at 0℃ A solution of 0.9 mmol) is added to 1-( 37 wt% aqueous solution of HCl (7.6 mL) at 0°C. 2-amino-4-bromophenyl)ethanone [123858-51-5] (3g, 14mg) It was added to a mol / m² solution. The reaction mixture was stirred at 0°C for 2 hours and at room temperature for 16 hours. The volatile substance was concentrated in a vacuum, and a saturated aqueous solution of AcOK [127-08-2] (6 mL) was prepared. It was added. The formed precipitate was collected by filtration and washed with DI water, and then I-133(2. 73g, with a yield of 80%, was obtained as a brown solid. LCMS Rt=0.51 min, 92%(UV), m / z(ES+)=225.0;m / z (ES-)=-, method 6. 1 1H NMR (300MHz, DMSO-d6) δ ppm 7.48(dd,J=8.7,1.7Hz,1H),7.69(d,J=2.5Hz,2 H), 7.87 (d, J=8.7Hz, 1H). NH was not observed.

[0237] Synthesis of 7-bromo-3-iodosinnoline-4(1H)-one (I-134) [ka] Iodine [7553-56-2] (1.85g, 7.28mmol), pyridine [110 -86-1] (1.08 mL, 13.34 mmol) and PIDA[3240-34-4 ](1.95g, 6.07mmol) in DCM (70mL) I-133(2.73 It was added to a stirred solution of (g, 12.13 mmol) at room temperature. This mixture was stirred at room temperature for 16 hours. Mixed. The formed precipitate was collected by filtration and washed with DI water, then I-134(3.3 g, yielding 74%, was obtained as a pale orange solid. LCMS Rt=0.71 min, 95%(UV), m / z(ES+)=350.8;m / z (ES-)=-, method 6. 1 1H NMR (300MHz, DMSO-d6) δ ppm 7.62(dd,J=8.7,1.7Hz,1H),7.77(d,J=1.6Hz,1 H), 7.96 (d, J=8.7Hz, 1H). NH was not observed.

[0238] 7-Bromo-3-iodo-1-isopropylcinnoline-4(1H)-one(I-135 ) synthesis [ka] NaH[7646-69-7](60% suspension in mineral oil, 564 mg, 14.1 mmol) Stirring of I-134 (3.3g, 9.4 mmol) in anhydrous DMF (44.8mL) It was added to the suspension at 0°C. Then, 2-iodopropane [75-30-9] (1.73 ml) (L, 15.05 mmol) was added, the reaction mixture was stirred, and the mixture was heated at 75°C for 6 hours. It was then diluted with a saturated aqueous solution of NaHCO3 and extracted with ethylacetate. Combined organic extraction The material was dried with MgSO4, filtered, and the solvent was concentrated under vacuum. The crude product was subjected to FCC (French filtration). Purified by butan / toluene (1:0-4:1), then I-135 (1.5g, yield 3%). 9% was obtained as a yellow solid. LCMS Rt=1.01 min, 95%(UV), m / z(ES+)=392.9;m / z (ES-)=-, method 6. 1 1H NMR (300MHz, DMSO-d6) δ ppm 1.41(d,J=6.3Hz,6H),5.25(spt,J=6.3Hz,1H), 7.69(dd,J=8.7,1.5Hz,1H),8.04(d,J=8.7Hz,1 H), 8.29 (d, J=1.3Hz, 1H).

[0239] tert-butyl(7-bromo-1-isopropyl-4-oxo-1,4-dihydrosine) Synthesis of Norin-3-yl)carbamate (I-136) [ka] Xantphos[161265-03-8](167.8mg, 0.29mmol) and Pd2(dba)3[51364-51-3](99.6mg, 0.11 mmol) I-135 (1.5g, 3.63 mmol) in anhydrous 1,4-dioxane (50mL) ), tert-butylcarbamate [4248-19-5] (467.2 mg, 3.99 mmol) and cesium carbonate [534-17-8] (1.77 g, 5.44 mmol) It was added to a stirred solution / suspension at room temperature. The mixture was sparged with nitrogen for 5 minutes, then stirred. It was heated at 60°C for 9 hours. Then it was diluted with a saturated aqueous solution of NaHCO3 and treated with HCl. Extraction was performed. The combined organic extracts were dried with MgSO4, filtered, and the solvent was evaporated under vacuum. The crude product was purified by FCC (heptane / acetate 1:0~4:1). I-136 (768 mg, 42% yield) was obtained as a white solid. LCMS Rt=1.07 min, 75%(UV), m / z(ES+)=326.0(Mt Bu);m / z(ES-)=-, method 6.

