NLRP3 inflammasome inhibitors

Abstract

To provide a compound for the treatment of diseases and disorders mediated by NOD-like receptor protein 3 (NLRP3) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and a combination thereof.SOLUTION: The present invention provides novel pyridazin-3-yl phenol compounds represented by Formula (I) (where R1 is Cl, CH3, -OCF3 or the like; R2 represents H, halo, C1-C4 alkyl, or halo C1-C4 alkyl; R3 and R4 each represent H, CN, C1-C4 alkyl, or halo C1-C4 alkyl; Z represents -O- or -NH-(CH2)n-; R5 represents a monocyclic or bicyclic heterocyclic group substituted with a substituent selected from C1-C4 alkyl, halo C1-C4 alkyl, and the like). The invention further relates to the processes for their preparation, pharmaceutical compositions and medicaments containing them, and their use in the treatment of diseases and disorders mediated by NLRP3.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to an inhibitor of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The present invention relates to a novel pyridazine-3-ylphenol compound that is useful as a chemical. The process of preparing the compound, the pharmaceutical composition containing the compound, and the treatment of various diseases and disorders. Methods for using the aforementioned compounds, pharmaceuticals containing them, and NLRP3 This also relates to their use in the treatment of mediated diseases and disorders. [Background technology]

[0002] NOD-like receptor protein 3 (NLRP3) is a protein-coding gene. The protein belongs to the family of nucleotide-binding multimer domain-like receptors (NLRs). It is also known as "pyrin domain-containing protein 3" (Inoue et al. l., Immunology, 2013, 139, 11-18). This gene is pyrin Domain, nucleotide binding site domain (NBD), and leucine-rich repeat (LR) Encodes a protein containing the R) motif. NLR responds to a sterile inflammatory risk signal. P3 is an adapter protein, apoptosis-related speck-like protein (ASC). It also interacts with procaspase-1 to form the NLRP3 inflammasome. RP3 inflammasome activation is followed by the activation of the inflammatory cytokine IL-1β (interlo). This leads to the release of ikin-1β and IL-18 (interleukin-18), resulting in dysregulation. In such cases, it can cause abnormalities in many disease situations.

[0003] NLRP3 inflammasome activation typically requires two steps. The first step is TEP stands for Pathogen Activation Molecular Pattern (PAMP) or Dangerous Activation Molecular Pattern (DAM). P) is recognized by Toll-like receptors, and nuclear factor kappa B (NF-κB) mediated sigma This leads to the activation of NLRP3 and proIL-1β ( Transduction of inflammasome-related components, including interleukin-1β, is accelerated. Pre-regulation is accompanied by a priming signal (Bauernfeind et al. al J.Immunol.2009,183,787-791;Franchi et al. al Nat.Immunol.2012,13,325-332;Franchi et al J.Immunol.2014,193,4214-4222). Second S TEP is involved in the oligomerization of NLRP3 and the combination of NLRP3, ASC, and procaspase-1. This is the subsequent assembly into the inflammasome complex. This is the case of procaspase-1 It triggers conversion to parase-1 and the production and secretion of mature IL-1β and IL-18. (Kim et al J.Inflamm.2015,12,41;Ozaki et al al J.Inflamm.Res.2015,8,15-27;Rabeony e t al.Eur.J.Immunol.2015,45,2847-2857). [Overview of the project] [Problems that the invention aims to solve]

[0004] NLRP3 inflammasome activation is associated with various inflammasome-related diseases / disorders. , immune diseases, inflammatory diseases, autoimmune diseases and autoinflammatory diseases, for example, cryopyrin-related diseases Autoinflammatory fever syndromes such as peritoneal fever syndrome (CAPS) (Mortimer et al. Nature Immunol. 2016, 17(10), 1176-1188); sickle Sclerocytosis; systemic lupus erythematosus (SLE); chronic liver disease, viral hepatitis, non-alcoholic hepatitis Non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease, etc. Liver-related diseases / disorders such as (Petrasek et al J. Clin. I nvest.2012,122,3476-89;Petrasek et al.Na t.Rev.Gastroenterol.Hepatol.2015,12,387- 400;Mridha et al J.Hepatol.2017,66,1037- 46); Gout, pseudogout (chondrocalcification), osteoarthritis (Ridker et al. N (Engl.J.Med.2017,377,1119-31) and rheumatoid arthritis (Ma thews et al Ann.Rheum.Dis.2014,73,1202-1 0) Diseases associated with inflammatory arthritis, such as acute or chronic arthropathy; hyperoxaluria (Knauf et al.Kidney Int.2013,84,895-901) Lupus nephritis, hypertensive nephropathy (Krishnan et al Br.J.Pharm) acol.2016,173,752-65), inflammation and diabetic symptoms associated with hemodialysis This is a kidney-related complication of diabetes (type 1, type 2, and diabetes mellitus), also known as kidney disease. Kidney-related diseases such as diabetic nephropathy (Shahzad et al. Kid This has been linked to ney int. 2015, 87, 74-84). New research suggests that Furthermore, the involvement of the increased production of IL-1β and IL-18 by the NLRP3 inflammasome is , disorders related to neuroinflammation, such as brain infections, acute injuries, multiple sclerosis, Alzheimer's disease - Diseases and neurodegenerative diseases (Shao et al. Front. Pharmacol. 20) 15,6,262); Cardiovascular / metabolic disorders / diseases, e.g., reduced cardiovascular risk (CvRR) ), atherosclerosis, type 1 and type 2 diabetes and related complications (e.g., nephropathy) , retinopathy), peripheral artery disease (PAD), acute heart failure and hypertension (Ridker et al.) al N.Engl.J.Med.2017,377,1119-31;Vandan masgar et al.Nat.Med.2011,17,179-88;Hu e t al Proc.Natl.Acad.Sci.2015,112,11318-2 3;Antonopoulos et al Curr.Opin.Pharmacol .2017,39,1-8;Toldo S et al Nat.Rev.Cardi ol.2018,15,203-214); Wound healing and scar formation; Inflammatory skin diseases, examples Acne, sweat gland abscess (Sweeney et al Br.J.Dermatol.20) 15,173,1361), asthma, sarcoidosis, age-related macular degeneration; cancer-related Diseases / disorders, such as myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), and myelofibrosis. , lung cancer, colon cancer (Ridker et al Lancet 2017,390,183 3-42;Derangere et al Cell.Death Differ.2 014,21,1914-24,Gelfo et al Oncotarget 20 16,7,72167-83,Baiorka et al Blood 2016,1 28,2960-75;Carey et al Cell.Rep.2017,18, It has become clear that it can be a contributing factor to the onset and progression of various diseases such as 3204-18). These diseases / disorders, being either immune or inflammatory, are by their nature usually not efficiently diagnosed. Or it is considered difficult to treat. Most treatments focus on treating the symptoms and preventing the progression of the disease / disability. Slowing down, lifestyle changes, and surgery as a last resort (e.g., atherosclerosis) Recent studies have shown that the progression of the disease can be managed through open-chest surgery. Mitochondrial dysfunction and NLRP3 activation are linked in neuroinflammatory diseases. (Sarkar et al npj Parkinson's disease) 2017,3:30;Zhou et al Nature,2011,469,221 One of the main problems associated with mitochondrial modifiers is that their metabolic stability is poor. This is a fact. Therefore, in neuroinflammation of this nature, selective and stable inhibition occurs. A drug is needed (Lee et al Eur J.Org.Chem.2017,1 41,240).