[0240] 3-Amino-7-Bromo-1-Isopropylsinnoline-4(1H)-one(I-137) ) synthesis [ka] A 4M solution of HCl in 1,4-dioxane (2 mL, 8 mmol) is prepared using I-136(7 It was added to 68 mg (2 mmol) and the mixture was stirred at room temperature for 3 hours. Then, NaHCO₃ Diluted with a saturated aqueous solution of 3 and extracted with ethyl acetate. The combined organic layer was dried with MgSO4. The solution was then filtered and concentrated under reduced pressure. The crude product was then subjected to FCC (heptane / acetate 1). Purified by (0-4:1), I-137 (325 mg, yield 57%) was obtained as a yellow solid. It was obtained as such. LCMS Rt=0.82 min, 99%(UV), m / z(ES+)=282.0;m / z (ES-)=-, method 6. 1 1H NMR (300MHz, DMSO-d6) δ ppm 1.37(d,J=6.4Hz,6H),5.11(spt,J=6.3Hz,1H), 6.01(s,2H),7.28(dd,J=8.8,1.4Hz,1H),7.98( d,J=8.8Hz,1H),8.07(s,1H).

[0241] 7-Bromo-3-isocyanato-1-isopropylcinnoline-4(1H)-one(I- 138) Synthesis [ka] Triethylamine [121-44-8] (54 μL, 0.39 mmol) and anhydrous TH F (1 mL) contains triphosgene [32315-10-9] (53 mg, 0.18 mmol) A solution of ) is prepared by adding I-137 (100 mg, 0.35 mmol) in anhydrous THF (2 mL). It was added to the solution. The mixture was stirred at room temperature for 3 hours. The reaction product was filtered, and the filtrate was concentrated to obtain the crude solution. I-138 (105 mg, 77% yield) was obtained and, without further purification, proceeded to the next reaction. I used it. LCMS Rt=1.03 min, 80%(UV), m / z(ES+)=308.0;m / z (ES-)=-, method 6.

[0242] 3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-6-amine(I-1 39) Synthesis [ka] 3-chloro-[1,2,4]triazolo[4,3-b]p Ridazine-6-amine [1150888-24-6] (1.25g, 7.37mmol) The mixture was stirred at room temperature and degassed by sparging with nitrogen for 5 minutes. -tert-butylphosphine)palladium(0)[53199-31-8](565. 1 mg (1.11 mmol) was added, and the reaction mixture was degassed again for 5 minutes. Then, commercially available 2M solution of MeZnCl in THF [5158-46-3] (7.37 mL, 14.7 4 mmol) was added dropwise, and the reaction mixture was stirred under nitrogen at 90°C for 8 hours. Then, Cool to room temperature, then quench by adding a saturated aqueous solution of NH4Cl (10 mL), 10 The mixture was stirred for minutes, and the pH was finally adjusted to pH > 8 with a saturated aqueous solution of NaHCO3. Volatile substances The solids were removed under vacuum, and the resulting mixture was stirred overnight in MeOH (50 mL). Filter the solution and separate the filtrate. RP-HPLC (stationary phase: RP XBridge Prep C1 8 OBD-10μm, 50×250mm, mobile phase: water, 0.25% N in CH3CN Purified with H4HCO3 solution, I-139 (402 mg, yield 37%) was obtained as a white solid. It was obtained as a physical object. LCMS Rt=0.31 min, 100%(UV), m / z(ES+)=150.1;m / z(ES-)=148.2, method 4.

[0243] Preparation of the final compound 2-(7-bromo-1-isopropyl-4-oxo-1,4-dihydrosinnoline-3- Il)-N-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imida Synthesis of zole-5-yl)acetamide, F-1 [ka] Et3N[121-44-8] (68μL, 0.73g / mL, 0.49mmol), Next, a 50 wt% solution of T3P in ¼ [68957-94-8] (0.18 m (L, 1.07 g / mL, 0.31 mmol) in DCM (1.3 mL) 2-(7-B Romo-1-isopropyl-4-oxo-1,4-dihydrosinnolin-3-yl)acetate -55 (40 mg, 0.12 mmol) and 5-amino-1-methyl-2,3-dihydro -1H-1,3-Benzodiazole-2-one [54732-89-7] (27.1 mg) It was added to a suspension of 0.17 mmol. The resulting brownish solution was stirred at room temperature for 2 hours. The mixture was stirred. The reaction mixture was concentrated under a stream of nitrogen until a solid was obtained, and this solid was subjected to a minimum amount of heat. Dissolve in acetonitrile (approximately 17 mL), and cool the hot solution to room temperature while vigorously stirring. Next, it was cooled to 5°C for 1 hour, the solids were filtered off, and it was dried under vacuum at 55°C for 20 hours. Dry it and 2-(7-bromo-1-isopropyl-4-oxo-1,4-dihydrosin) Phosphate-3-yl)-N-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[ d) Imidazole-5-yl)acetamide F-1 (33 mg, yield 57%), light brown It was obtained as a greenish solid. LCMS Rt=1.65 min, 100%(UV), m / z(ES+)=470.2 / 47 2.2;m / z(ES-)=468.2 / 470.2.Method 1. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.41(d,J=6.4 Hz,6H),3.24(s,3H),3.76(s,2H),5.26(spt,J= 6.4Hz,1H),6.99(d,J=8.4Hz,1H),7.10(dd,J=8 .5,1.9Hz,1H),7.48(d,J=1.8Hz,1H),7.61(dd, J=8.6,1.5Hz,1H),8.05(d,J=8.6Hz,1H),8.27( d,J=1.5Hz,1H),10.03(s,1H),10.75(s,1H).

[0244] Additional analogs were synthesized according to the above procedure, with reagents replaced as needed. DC M and DMF may be used interchangeably as solvents.

[0245] [Table 34]

[0246] [Table 35]

[0247] [Table 36]

[0248] [Table 37]

[0249] [Table 38]

[0250] [Table 39]

[0251] [Table 40]

[0252] [Table 41]

[0253] [Table 42]

[0254] [Table 43]

[0255] [Table 44]

[0256] [Table 45]

[0257] [Table 46]

[0258] In the table above, the compounds can be separated or isolated using conventional separation techniques. Any technology may be used. For example, the F-12 and F-13 derived from the F-11 may be used. The following method may be used: Purification / separation (of F-11), preparative SFC (stationary phase: Ch iralcel Diacel IH 20×250mm, mobile phase: CO2, EtOH+ The procedure was carried out via 0.4iPrNH2) and F-12 and F-13 were obtained as white solids. Those skilled in the art can also identify other methods / techniques.

[0259] 2-(7-cyclopropyl-1-isopropyl-4-oxo-1,4-dihydrosinol Synthesis of n-3-yl)-N-(pyrimidine-4-yl)acetamide F-79 [ka] 0.5 M solution of cyclopropylzinc bromide in THF (1.1 mL, 0.55 mmol) 2-(7-bromo-1-isopropyl-4-oxo-1,4- Dihydrosinnolin-3-yl)-N-(pyrimidine-4-yl)acetamide F-2( 43 mg, 0.107 mmol) and bis(tri-tert-butylphosphine) paradi In a suspension of Um(0) (9.8 mg, 0.0192 mmol), slowly under nitrogen for 2 minutes... Chestnut was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under vacuum, and the crude product was collected. Flash column chromatography (heptane / acetone 1:0~0:1) Purified, 2-(7-cyclopropyl-1-isopropyl-4-oxo-1,4-dihydr Rosinnolin-3-yl)-N-(pyrimidine-4-yl)acetamide F-79(26 mg was obtained as a white solid (yield 67%). 1 H NMR(400MHz,DMSO-d6)δ ppm 0.88-0.96(m, 2H),1.07-1.17(m,2H),1.38-1.42(m,6H),2.13 -2.23(m,1H),3.87(s,2H),5.28(dt,J=12.6,6. 2Hz,1H),7.12(d,J=8.1Hz,1H),7.65(s,1H),7. 96-8.05(m,2H),8.63(d,J=5.7Hz,1H),8.88(s, 1H), 11.09(s,1H). LCMS Rt=1.76 min, 100%(UV), m / z(ES+)=364.2;m / z(ES-)=362.2. Method 1.

[0260] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0261] [Table 47]

[0262] 2-(1-isopropyl-4-oxo-7-(trifluoromethyl)-1,4-dihydro Synnolin-3-yl)-N-(6-(trifluoromethyl)pyridazine-3-yl) Cetoamide, F-84 synthesis [ka] 2-(1-isopropyl-4-oxo-7-(triflu) in MeCN (1.74 mL) Oromethyl)-1,4-dihydrosinnolin-3-yl)acetic acid I-58 (70 mg, 0. 22 mmol) and 6-(trifluoromethyl)pyridazine-3-amine [935777 A stirred suspension of -24-5] (61.8 mg, 0.38 mmol) was mixed with 1-methylimidazo Add 1.03 g / mL (89 μL, 1.03 mmol, 1.11 mmol), followed by solid TCF. H[207915-99-9] (125 mg, 0.45 mmol) was added to the mixture. The mixture was vigorously stirred at room temperature for 5 hours. After stirring at room temperature for 5 hours, the reaction mixture was stored in the freezer for 16 hours. Next, flash column chromatography (heptane / 93:7 Purified twice using a ratio of ~3:2, 2-(1-isopropyl-4-oxo-7-(triflu Oromethyl)-1,4-dihydrosinnolin-3-yl)-N-(6-(trifluoromethyl (1) Pyridazine-3-yl)acetamide F-84 was obtained as a dark pink solid. 4.8 mg, approximately 94% purity, 14% yield. LCMS Rt=2.04~2.06 min, 100%(UV), m / z(ES+)=460 .2;m / z(ES-)=458.2.Method 1. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 1.62 (d, J=6). 5Hz,6H),4.17(s,2H),5.08(spt,J=6.5Hz,1H), 7.66(dd,J=8.5,1.1Hz,1H),7.76(d,J=9.2Hz,1 H),7.90(s,1H),8.58(d,J=8.5Hz,1H),8.64(d, J=9.2Hz,1H),10.71(br s,1H).