[0005] Therefore, diseases / disorders related to these inflammasomes, as well as autoinflammatory fever syndromes, Cryopyrin-associated periodic syndromes (e.g., CAPS), sickle cell disease, chronic liver disease, non-associated Non-alcoholic steatohepatitis (NASH), gout, hyperoxaluria, pseudogout (chondrocalcification), Type 1 / Type 2 diabetes and related complications (e.g., nephropathy, retinopathy), and neuroinflammation. Disorders (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease) ), atherosclerosis and cardiovascular risk (for example, reduced cardiovascular risk (CvR) R), hypertension, sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, Other conditions such as myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), and myelofibrosis. To provide new and / or alternative treatments for the condition, NLRP3 Inframas Inhibitors of the genomic pathway are needed. [Means for solving the problem]

[0006] The present invention relates to compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof. The compound provides and inhibits the NLRP3 inflammasome pathway. This invention relates to NLRP A method for treating or preventing diseases and / or disorders related to 3, which is the present invention. To administer an effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject in need. Further methods including the above are provided.

[0007] Various embodiments of the present invention are described herein.

[0008] In one embodiment, equation (I): [ka] (In the formula, R 1 is Cl, CH3, -OCF3, or CF3; R 2 is H, halo, C1-C4 alkyl, or halo-C1-C4 alkyl; R 3 , R 4 is H, CN, C1-C4 alkyl, or halo-C1-C4 alkyl; Z is -O- or -NH-(CH2) n - and n is 0, 1, or 2; R 5 These are C1-C4 alkyl, halo-C1-C4 alkyl, and hydroxy-C1-C4 alkyl , by 1-2 substituents independently selected from -OH, halo, oxo, and -CO2H is a monocyclic or bicyclic heterocyclyl optionally substituted with 1 or 2 substituents independently selected from halo, halo C1-C4 alkyl, C1-C4 alkyl, and -SO2NH2; or R 5 is aryl or heteroaryl optionally substituted with 1 or 2 substituents independently selected from halo, halo C1-C4 alkyl, C1-C4 alkyl, and -SO2NH2; or is C3-C6 cycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from C1-C4 alkyl, halo, halo C1-C4 alkyl, and -OH; or is C2-C6 alkyl substituted with one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2) R 5 is C3-C6 cycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from C1-C4 alkyl, halo, halo C1-C4 alkyl, and -OH; or is C2-C6 alkyl substituted with one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2) or R 5 is C2-C6 alkyl substituted with one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)2) ) and compounds or pharmaceutically acceptable salts thereof are provided herein. In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the definition of formula (I) or a subformula thereof disclosed herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is useful in the treatment of diseases and / or disorders associated with NLRP3 activity.

[0009] In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of a compound according to the definition of formula (I) or a subformula thereof disclosed herein or a pharmaceutically acceptable salt thereof and one or more therapeutic agents. In another aspect, the present invention provides a composition disclosed herein for use as a medicament In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of a compound according to the definition of formula (I) or a subformula thereof disclosed herein or a pharmaceutically acceptable salt thereof and one or more

[0010] In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of a compound according to the definition of formula (I) or a subformula thereof disclosed herein or a pharmaceutically acceptable salt thereof and one or more therapeutic agents. In another aspect, the present invention provides a combination, particularly a pharmaceutical combination, comprising a therapeutically effective amount of a compound according to the definition of formula (I) or a subformula thereof disclosed herein or a pharmaceutically acceptable salt thereof and one or more

[0011] In another aspect, the present invention provides a composition disclosed herein for use as a medicament We provide combinations, especially combinations of pharmaceuticals.

[0012] In another embodiment, the present invention relates to a disease or disorder in which NLRP3 signaling is impaired. In the treatment of a disease or disorder that contributes to the abnormality, and / or symptoms, and / or progression of the illness or disorder. Compounds of formula (I) or its subforms disclosed herein for use in Provide a substance or a pharmaceutically acceptable salt thereof.

[0013] In another embodiment, the present invention relates to a disease or disorder in which NLRP3 signaling is impaired. To treat the disease or disorder that contributes to the abnormality, and / or symptoms, and / or progression of the illness or disorder. A method comprising, a therapeutically effective amount of formula (I) or a portion thereof disclosed herein. The present invention provides a method comprising administering a compound of the formula or a pharmaceutically acceptable salt thereof.

[0014] In another embodiment, the present invention inhibits NLRP3 inflammasome activity, which requires A method performed on a subject, wherein the therapeutically effective amount is the formula disclosed herein ( I) A compound of the subformula thereof or a pharmaceutically acceptable salt thereof, if required The present invention provides a method that includes administering the substance to a target.

[0015] Another aspect of the present invention relates to a pharmaceutical product of formula (I) or the formula disclosed herein. This relates to the use of compounds of the subformula or pharmaceutically acceptable salts thereof.

[0016] Another aspect of the present invention is the formula (I) disclosed herein, for use as a pharmaceutical agent. ) or compounds of its subformula or pharmaceutically acceptable salts thereof.

[0017] Another aspect of the present invention also provides compounds of formula (I) or a subformula thereof disclosed herein, or pharmaceutically acceptable salts thereof, for use in the treatment of a disease or disorder selected from inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases. The present invention includes the following embodiments. <1> Compound of formula (I) [ka] (In the ceremony R 1 Cl, CH 3 , -OCF 3 , or CF 3 and; R 2 H, Halo, C 1 ~C 4 Alkyl, or halo C 1 ~C 4 It is alkyl; R 3 、R 4 H, CN, C 1 ~C 4 Alkyl, or halo C 1 ~C 4 It is alkyl; Z is -O- or -NH-(CH 2 ) n - and n is 0, 1, or 2; R 5 C 1 ~C 4 Alkyl, Halo C 1 ~C 4 Alkyl, hydroxy C 1 ~C 4 Alkyl, -OH, halo, oxo, and -CO 2 It is a monocyclic or bicyclic heterocycline that is optionally substituted with one or two substituents independently selected from H; or R 5 Hello, Hello C 1 ~C 4 Alkyl, C 1 ~C 4 Alkyl and -SO 2 NH 2 It is an aryl or heteroaryl compound that is optionally substituted with one or two substituents independently selected from it; or R 5 C 1 ~C 4 alkyl, halo, halo C 1 ~C 4 C is optionally substituted with 1 to 3 substituents independently selected from alkyl and -OH groups. 3 ~C 6 It is cycloalkyl; or R 5 is -OH, C 1 ~C 4 Alkoxy, Halo, -NH 2 , -NH(C 1 ~C 4 Alkyl), and -N(C 1 ~C 4 Alkyl) 2 C substituted with one or more substituents independently selected from 2 ~C 6 (It is alkyl.) , or a pharmaceutically acceptable salt thereof. <2> Formula (II):