[0263] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0264] [Table 48]

[0265] [Table 49]

[0266] [Table 50]

[0267] [Table 51]

[0268] [Table 52]

[0269] [Table 53]

[0270] N-(6-bromoimidazo[1,2-a]pyrazine-2-yl)-2-(isopropyl- 4-Oxo-7-(trifluoromethyl)-1,4-dihydrosinnoline-3-yl) Cetoamide, F-116 synthesis [ka] 6-bromoimidazo[1,2-a]pyrazine-2-a in DMF (0.23 mmol) The storage solution of min [1103861-38-6] is the storage solution of I-58 in DMF (0.15 It was added to a molecule at room temperature. The solution was stirred at room temperature, and TCFH

[20791] was added to DMF. Storage solution (0.3 mmol) of [5-99-9] and 1-methylimidazole [616-47 -7] (60 μL, 0.75 mmol) was added sequentially (the final total volume of the mixture was approximately The resulting mixture was stirred at room temperature for 24 hours. Then, DMSO(0 The solution was diluted (0.75 mL) and concentrated under vacuum to remove all DMF. The resulting solution was then prepared using M Dilute with a 1:1 mixture of eCN / MeOH (2 mL), filter (filter, MeCN (Rinse with 0.5 mL of a 1:1 mixture of / MeOH), separate the filtrate and perform RP-HPLC (stationary phase) :RP XBridge Prep C18 OBD-10μm, 50×250mm, transfer Dynamic phase: Purified using a 0.25% NH4HCO3 solution in water, CH3CN, or MeOH. Then, F-116 (14 mg, yield 18%) was obtained as a grayish-white solid. LCMS Rt=1.03 min, 100%(UV), m / z(ES+)=509.3 / 51 1.3;m / z(ES-)=507.3 / 509.3.Method 4.

[0271] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0272] [Table 54]

[0273] [Table 55]

[0274] [Table 56]

[0275] N-(6-fluoro-2-oxo-1,2-dihydropyridine-4-yl)-2-(1- Isopropyl-4-oxo-7-(trifluoromethyl)-1,4-dihydrosinnoline Synthesis of -3-yl)acetamide, F-130 [ka] A 1M solution of LiHMDS in commercially available THF [4039-32-1] (0.88 mL, 0 (0.88 mmol) in dry toluene (2.7 mL) ethyl 2-(1-isopropyl- 4-Oxo-7-(trifluoromethyl)-1,4-dihydrosinnoline-3-yl) Ceteate I-77 (120 mg, 0.35 mmol) and 4-amino-6-fluoro-1 H-pyridine-2-one [105252-99-1] (53.9 mg, 0.42 mmol) The suspension of ) was added dropwise under nitrogen. The resulting mixture was stirred at room temperature for 2 hours. Then, Quench the solution by adding DI water (2 mL) and saturated aqueous solution of NH4Cl (3 mL). Extraction was performed using DCM (2 × 3 mL). The combined organic layers were dried with MgSO4 and filtered. The product was concentrated in air. The crude product was subjected to preparative RP-chromatography (stationary phase: RP XBri). dge Prep C18 OBD-10μm, 50×250mm, mobile phase: water, CH3 Purified in CN with a 0.25% NH4HCO3 solution, then F-130 (55 mg, yield A 37% yield was obtained as a white solid. Melting point 242.5°C (Method A). LCMS Rt=1.55 min, 100%(UV), m / z(ES+)=425.2;m / z(ES-)=423.1. Method 1. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.43(d,J=6.2 Hz,6H),3.84(s,2H),5.42(spt,J=6.4Hz,1H),6 .75(s,1H),6.76(s,1H),7.75(dd,J=8.6,1.1Hz ,1H),8.34(d,J=8.4Hz,1H),8.36(s,1H),10.68 (s,1H), 11.13(br s,1H).

[0276] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0277] [Table 57]

[0278] N-([1,2,4]triazolo[4,3-b]pyridazine-6-yl)-2-(7-syl) Clopropyl-1-isopropyl-4-oxo-1,4-dihydrosinnolin-3-yl ) Synthesis of acetamide, F-133 [ka] A 1M solution of LiHMDS in commercially available THF (1.95 mL, 1.95 mmol) was prepared anhydrous. [1,2,4]triazolo[4,3-b]pyridazine-6-a in DMF (3.2 mL) In a solution of Min [19195-46-1] (161.5 mg, 1.14 mmol) under nitrogen, The solution was added dropwise at 0°C. The resulting solution was stirred at 0°C for 2 minutes, at which point a fine suspension was formed. Next, I-81 (255 mg, 0.81 mmol) in anhydrous THF (2.6 mL) The solution of ) was added dropwise over 2 minutes at 0°C. The resulting mixture was warmed to room temperature and stirred at room temperature for 7 hours. Mixed. Add 10 mL of DI water to the crude mixture, then add a 1 M aqueous solution of HCl (pH weakly acidic). Quench by adding (2.1 mL in total) until it reaches [a certain state], then add NaHCO3 Add a saturated solution (10 mL) and the resulting light brown mixture to DCM (5 × 10 mL) and Extraction was performed using a 1:1 ratio (2 × 10 mL) of DCM / DMF. The combined organic extract was then treated with Na2SO4. The mixture was dried, filtered, and concentrated. The resulting residue was then subjected to preparative RP-HPLC (stationary phase: RP). XBridge Prep C18 OBD-10μm, 50×250mm, mobile phase: Purified with water, CH3CN, and 0.25% NH4HCO3 solution, then F-133(1 29 mg was obtained as a grayish-white, fluffy solid (39% yield). LCMS Rt=1.61 min, 94%(UV), m / z(ES+)=404.3;m / z (ES-)=402.2. Method 1. 1 H NMR(400MHz,DMSO-d6)δ ppm 0.85-0.97(m, 2H),1.05-1.17(m,2H),1.42(d,J=6.4Hz,6H),2 .13-2.26(m,1H),3.89(s,2H),5.29(spt,J=6.3 Hz,1H),7.12(dd,J=8.6,1.1Hz,1H),7.66(s,1H ),7.98(d,J=9.9Hz,1H),8.02(d,J=8.6Hz,1H), 8.33(dd,J=10.1,0.7Hz,1H),9.50(s,1H),11.2 8(br s,1H).