change

change

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[0018] Therefore, the present invention relates to formula (I): [ka] (In the formula, R 1 is Cl, CH3, -OCF3, or CF3; R 2 is H, halo, C1-C4 alkyl, or halo-C1-C4 alkyl; R 3 , R 4 is H, CN, C1-C4 alkyl, or halo-C1-C4 alkyl; Z is -O- or -NH-(CH2) n - and n is 0, 1, or 2; R 5 These are C1-C4 alkyl, halo-C1-C4 alkyl, and hydroxy-C1-C4 alkyl , by 1-2 substituents independently selected from -OH, halo, oxo, and -CO2H It is a monocyclic or bicyclic heterocycline that is optionally substituted; or R 5 These are derived from halo, halo C1-C4 alkyl, C1-C4 alkyl, and -SO2NH2. Aryl or heterovalent substituted with one or two independently selected substituents Is it a loaryl? Or R 5 These are independently of C1-C4 alkyl, halo, halo-C1-C4 alkyl, and -OH. A C3-C6 cycloalkyl group that is optionally substituted with 1-3 selected substituents. Ruka; or R 5 -OH, C1~C4 alkoxy, halo, -NH2, -NH(C1~C4 alkyl ), and one or more substituents independently selected from -N(C1~C4 alkyl)2 (The substituted C2-C6 alkyl group) The compound is provided.

[0019] definition For the purposes of interpreting this specification, unless otherwise specified, the following definitions shall apply and appropriate In some cases, a term used in the singular form also includes its plural form, and vice versa.

[0020] As used herein and in the appended claims, in relation to the present invention (in particular, please The singular forms "a", "an", and "that" are used in relation to the requested term. The term "(the)" and similar terms are used unless the context clearly indicates or is evident from the context. Unless explicitly denied, it should be interpreted as encompassing both singular and plural referents. Please note that, for example, a reference to "compound" means one or more compounds This includes references to objects, etc.

[0021] As used herein, the term "C2-C6 alkyl" refers exclusively to the carbon source. It consists of carbon atoms and hydrogen atoms, does not contain unsaturated atoms, has 2 to 6 carbon atoms, and is bonded by single bonds. This refers to a linear or branched hydrocarbon chain radical that attaches to the remaining molecule. The "C2-C6 alkyl" is preferably composed of one or more substituents, specifically 1 to 13 substituents. This is more preferably substituted with 1 to 8 substituents, which can be optionally replaced. 7 or fewer substituents A substitution group is more preferable. The term "C1-C4 alkyl" should be interpreted accordingly. Examples of 2-C6 alkyl groups include ethyl, n-propyl, and 1-methylethyl (isopropyl). It contains n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl), however These are not the only options.

[0022] As used herein, the term "halo C1-C4 alkyl" or "halogen" "C1-C4 alkyl" is defined as being formed by one or more halo radicals, as described above. This refers to the converted C1-C4 alkyl radicals as defined above. Examples of chloromethyl include trifluoromethyl, difluoromethyl, fluoromethyl, and trichloromethyl. Tyl, 2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3- It contains rom-2-fluoropropyl and 1,4,4-trifluorobutan-2-yl, , but not limited to these.

[0023] As used herein, the term "C1-C4 alkoxy" refers to the formula -OR a of R refers to a radical. a As generally defined above, C1-C4 alkyl radicals Examples of "C1-C4 alkoxys" are methoxy, ethoxy, propoxy, and isopropyl. This includes, but is not limited to, poxy, butoxy, and isobutoxy.

[0024] As used herein, the term "hydroxy C1-C4 alkyl" means C1 ~C4 alkyl radicals in which one of the hydrogen atoms is replaced by an OH group C1~C4 alkyl radical This refers to a hydroxyl radical. Examples of hydroxy C1-C4 alkyl groups include hydroxymethyl and 2- Hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, and 4- This includes, but is not limited to, hydroxybutyl.

[0025] As used herein, the terms "halogen" or "halo" refer to bromo, chloro It refers to fluorocarbon or iodine.

[0026] As used herein, the terms “heterocyclyl” or “heterocyclic formula” are defined as follows: ~24, preferably 4~16, most preferably 5~10 ring atoms, with a stability of 5 Refers to a member or 6-membered non-aromatic monocyclic, bicyclic, or polycyclic ring radical, one or more, preferably Or 1 to 4, in particular 1 or 2 ring atoms, selected from, for example, oxygen, sulfur, and nitrogen. The selected heteroatom is (the remaining ring atom is therefore carbon). Heterocycline The term excludes heteroaryl groups. Heterocyclic groups are selected from, for example, oxygen, sulfur, and nitrogen. It can be attached to the remaining molecule through a selected heteroatom or carbon atom. The ryl can include, for example, a fused ring or a bridging ring and a spiro ring. For example, the term "H" "Telocyclyl" is a compound of one, two, or three heterogen selected from oxygen, nitrogen, and sulfur. It can refer to a monocyclic ring containing 5 to 7 molecules. An example of a monoheterocyclyl is a dihydro Furanil, dioxolanil, dioxanil, dithianil, piperazinil, pyrrolidine, di Hydropyranil, oxathiolanil, dithiolane, oxathianil, thiomorpholino, o Xylanil, Azilidinil, Oxetanil, Oxepanil, Azetidinil, Tetrahydro Furanil, tetrahydrothiophenyl, pyrrolidinil, tetrahydropyranil, piperidinil Nyl, Morpholino, Piperazinyl, Oxapinyl, Oxazepanil, Oxathianil, It includes thiepanil, azepanil, dioxepanil, and diazepanil. Preferably mono Heterocyclyls are morpholino, pyrrolidine, or piperidinyl. Bicyclic heterocyclyl Examples of krill include, for instance, azabicyclooctanil or octahydroindolidinil. In this invention, the term "heterocyclyl" substituted with an "OH" substituent is also used to mean a heterocyclyl. A tetraatom, for example N or S, is oxidized, for example, heterocyclyl N-oxide, heterocyclyl "Heterocyclyl" from which lyl S-oxide or heterocyclyl S-dioxide can be obtained. Includes. An example of heterocyclyl N-oxide is piperidinyl-N-oxide. 1-Me Tylpyrrolidine 1-oxide. Heterocyclyl S-oxide or Heterocyclyl S-dioxide Examples of oxides include tetrahydro-2H-thiopyran-1-oxide, tetrahydro-2H- It contains thiopyran-1,1-dioxide and tetrahydrothiophene-1-oxide.