[0279] Additional analogues were synthesized according to the above procedure, with reagents replaced as needed.

[0280] [Table 58]

[0281] [Table 59]

[0282] [Table 60]

[0283] N-([1,2,4]triazolo[4,3-a]pyridine-6-yl)-2-(7-(1 ,1-difluoroethyl)-1-isopropyl-4-oxo-1,4-dihydrosinnoly Synthesis of 0-3-yl acetamide, F-149 [ka] [1,2,4]Triazolo[4,3-a]pyridine-6-amine[1082448-5 8-5] (38.9 mg, 0.29 mmol) in I-10 in dried pyridine (5 ml) The mixture was added under N2 conditions to a mixture of 7 (55 mg, 0.177 mmol). The mixture was left for more than 10 minutes. The solution was subjected to ultrasonic treatment, then stirred at room temperature for 40 minutes to obtain a 1M solution of titanium(IV) chloride in DCM. [7550-45-0] (0.71 mL, 0.709 mmol) was added dropwise at room temperature. Mixing The substance was stirred at room temperature for 1 hour, and then heated at 80°C for 24 hours. The volatile substance was concentrated in a vacuum. The shrunk crude material was treated with a 2M aqueous solution of HCl until the pH was < 7. Then, AcOEt( Extraction was performed using 3 × 5 mL, and the combined organic extract was concentrated in a vacuum. The crude product was then processed at FCC ( Purified using DCM / MeOH 100 / 0~95:5), F-149 (30 mg, A 36% yield was obtained as a grayish-white solid. LCMS Rt=1.53 min, 100%(UV), m / z(ES+)=427.2;m / z(ES-)=-.Method 9. 1 H NMR(400MHz,DMSO-d6)1.44(d,J=6.5Hz,6H) ,2.09(t,J=19.2Hz,3H),3.86(s,2H),5.38(spt ,J=6.4Hz,1H),7.31(dd,J=9.8,2.0Hz,1H),7.6 3(dd,J=8.6,1.4Hz,1H),7.78(d,J=9.7Hz,1H), 8.07(s,1H),8.25(d,J=8.6Hz,1H),9.17-9.32( m,2H), 10.46(s,1H).

[0284] 1-([1,2,4]triazolo[4,3-a]pyridine-6-yl)-3-(1-iso Propyl-4-oxo-7-(trifluoromethyl)-1,4-dihydrosinnoline-3 -Il) Urea, F-150 synthesis [ka] A 1M solution of LiHMDS in commercially available THF [4039-32-1] (0.3 mL, 0. (3 mmol) in anhydrous DMF (3 mL) [1,2,4]triazolo[4,3-a] Lysine-6-amine [1082448-58-5] (40.2 mg, 0.3 mmol) The solution was added under nitrogen at 0°C. The mixture was stirred at room temperature for 1 hour. Then, I-138 (105 mg, 0.27 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. This was diluted with a saturated aqueous solution of NH4Cl and extracted with ethylacetate. The combined organic extract was then... The product was dried with MgSO4, filtered, and concentrated under reduced pressure. The crude product was then processed using FCC (DCM to D Purified by CM / MeOH 9:1, F-150 (4.4 mg, yield 3%) is obtained using green It was obtained as a colored gum-like substance. LCMS Rt=2.78 min, 04%(UV), m / z(ES+)=442.1;m / z (ES-)=-.Method 7. 1 H NMR(400MHz,DMSO-d6)δ ppm 1.46(d,J=6.3 Hz,6H),5.19-5.39(m,1H),7.15(dd,J=9.7,1.7 Hz,1H),7.53(dd,J=8.7,1.5Hz,1H),7.77(d,J= 9.7Hz,1H),8.11(d,J=8.7Hz,1H),8.29(s,1H), 9.10(s,1H),9.18(s,1H),9.29(s,1H),9.72(d, J = 4.1 Hz, 1 H).

[0285] Additional characterization data - LC-MS and melting point LCMS:[M+H] + This refers to the protonated mass of the free base of the compound, R t `retention time` refers to the retention time (in minutes), and `method` refers to the method used for LCMS.

[0286] [Table 61]

[0287] [Table 62]

[0288] [Table 63]

[0289] [Table 64]

[0290] [Table 65]

[0291] [Table 66]

[0292] [Table 67]

[0293] [Table 68]

[0294] [Table 69]

[0295] Table 70

[0296] Table 71

[0297] Table 72

[0298] Table 73

[0299] Table 74

[0300] Table 75

[0301] Table 76

[0302] Table 77

[0303] Table 78

[0304] Table 79

[0305] [Table 80]

[0306] [Table 81]

[0307] [Table 82]

[0308] [Table 83]

[0309] [Table 84]

[0310] Example B - Pharmaceutical Composition The compounds of the present invention (for example, the compounds of the examples) are linked with a pharmaceutically acceptable carrier. The present invention provides a pharmaceutical composition containing such an active compound. The compound (for example, the compound in the example) is used in a process for preparing a pharmaceutical composition. It is then homogeneously mixed with a pharmaceutically acceptable carrier.

[0311] Example C - Biological Example The activity of the compounds according to the present invention can be evaluated by in vitro methods. The compound exhibits useful pharmacological properties, such as those shown in the following tests, e.g., NLRP. 3. It exhibits properties that easily inhibit activity, and therefore, its application is NLRP3 inflammaso This is a therapy related to activating the immune system.

[0312] PBMC assay Peripheral venous blood was collected from healthy individuals, and human peripheral blood mononuclear cells (PBMCs) were extracted using Ficol. l-Histopaque (Sigma-Aldrich, A0561) Density Gradient Centrifugal Portion It was isolated from blood by filtration. After isolation, the PBMCs were stored in liquid nitrogen for later use. The viability of PBMC cells was measured simultaneously with thawing in a growth medium (10% fetal bovine serum, 1% P). The determination was made in RPMI medium supplemented with en-Strep and 1% L-glutamine. Spot the compound in DMSO in 1:3 serial dilutions and plate it in a 96-well plate (Fa The final concentration was obtained by diluting 30 μl of culture medium in lcon (353072). PBMC 7.5 x 10 per well 4 Add at individual cell densities and place in a 5% CO2 incubator. The sample was incubated at 37°C for 30 minutes. LPS stimulation was administered at 100 ng / ml L The procedure was performed for 6 hours with the addition of PS (final concentration, Invivogen, tlrl-smlps). Afterward, the cell supernatant was collected and processed according to the manufacturer's guidelines (MSD, K151A0H). Analysis of IL-1β (μM) and TNF cytokine levels (μM) via MSD technology. They did that.

[0313] I C 50 Values ​​(for IL-1β) and EC 50 The value (TNF) is the chemical formula of the present invention / example. The results obtained from the combined product are shown in the table below.

[0314] [Table 85]

[0315] [Table 86]

[0316] Table 87

[0317] Table 88

[0318] Table 89

[0319] Table 90

[0320] Table 91

[0321] Table 92

[0322] Table 93

[0323] Table 94

[0324] Table 95

[0325] Table 96

[0326] [Table 97]

[0327] [Table 98]

[0328] [Table 99]

[0329] [Table 100]

[0330] [Table 101]

[0331] [Table 102]

[0332] [Table 103]

[0333] [Table 104]

[0334] Example D - Further testing One or more compounds of the present invention (including the compound of the final example) possess other properties, permeability, and stability. To evaluate its properties (including metabolic stability and blood stability) and solubility, several other factors were considered. It will be tested by law.

[0335] Permeability test Passive permeability in vitro and the transport of P-glycoprotein (P-gp) to its substrates. The ability to do so is tested using MDCK cells that have been stably transduced with MDR1 (this This is carried out by commercial entities that provide ADME, PK services, for example, Cyprotex. (Obtained). Permeability experiments were conducted in a Transwell system at a single concentration (5 μM) for 120 minutes. The incubation process is performed in pairs. And apex-to-basal (A-B) transport in the absence of and basal-to-apex transport in the absence of P-gp inhibitors Partial transport (B~A) is measured, and the transmittance (apparent transmittance) of the test compound (P app ×10 -6 The value (cm / second) is calculated.

[0336] Metabolic stability study in liver microsomes The metabolic stability of the test compound was determined by incubation with a 1 μM test compound at 37°C for up to 60 minutes. Liver microsomes (0.5 mg / ml protein) from human and preclinical species were used. This is tested by (this is ADME, PK service, for example, Cyprot (This may be implemented by commercial institutions that provide ex.)

[0337] Metabolic half-life in vitro (t 1 / 2 ) is the remaining parent for the temporal relationship (κ) It is calculated using the gradient of a log-linear regression from the percentage of compounds. t 1 / 2 = ln(2) / κ.