[0027] As used herein, the term "heteroaryl" refers to nitrogen, oxygen, and sulfur. Five-membered or six-membered aromatic compounds containing one, two, three, or four heteroatoms, individually selected from yellow. This refers to a monocyclic ring radical. Heteroaryl radicals are formed via carbon atoms or heteroatoms. They may be bound together. Examples of heteroaryls are furyl, pyrrolyl, thienyl, pyrazolyl, Imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tria Contains zolyl, tetrazolyl, pyrazinyl, pyridadinyl, pyrimidyl, or pyridyl. , but not limited to these.

[0028] As used herein, the term "C3-C6 cycloalkyl" means exclusively Stable monocyclic and bicyclic compounds consisting of carbon and hydrogen atoms, with 3 to 10 carbon atoms. The term bicyclic cycloalkyl also refers to a tricyclic saturated hydrocarbon radical. This also includes pyronicyclic cycloalkyls. An example of monocyclic C3-C6 cycloalkyls is cyclopro This includes, but is not limited to, pyr, cyclobutyl, cyclopentyl, and cyclohexyl. No. Double-ring type C3~C 10 Examples of cycloalkyls include bicyclo[1.1.1]pentane. However, it is not limited to this.

[0029] As used herein, the term "aryl" refers to a ring portion with 6 to 20 carbon atoms. This refers to an aromatic hydrocarbon group that contains elementary atoms. Typically, aryl groups have 6 to 20 carbon atoms. It is a mono-ring, bi-ring, or tri-ring aryl. In a preferred embodiment, the aryl is It is phenyl.

[0030] Unless otherwise specified, the term "compound of the present invention" refers to compounds of formula (I) and its subformulas. Compounds of formula (II), compounds of formula (III), or compounds of formula (II) described herein. Compounds of IA) and their salts and all stereoisomers (diastereoisomers and (including enantiomers), rotational isomers, tautomers, and isotope-labeled compounds (deuterium substitution) This refers to (including). One or more terms, "(the compound of this invention)," refer to the implementation described below. This refers to a compound defined in any one of its states.

[0031] Various embodiments of the present invention are described herein and specified in each embodiment. Features are combined with other specific features to provide further embodiments of the present invention. It will be recognized that this is a good thing.

[0032] In Embodiment 1, the present invention relates to a compound of formula (I) or its pharmaceutical product as described above. Provides a generally acceptable salt.

[0033] In Embodiment 2, the present invention is represented by formula (II): [ka] The present invention provides a compound of formula (I) according to Embodiment 1, or a pharmaceutically acceptable salt thereof, having the following characteristics: In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 This is as defined in Embodiment 1. ru.

[0034] In Embodiment 3, the present invention is expressed by formula (III): [ka] The present invention provides a compound of formula (I) according to Embodiment 1, or a pharmaceutically acceptable salt thereof, having the following characteristics: In the formula, n is 0, 1, or 2; R 1 , R 2 , R 3 , R 4 , and R 5This is Embodiment 1 As defined in [the relevant section].

[0035] In Embodiment 3a, according to Embodiment 3, the present invention is given by formula (III-A): [ka] The present invention provides a compound of formula (III) or a pharmaceutically acceptable salt thereof having the following characteristics: In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 This is as defined in Embodiment 1. ru.

[0036] In Embodiment 4, the present invention relates to formulas (I), (II) according to Embodiments 1, 2, 3, or 3a. One of the compounds (III) and (III-A) or their pharmaceutically acceptable Provide salt, in the formula, R 5 These are C1-C4 alkyl, halo-C1-C4 alkyl, and hydroxy One independently selected from C1-C4 alkyl, -OH, halo, oxo, and -CO2H It is a monocyclic or bicyclic heterocycline that is optionally substituted with ~2 substituents.

[0037] In Embodiment 5, the present invention relates to formulas (I), (II), (III), and according to Embodiment 4. The present invention provides one of the compounds (III-A) or a pharmaceutically acceptable salt thereof, In the formula, R 5 The following can be selected: [ka] R 5a These are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H. Selected; and R 5bis -OH, hydroxy C1-C4 alkyl, H, halo, oxo, Halo C1-C4 alkyl and -CO2H are independently selected; X is O or CH2. Yes; and m is either 0 or 1.

[0038] In Embodiment 5a, according to Embodiment 5, the present invention relates to formulas (I), (II), and (III). The invention provides one of the compounds (III-A) or a pharmaceutically acceptable salt thereof, In the formula, R 5 The following can be selected: [ka] R 5a These are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H. Selected; and R 5b These are -OH, C1-C4 alkyl, and hydroxy C1-C4 alkyl Independently selected from H, halo, oxo, halo-C1-C4 alkyl, and -CO2H; X is either O or CH2; and m is either 0 or 1.

[0039] In Embodiment 5b, according to Embodiments 5 and 5b, the present invention relates to formulas (I), (II), ( III) and (III-A), one of the compounds or a pharmaceutically acceptable salt thereof Provided, in the formula, R 5 This is as described above in this specification and marked with an asterisk (*). The stereochemistry at the carbon is (R) or (S). Preferably, Z is -NH-(C H2) n - and if n=1 or 2, the stereochemistry at the carbon labeled "*" is (S) Preferably, Z is -O- or -NH-(CH2) n - and n=0 In some cases, the stereochemistry of the carbon labeled "*" is (R).

[0040] In Embodiment 5c, the present invention relates to the formula (I), (I I), (III), and (III-A) one compound or its pharmaceutically acceptable Provides a salt, in the formula, R 5 The structure is preferably selected from the following: [ka] R 5a These are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H. Selected; and R 5b These are -OH, C1-C4 alkyl, and hydroxy C1-C4 alkyl Independently selected from H, halo, oxo, halo-C1-C4 alkyl, and -CO2H; Furthermore, m is either 0 or 1.

[0041] In Embodiment 5d, according to Embodiments 5, 5a, 5b, and 5c, the present invention relates to formula (I) , (II), (III), and (III-A) or any one of the compounds thereof pharmaceutically Provides an acceptable salt, in the formula, R 5 The structure is preferably selected from the following: [ka] R 5a These are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H. Selected; and R 5b These are -OH, C1-C4 alkyl, and hydroxy C1-C4 alkyl Independently selected from H, halo, oxo, halo-C1-C4 alkyl, and -CO2H; Furthermore, m is either 0 or 1.

[0042] In Embodiment 5e, according to Embodiments 5, 5a, 5b, 5c, and 5d, the present invention is expressed by Formula (I), (II), (III), and (III-A) one compound or drug thereof Provides a scientifically acceptable salt, in the formula, R 5 It preferably has the following structure: [ka] R 5a These are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H. It will be selected.