[0338] Intrinsic clearance in vitro (Cl int (ml / min / mg microsomal protein The quality is calculated using the following formula:

number

[0339] Metabolic stability testing in hepatocytes The metabolic stability of the test compound was determined by incubation with a 1 μM test compound at 37°C for up to 120 minutes. The study will be conducted using hepatocytes (1milj cells) from conditioned human and preclinical species.

[0340] Metabolic half-life in vitro (t 1 / 2 ) is the remaining parent for the temporal relationship (κ) It is calculated using the gradient of a log-linear regression from the percentage of compounds. t 1 / 2 = ln(2) / κ.

[0341] Intrinsic clearance in vitro (Cl int (μl / min / million cells) is expressed by the following formula Calculated using:

number

[0342] Solubility test The tests / assays were performed in sets of three, and Tecan Flu was used for handling all fluids. Using ent, the following common processes are semi-automated: - Dispense 20 μL of 10 mM stock solution into a 500 μL 96-well plate. - Evaporate DMSO (Genevac) - Add the stirring bar and 400 μl of buffer / biological medium. - Leave this solution for 72 hours (pH 2 and pH 7) or 24 hours (FaSSIF and FeS SIF) Stir - Filter this solution. - The filtrate is quantified by UPLC / UV using a three-point calibration curve. The LC conditions are, - Waters Acquity UPLC - Mobile phase A: 0.1% formic acid in H2O, B: 0.1% formic acid in CH3CN - Column: Waters HSS T3 1.8μm 2.1×50mm - Column temperature: 55℃ - Injection volume: 2μl - Flow rate: 0.6ml / min - Wavelength UV:250_350nm - Gradient: 0 min: 0%B, 0.3 min: 5%B, 1.8 min: 95%B, 2.6 min: 95% B

[0343] Blood Stability Assay The compounds of the present invention / examples are found in plasma or blood from a consenting preclinical species in a specific way. It is added at the specified concentration; and then incubated for a predetermined time and under the specified conditions (37°C, 0°C (ice), or room temperature). After incubation, the concentration of the test compound in the blood or plasma matrix is ​​measured by LCMS / MS. It can be determined by further consideration.

Claims

1. Compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, R １ but, (i) -OH, -C １～３ Alkyl and hydroxy C １～３ Selected independently of alkyl groups C is optionally substituted with one or more substituents. ３～６ Cycloalkyl; (ii) Each is Halo, -CN, =O, -OH, -O-C １～３ Alkyl, -C １～３ a Lukil, C ３～６ Cycloalkyl, halo C １～３ Alkyl, hydroxy C １～３ Alkyl , C １～３ Alkoxy, Halo C １～３ Alkoxy and -S(O) ２ C １～４ Alkyl aryl or aryl compounds, which are optionally substituted with one to three substituents that are independently selected from the above. heteroaryl; or (iii) = O, C １～３ Alkyl and C ３～６ Selected independently from cycloalkyl groups This represents a heterocyclyl that is optionally substituted with 1 to 3 substituents; R ２ but, (i) Halo, -OH and -OC １～３ One or more substitutions independently selected from alkyl groups C, which is replaced by arbitrary selection in the base １～３ Alkyl; (ii) C ３～６ Cycloalkyl; or (iii)-OC １～３ C substituted with alkyl as optional ２～４ Alkenil death; R ３ but, (i) Hydrogen; (ii) Hello; (iii) Halo, -OH and -OC １～３ One or more elements independently selected from alkyl groups C substituted with a substituent of any choice １～４ Alkyl; (iv)-OC １～３ C substituted with alkyl as optional ２～４ Alkenil; (v) C ３～６ Cycloalkyl; or (vi)-OC １～３ Representing alkyl, The aforementioned compound, or a pharmaceutically acceptable salt thereof.

2. R １ However, C １～３ Alkyl, -OH, and hydroxyC １～３ Selected from alkyl groups C is optionally substituted with one or two substituents. ３～６ Represents cycloalkyl, The compound described in item 1.

3. R １ but, 【Chemistry 2】 This represents, and in the formula, each R １ａ However, -OH, C １～３ Alkyl and hydroxy C １～３ Alkyl The compound according to claim 2, representing one or two optionally selected substituents from the following.

4. R １ However, (i) phenyl; (ii) a six-membered monocyclic heteroaryl group; or (iii) a nine-membered group Alternatively, it represents a 10-membered bicyclic heteroaryl group, and all of these are halo, =O, -OH, C １～３ Alkyl, -OC １～３ Alkyl and -halo C １～３ Selected from alkyl groups The compound according to claim 1, wherein is optionally substituted with two substituents.

5. R １ However, phenyl or monocyclic six-membered heteroaryl group: 【Transformation 3】 This represents, and in the formula, R １ｂ However, halos (e.g., fluoro, iodine) = O, -OH, C １～３ Alkyl (e.g., methyl), halo C １～３ Alkyl (e.g., -CF) ３ ) Selected from R represents one or two optionally selected substituents. ｂ , R ｃ , R ｄ , R ｅ and R ｆ one of the following Alternatively, the present invention according to claim 4, wherein two of the atoms represent a nitrogen heteroatom (and the others represent CH). compound.