[0043] In Embodiment 6, the present invention relates to formulas (I), (II) according to Embodiments 1, 2, 3, or 3a. One of the compounds (III) and (III-A) or their pharmaceutically acceptable Provide salt, in the formula, R 5 This includes halo, halo C1-C4 alkyl, C1-C4 alkyl, and -SO2NH2 is optionally substituted with 1-2 substituents independently selected. It is either a reel or a heteroaryl.

[0044] In Embodiment 6a, according to Embodiment 6, the present invention relates to formulas (I), (II), and (III). The invention provides one of the compounds (III-A) or a pharmaceutically acceptable salt thereof, In the formula, R 5 The structure is preferably selected from the following: [ka] R 5c is independently selected from H, C1-C4 alkyl, and -SO2NH2; and s is 0, 1, or 2.

[0045] In Embodiment 6b, the present invention relates to formulas (I), (II), and (III) according to Embodiment 6. and a compound of any one of (III-A) or a pharmaceutically acceptable salt thereof are provided, wherein R 5 is preferably selected from the following structures:

Chemical formula

[0046] In Embodiment 6c, according to Embodiments 6 and 6b, the present invention provides a compound of any one of formula (I), (II), ( III), and (III-A) or a pharmaceutically acceptable salt thereof, wherein R 5 is preferably selected from the following structures:

Chemical formula

[0047] In Embodiment 7, the present invention provides a compound of any one of formula (I), (II) according to Embodiments 1, 2, 3, or 3a , (III), and (III-A) or a pharmaceutically acceptable salt thereof, and R 5 is optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, halo, halo C1-C4 alkyl, and -OH and is C3-C6 cycloalkyl.

[0048] In Embodiment 7a, according to Embodiment 7, the present invention provides a compound of any one of formula (I), (II), (III) , and (III-A) or a pharmaceutically acceptable salt thereof, wherein R 5 ​is preferably cyclo propyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with 1 to 3 substituents independently selected from C1-C4 alkyl, halo, halo C1-C4 alkyl, and

[0049] -OH. In Embodiment 7b, according to Embodiments 7 and 7a, the present invention provides a compound of any one of formulas (I), (II), ( III), and (III-A) or a pharmaceutically acceptable salt thereof, wherein R is preferably selected from the following structures: 5

Chemical formula

Chemical formula

[0052] In Embodiment 8, the present invention relates to formulas (I), (II), and (I) according to Embodiments 1, 2, or 3. II) and (III-A) provide one compound or a pharmaceutically acceptable salt thereof. Provided, during the ceremony, R 5 -OH, C1~C4 alkoxy, halo, -NH2, -NH(C1~ One or more independently selected from C4 alkyl and -N(C1~C4 alkyl)2 These are C2-C6 alkyl groups substituted with substituents.

[0053] In Embodiment 8a, according to Embodiment 8, the present invention relates to formulas (I), (II), and (III). The invention provides one of the compounds (III-A) or a pharmaceutically acceptable salt thereof, In the formula, R 5 The structure is preferably selected from the following: [ka] R 5h These are -NH2, -OH, -NH(C1~C4 alkyl), and -N(C1~C4 alkyl) (Lucil) Selected from 2.

[0054] In Embodiment 9, the present invention is described in Embodiments 1, 2, 3, 3a, 4, 5, 5a-5e, 6, 6 Formulas (I) and (II) (I) that follow one of the following: a~6c, 7, 7a~7d, 8, and 8a II) and (III-A) provide one compound or a pharmaceutically acceptable salt thereof. Provided, during the ceremony, R 2 and R 3 At least one of them is H.

[0055] In Embodiment 9a, according to Embodiment 9, the present invention relates to formulas (I), (II), and (III). The invention provides one of the compounds (III-A) or a pharmaceutically acceptable salt thereof, In the formula, R 2 is a halo, C1-C4 alkyl, or halo-C1-C4 alkyl; and R 3 H is H.

[0056] In Embodiment 9b, according to Embodiment 9, the present invention relates to formulas (I), (II), and (III). The invention provides one of the compounds (III-A) or a pharmaceutically acceptable salt thereof, In the formula, R 2 H is; and R 3 This is CN, C1-C4 alkyl, or halo C1-C4 It is alkyl.

[0057] In Embodiment 10, the present invention relates to formulas (I), (II), and (III) according to Embodiments 1 to 9. The invention provides one of the compounds (III-A) or a pharmaceutically acceptable salt thereof, In the formula, R 1 This is -OCF3 or -CF3.

[0058] In Embodiment 10a, the present invention relates to formulas (I), (II), and (II) in accordance with Embodiment 10. Provides one compound from (I) and (III-A) or a pharmaceutically acceptable salt thereof. And in the formula, R 1 This is CF3.