6. R １ However, a 9 or 10-membered bicyclic heteroaryl group, for example: 【Chemistry 4】 This represents, and in the formula, R １ｂ However, halo, = O, C １～３ Alkyl (e.g., methyl) and halo C １～３ Alkyl (e.g., -CF) ３ ) one or two optional substituents selected from the list Furthermore, the ring in the bicyclic system is aromatic (as indicated), R ｋ is an N or C atom Represented by R ｇ represents an N or C atom, and R ｈ , R ｉ and R ｊ One or two of these are N The compound according to claim 4, wherein one represents C and the other represents C.

7. R ２ However, (i) Halo, -OH and -OC １～２ One or more elements independently selected from alkyl groups C substituted with the substituents above by choice １～３ Alkyl; (ii) C ３～６ Cycloal Kill; or (iii)-OC １～２ C substituted with alkyl as optional ２～４ Alke A compound according to any one of claims 1 to 6, representing nyl.

8. R ２ However, non-substituted C １～３ The compound according to claim 7, representing an alkyl group.

9. R ３ However, (i) halo; (ii) halo, -OH and -OC １～２ Selected independently of alkyl C is optionally substituted with one or more selected substituents. １～４ alkyl; or (iii) ) C ３～６ A compound according to any one of claims 1 to 8, representing a cycloalkyl group.

10. R ３ However, halo (e.g., bromo); one or more fluoro atoms (therefore, e.g., -C) F ３ C is optionally (and preferably) replaced by (forming) C １～３ Alki Ru; or C ３～６ (For example, C ３～４ ) Cycloalkyl (e.g., cyclopropyl) The compound according to any one of claims 1 to 9.

11. A therapeutically effective amount of a compound as defined in any one of claims 1 to 10 and pharmaceutically A pharmaceutical composition comprising an acceptable carrier.

12. A pharmaceutically acceptable carrier is defined in any one of claims 1 to 10 in a therapeutically effective amount. A compound as defined in claim 11, characterized in that it is homogeneously mixed with the compound as defined in claim 11. A process for preparing pharmaceutical compositions.

13. A compound according to any one of claims 1 to 10 for use as a pharmaceutical or drug. 。

14. (a) a compound according to any one of claims 1 to 10, and (b) one or more other therapeutic agents A combination that includes and.

15. Use in the treatment of diseases or disorders related to inhibition of NLRP3 inflammasome activity For the purpose of, a compound according to any one of claims 1 to 10, a composition according to claim 11, or The combination described in claim 14.

16. Diseases or disorders related to inhibition of NLRP3 inflammasome activity in the target population. A method for treating harm, wherein the method provides a therapeutically effective amount to the target, according to any of claims 1 to 10. A compound according to any one of the claims, a composition according to claim 11, or a combination according to claim 14. A method including administering [a substance].

17. The disease or disorder associated with the inhibition of NLRP3 inflammasome activity is, Masome-related diseases and disorders, immune diseases, inflammatory diseases, autoimmune diseases, autoinflammatory fever syndromes, Cryopyrin-associated periodic syndromes, chronic liver disease, viral hepatitis, non-alcoholic fatty liver disease Inflammation, alcoholic steatohepatitis, alcoholic liver disease, inflammatory arthritis-related disorders, gout, cartilage Calcification, osteoarthritis, rheumatoid arthritis, chronic arthritis, acute arthritis, kidney-related diseases, hypertension Oxaluria, lupus nephritis, type 1 and type 2 diabetes, nephropathy, retinopathy, hypertensive nephropathy, hematology Dialysis-related inflammation, neuroinflammatory diseases, multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease, cardiovascular disease, metabolic disease, reduction of cardiovascular risk, hypertension, atherosclerosis Arteriosclerosis, peripheral vascular disease, acute heart failure, inflammatory skin disease, acne, wound healing, and scar formation. Asthma, sarcoidosis, age-related macular degeneration, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, A chemical for use according to claim 15, selected from myelodysplastic syndrome and myelofibrosis. A compound, composition or combination, or a method of treatment according to claim 16.

18. For the preparation of a compound of formula (I) as described in any one of claims 1 to 10 It is a process, (i) Compound of formula (II), 【Transformation 5】 or its derivatives (wherein R ２ and R ３ The formula (II) is defined in claim 1. I) Compound, H ２ !! １ (_=) or its derivatives (wherein R １ The amide-forming reaction is as defined in claim 1. Reaction under specific conditions; (ii) Compound of formula (IV), 【Transformation 6】 (In the formula, R １ and R ３ A compound of formula (V) as defined in claim 1, R ２ -LG ａ (V) (In the formula, LG ａ However, it represents a suitable leaving group, R ２ However, as defined in claim 1.) The response: (iii) Conversion of a particular compound of formula (I) to another A process that includes this.

19. A compound of formula (II) as shown in claim 18, 【Transformation 7】 wherein R ２ and R ３ are as defined in claim 1, a compound.

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