[0059] In Embodiment 11, the present invention relates to formulas (I), (II), (III), and according to Embodiment 1. Provides one of the compounds (III-A) or a pharmaceutically acceptable salt thereof, and The item can be selected from the following: 2-(6-((1-ethylpiperidine-3-yl)amino)pyridazin-3-yl)-3 -methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-ethylpiperidine-3-yl)amino)pyridazine-3-yl (Lu)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((1-ethylpiperidine-3-yl)amino)pyridazine-3-yl (Lu)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)pyridazine-3-i (Lu)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)pyri Dazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxycyclohexyl)amino)pyridazine-3-yl)-3- Methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,3R)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(4-methyl-6-((1-methylpiperidine-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-2-(4-methyl-6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(4-methyl-6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(5-methyl-6-((1-methylpiperidine-3-yl)amino)pi Ridazine-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(5-methyl-6-((1-methylpiperidine-3-yl) Minopyridazine-3-yl-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidine-3-yl) Minopyridazine-3-yl-5-(trifluoromethyl)phenol; 2-(6-((1-(2-hydroxyethyl)piperidine-3-yl)aminopyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-(2-hydroxyethyl)piperidine-3-yl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((1-(2-hydroxyethyl)piperidine-3-yl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((1-isopropylpiperidine-3-yl)amino)pyridazine-3-yl )-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1-ethylpyrrolidine-2-yl)methyl)amino)pyridazine-3- Iyl-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-(((1-ethylpyrrolidine-2-yl)methyl)amino)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-(((1-ethylpyrrolidine-2-yl)methyl)amino)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5,5-difluoropiperidine-3-yl)amino)pyridazine-3-yl (Lu)-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-(trif (Pyromethyl)propyl)amino)pyridazine-3-yl)-5-(trifluoromethyl) ) Phenol; 3-((1-ethylpiperidine-3-yl)amino)-6-(2-hydroxy-6-methyl Lu-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile; (S)-3-((1-ethylpiperidine-3-yl)amino)-6-(2-hydroxy- 6-Methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile; (R)-3-((1-ethylpiperidine-3-yl)amino)-6-(2-hydroxy- 6-Methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile; 3-Methyl-2-(6-((1-methylpiperidine-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((1-(2-hydroxyethyl)piperidine-3-yl)amino)-5-methyl Tylpyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-(2-hydroxyethyl)piperidine-3-yl)amino) -5-methylpyridazine-3-yl)-3-methyl-5-(trifluoromethyl)pheno Ru; (R)-2-(6-((1-(2-hydroxyethyl)piperidine-3-yl)amino) -5-methylpyridazine-3-yl)-3-methyl-5-(trifluoromethyl)pheno Ru; 3-methyl-2-(6-((pyrrolidine-2-ylmethyl)amino)pyridazine-3- (Lu)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((pyrrolidine-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((pyrrolidine-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; 2-(6-((2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl) -3-methyl-5-(trifluoromethyl)phenol; 2-(6-((2-(dimethylamino)-2-methylpropyl)amino)pyridazine-3 -yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpyrrolidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((1-methylpyrrolidine-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-methylpyrrolidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(2-hydroxy-2-methylpropoxy)pyridazine-3-yl)-3-methyl Tyl-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((piperidine-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-((piperidine-2-ylmethyl)amino)pyridazine-3- (Lu)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((piperidine-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; (S)-2-(6-(((4,4-difluoropyrrolinidine-2-yl)methyl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((4,4-difluoropyrrolidine-2-yl)methyl)amino)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-(((4,4-difluoropyrrolidine-2-yl)methyl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((2-hydroxycyclopentyl)amino)pyridazine-3-yl)-3- Methyl-5-(trifluoromethyl)phenol; (cis)-2-(6-((2-hydroxycyclopentyl)amino)pyridazine-3-i (Lu)-3-methyl-5-(trifluoromethyl)phenol; (Trans)-2-(6-((2-hydroxycyclopentyl)amino)pyridazine-3 -yl)-3-methyl-5-(trifluoromethyl)phenol; 3,5-Dichloro-2-(6-((2-hydroxyethyl)amino)pyridazine-3-i Phenol; 2-(6-((2-hydroxyethyl)amino)-5-(trifluoromethyl)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 3,5-Dichloro-2-(6-((2,2,2-trifluoroethyl)amino)pyridadi 0-3-yl)phenol; 3-Methyl-2-(6-((pyridine-2-ylmethyl)amino)pyridazine-3-yl )-5-(trifluoromethyl)phenol; 2-(6-((2-amino-2-methylpropyl)amino)pyridazin-3-yl)-3 -methyl-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((2-hydroxy-2-methylpropyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((cis-3-hydroxycyclobutyl)amino)pyridazine- 3-yl)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((3-hydroxycyclobutyl)amino)pyridazine-3-i (Lu)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((trans-3-hydroxycyclobutyl)amino)pyridadi (n-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(piperidine-3-ylamino)pyridazine-3-yl)-5- (trifluoromethyl)phenol; (R)-3-methyl-2-(6-(piperidine-3-ylamino)pyridazine-3-yl )-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-(piperidine-3-ylamino)pyridazine-3-yl )-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-(((2-methylpyridine-3-yl)methyl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 5-Chloro-2-(6-(((2-methylpyridine-3-yl)methyl)amino)pyrida Zin-3-yl)-3-(trifluoromethyl)phenol; 3-Methyl-2-(6-((1-methylpiperidine-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((2-hydroxyethyl)amino)pyridazin-3-yl)- 5-(trifluoromethyl)phenol; 5-Chloro-3-fluoro-2-(6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)phenol; (S)-5-chloro-3-fluoro-2-(6-((1-methylpiperidine-3-yl) Amino)pyridazine-3-yl)phenol; (R)-5-chloro-3-fluoro-2-(6-((1-methylpiperidine-3-yl) Amino)pyridazine-3-yl)phenol; 5-Chloro-3-fluoro-2-(6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)phenol TFA salt; (S)-5-chloro-3-fluoro-2-(6-((1-methylpiperidine-3-yl) Amino)pyridazine-3-yl)phenol TFA salt; (R)-5-chloro-3-fluoro-2-(6-((1-methylpiperidine-3-yl) Amino)pyridazine-3-yl)phenol TFA salt; 2-(6-((1-methylpiperidine-3-yl)amino)pyridazine-3-yl)-3 ,5-bis(trifluoromethyl)phenol; (S)-2-(6-((1-methylpiperidine-3-yl)amino)pyridazine-3-yl (Lu)-3,5-bis(trifluoromethyl)phenol; (R)-2-(6-((1-methylpiperidine-3-yl)amino)pyridazine-3-yl (Lu)-3,5-bis(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-((1-methylpiperidine-3-yl)amino)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-(((S)-1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-(((R)-1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-((1-methylpiperidine-3-yl)amino)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA salt; 2-(4,5-dimethyl-6-(((S)-1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA salt ; 2-(4,5-dimethyl-6-(((R)-1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA salt ; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)py Ridazine-3-yl)amino)piperidine-2-carboxylic acid; 3-Methyl-2-(6-((1-methylpiperidine-3-yl)oxy)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-methylpiperidine-3-yl)oxy)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpiperidine-3-yl)oxy)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(pyrimidine-5-ylamino)pyridazin-3-yl)-5- (trifluoromethyl)phenol; 3,5-Dichloro-2-(6-(cyclopropylamino)pyridazine-3-yl)phen Ru; 3,5-Dichloro-2-(6-((1-methylpiperidine-3-yl)amino)pyridadi 0-3-yl)phenol; (S)-3,5-dichloro-2-(6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)phenol; (R)-3,5-dichloro-2-(6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)phenol; 3,5-Dichloro-2-(6-((1-methylpiperidine-3-yl)amino)pyridadi (N-3-yl)phenol TFA salt; (S)-3,5-dichloro-2-(6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)phenol TFA salt; (R)-3,5-dichloro-2-(6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)phenol TFA salt; 3-methyl-2-(6-(pyridin-3-ylamino)pyridazine-3-yl)-5-( Trifluoromethylphenol; 3,5-dimethyl-2-(6-((1-methylpiperidine-3-yl)amino)pyridadi 0-3-yl)phenol; (S)-3,5-dimethyl-2-(6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)phenol; (R)-3,5-dimethyl-2-(6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)phenol; 2-(4,5-dimethyl-6-((1-methylpiperidine-3-yl)amino)pyridadi (n-3-yl)-5-(trifluoromethyl)phenol; (S)-2-(4,5-dimethyl-6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(4,5-dimethyl-6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((1-methylpiperidine-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-3-chloro-2-(6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-chloro-2-(6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 5-methyl-2-(6-((1-methylpiperidine-3-yl)amino)-4-(trif Luoromethyl)pyridazine-3-yl)phenol; (S)-5-methyl-2-(6-((1-methylpiperidine-3-yl)amino)-4- (Trifluoromethyl)pyridazine-3-yl)phenol; (R)-5-methyl-2-(6-((1-methylpiperidine-3-yl)amino)-4- (Trifluoromethyl)pyridazine-3-yl)phenol; 5-Chloro-2-(6-((1-methylpiperidine-3-yl)amino)pyridazine-3 -yl)-3-(trifluoromethyl)phenol; (S)-5-chloro-2-(6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-3-(trifluoromethyl)phenol; (R)-5-chloro-2-(6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-3-(trifluoromethyl)phenol; 2-(6-((1,3-dimethylpiperidine-3-yl)amino)pyridazine-3-yl )-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((1,3-dimethylpiperidine-3-yl)amino)pyridazine-3-yl )-3-methyl-5-(trifluoromethyl)phenol TFA salt; 2-(6-((1-methylpiperidine-3-yl)amino)-4-(trifluoromethyl Pyridazine-3-yl)-5-(trifluoromethyl)phenol; (S)-2-(6-((1-methylpiperidine-3-yl)amino)-4-(trifluor (Methyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(6-((1-methylpiperidine-3-yl)amino)-4-(trifluor (Methyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-5-methylpyridan Zin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-5 -Methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol ; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-methyl Tylpyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridan Zin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4 -methylpyridazine-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methyl Tylpyridazine-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-5-(trifluoro (Methyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Lu; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-5 -(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl (Tyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-( (trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl ) Phenol; 2-(6-((3-hydroxycyclohexyl)amino)pyridazine-3-yl)-3- Methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,3R)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)py Ridazine-3-yl)amino)-1-methylpiperidine-2-one; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)pyridazine-3-yl)amino)-1-methylpiperidine-2-one; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)pyridazine-3-yl)amino)-1-methylpiperidine-2-one; 2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino)pyridazine -3-yl)3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino) Ridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino) Ridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)py Ridazine-3-yl)amino)piperidine-2-one; (S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)pyridazine-3-yl)amino)piperidine-2-one; (R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)pyridazine-3-yl)amino)piperidine-2-one; 3-methyl-5-(trifluoromethyl)-2-(6-((6-(trifluoromethyl) Piperidine-3-yl)amino)pyridazine-3-yl)phenol; 3-methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidine-3- Il)amino)pyridazine-3-yl)5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidi (-3-yl)amino)pyridazine-3-yl)-5-(trifluoromethyl)phenol Lu; (R)-3-methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidi (-3-yl)amino)pyridazine-3-yl)-5-(trifluoromethyl)phenol Lu; 3-methyl-2-(6-((1-methylpiperidine-3-yl)amino)-5-(trif (Pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-methylpiperidine-3-yl)amino)-5- (Trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol Lu; (R)-3-methyl-2-(6-((1-methylpiperidine-3-yl)amino)-5- (Trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol Lu; 2-(5-methyl-6-((1-methylpiperidine-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-2-(5-methyl-6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(5-methyl-6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoro (Methyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4 -(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)pheno Ru; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-( (Trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol ; 2-(6-((3-hydroxy-3-(trifluoromethyl)cyclobutyl)amino)pi Ridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-(trifluoromethyl)cyclobutyl (Amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)pheno Ru; 2-(6-(((cis)-3-hydroxy-3-(trifluoromethyl)cyclobutyl) Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol ; 5-Chloro-2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4- Methylpyridazine-3-yl)phenol; 5-Chloro-2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl) Amino)-4-methylpyridazine-3-yl)phenol; 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amide (no)-4-methylpyridazine-3-yl)phenol; 5-Chloro-2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4- (Trifluoromethyl)pyridazine-3-yl)phenol; 5-Chloro-2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl) Amino)-4-(trifluoromethyl)pyridazine-3-yl)phenol; 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amide (no)-4-(trifluoromethyl)pyridazine-3-yl)phenol; 5-Chloro-2-(6-((1-methylpiperidine-3-yl)amino)-4-(Trif Luoromethyl)pyridazine-3-yl)phenol; (S)-5-chloro-2-(6-((1-methylpiperidine-3-yl)amino)-4- (Trifluoromethyl)pyridazine-3-yl)phenol; (R)-5-chloro-2-(6-((1-methylpiperidine-3-yl)amino)-4- (Trifluoromethyl)pyridazine-3-yl)phenol; 5-Chloro-2-(4-methyl-6-((1-methylpiperidine-3-yl)amino)pi Ridazine-3-yl)phenol; (S)-5-chloro-2-(4-methyl-6-((1-methylpiperidine-3-yl) Minopyridazine-3-ylphenol; (R)-5-chloro-2-(4-methyl-6-((1-methylpiperidine-3-yl) Minopyridazine-3-ylphenol; 2-(6-((2-hydroxy-2-methylpropyl)amino)-5-methylpyridazine -3-yl)3-methyl-5-(trifluoromethyl)phenol; 2-(6-((2-hydroxy-2-methylpropyl)amino)-4-methylpyridazine -3-yl)3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(piperidine-3-ylamino)pyridazine-3-yl)-5- (trifluoromethyl)phenol; (S)-3-methyl-2-(6-(piperidine-3-ylamino)pyridazine-3-yl )-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-(piperidine-3-ylamino)pyridazine-3-yl )-5-(trifluoromethyl)phenol; 2-(6-(((4-fluoropyrrolidine-2-yl)methyl)amino)pyridazine-3 -yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2S,4S)-4-fluoropyrrolidine-2-yl)methyl)amino Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2R,4S)-4-fluoropyrrolidine-2-yl)methyl)amino Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2R,4R)-4-fluoropyrrolidine-2-yl)methyl)amino Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2S,4R)-4-fluoropyrrolidine-2-yl)methyl)amino Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-(((4-methylmorpholine-3-yl)methyl)amide (no)pyridazine-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-(((4-methylmorpholine-3-yl)methyl)amide (no)pyridazine-3-yl)-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-(6-(((4-methylmorpholine-3-yl)methyl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methyl Ropyr (amino)pyridazine-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2- Methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)pheno Ru; (R)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2- Methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)pheno Ru; 3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methyl (Pyridazine-3-yl)-5-(trifluoromethyl)phenol HCl l salt; (R)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2- Methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)pheno HCl salt; (S)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2- Methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)pheno HCl salt; 2-(6-((1-hydroxy-2-methylpropan-2-yl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((1-(2-hydroxy-2-methylpropyl)piperidine-3-yl) Mino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidine-3- (yl)amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phen Knoll; (R)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidine-3- (yl)amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phen Knoll; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridan Zin-3-yl)-5-(trifluoromethoxy)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4 -methylpyridazin-3-yl)-5-(trifluoromethoxy)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methyl Tylpyridazine-3-yl)-5-(trifluoromethoxy)phenol; 2-(4-methyl-6-((1-methylpiperidine-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethoxy)phenol; (S)-2-(4-methyl-6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethoxy)phenol; (R)-2-(4-methyl-6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethoxy)phenol; 3-Methyl-2-(6-((Octahydroindolidine-8-yl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((8R,8aR)-octahydroindolidine-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((8R,8aS)-octahydroindolidine-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((8S,8aR)-octahydroindolidine-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((8S,8aS)-octahydroindolidine-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(6-(((1-(2-hydroxyethyl)piperidine-2-yl)methyl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Lu; 2-(6-(((1-(2-hydroxyethyl)piperidine-2-yl)methyl)amino Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-(((1-(2-hydroxyethyl)piperidine-2-yl)methyl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Lu; 3-methyl-2-(6-((8-methyl-8-azabicyclo[3.2.1]octane-2 -yl)amino)pyridazine-3-yl)5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1S,2S,5S)-8-methyl-8-azabicyclo[3 .2.1] Octane-2-yl)amino)pyridazine-3-yl)-5-(trifluoro Methylphenol; 3-methyl-2-(6-(((1S,2R,5S)-8-methyl-8-azabicyclo[3 .2.1] Octane-2-yl)amino)pyridazine-3-yl)-5-(trifluoro Methylphenol; 3-methyl-2-(6-(((1S,2R,5R)-8-methyl-8-azabicyclo[3 .2.1] Octane-2-yl)amino)pyridazine-3-yl)-5-(trifluoro Methylphenol; 3-methyl-2-(6-(((1S,2S,5R)-8-methyl-8-azabicyclo[3 .2.1] Octane-2-yl)amino)pyridazine-3-yl)-5-(trifluoro Methylphenol; 3-methyl-2-(6-(((1R,2R,5S)-8-methyl-8-azabicyclo[3 .2.1] Octane-2-yl)amino)pyridazine-3-yl)-5-(trifluoro Methylphenol; 3-methyl-2-(6-(((1R,2S,5S)-8-methyl-8-azabicyclo[3 .2.1] Octane-2-yl)amino)pyridazine-3-yl)-5-(trifluoro Methylphenol; 3-methyl-2-(6-(((1R,2S,5R)-8-methyl-8-azabicyclo[3 .2.1] Octane-2-yl)amino)pyridazine-3-yl)-5-(trifluoro Methylphenol; 3-methyl-2-(6-(((1R,2R,5R)-8-methyl-8-azabicyclo[3 .2.1] Octane-2-yl)amino)pyridazine-3-yl)-5-(trifluoro Methylphenol; 2-(6-((8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octa (-2-yl)amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl) Phenol; 2-(6-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabisic [3.2.1]octan-2-yl)amino)pyridazine-3-yl)-3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1R,2S,5S)-8-(2-hydroxyethyl)-8-azabisic [3.2.1]octan-2-yl)amino)pyridazine-3-yl)-3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1R,2S,5R)-8-(2-hydroxyethyl)-8-azabisic [3.2.1]octan-2-yl)amino)pyridazine-3-yl)-3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1R,2R,5S)-8-(2-hydroxyethyl)-8-azabisic [3.2.1]octan-2-yl)amino)pyridazine-3-yl)-3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1S,2S,5R)-8-(2-hydroxyethyl)-8-azabisic [3.2.1]octan-2-yl)amino)pyridazine-3-yl)-3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1S,2R,5R)-8-(2-hydroxyethyl)-8-azabisic [3.2.1]octan-2-yl)amino)pyridazine-3-yl)-3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1S,2R,5S)-8-(2-hydroxyethyl)-8-azabisic [3.2.1]octan-2-yl)amino)pyridazine-3-yl)-3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabisic [3.2.1]octan-2-yl)amino)pyridazine-3-yl)-3-methyl- 5-(trifluoromethyl)phenol; 2-(6-((6-(hydroxymethyl)-1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,6R)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl) Enol; 2-(6-(((3S,6R)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl) Enol; 2-(6-(((3R,6S)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl) Enol; 2-(6-(((3S,6S)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl) Enol; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)pyridazine-3-yl)amino)2-methylpropane-1,2-diol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)py Ridazine-3-yl)amino)-2-methylpropane-1,2-diol; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)pyridazine-3-yl)amino)2-methylpropane-1,2-diol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)py Ridazine-3-yl)amino)cyclopentan-1,2-diol; (1S,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro Methyl(phenyl)pyridazin-3-yl)amino(cyclopentan-1,2-diole Lu; (1S,2R,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro Methyl(phenyl)pyridazin-3-yl)amino(cyclopentan-1,2-diole Lu; (1S,2S,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro Methyl(phenyl)pyridazin-3-yl)amino(cyclopentan-1,2-diole Lu; (1S,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro Methyl(phenyl)pyridazin-3-yl)amino(cyclopentan-1,2-diole Lu; (1R,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro Methyl(phenyl)pyridazin-3-yl)amino(cyclopentan-1,2-diole Lu; (1R,2S,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluor Methyl(phenyl)pyridazin-3-yl)amino(cyclopentan-1,2-diole Lu; (1R,2R,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro Methyl(phenyl)pyridazin-3-yl)amino(cyclopentan-1,2-diole Lu; (1R,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro Methyl(phenyl)pyridazin-3-yl)amino(cyclopentan-1,2-diole Lu; (S)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazine-3- Iyl-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)- 3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazine-3- Iyl-3-methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((2-methylpiperidine-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((2S,3S)-2-methylpiperidine-3-yl)amino Pyridazine-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((2R,3S)-2-methylpiperidine-3-yl)amino Pyridazine-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((2S,3R)-2-methylpiperidine-3-yl)amino Pyridazine-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((2R,3R)-2-methylpiperidine-3-yl)amino Pyridazine-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((2-hydroxypropyl)piperidine-3-yl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((R)-1-((S)-2-hydroxypropyl)piperidine-3-yl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Lu; 2-(6-(((S)-1-((R)-2-hydroxypropyl)piperidine-3-yl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Lu; 2-(6-(((S)-1-((S)-2-hydroxypropyl)piperidine-3-yl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Lu; 2-(6-(((R)-1-((R)-2-hydroxypropyl)piperidine-3-yl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Lu; 2-(6-((5-fluoropiperidine-3-yl)amino)pyridazine-3-yl)- 3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoropiperidine-3-yl)aminopyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoropiperidine-3-yl)aminopyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoropiperidine-3-yl)aminopyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoropiperidine-3-yl)amino)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5-fluoro-1-methylpiperidine-3-yl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidine-3-yl)amide (no)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidine-3-yl)amide (no)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidine-3-yl)ami (no)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amide (no)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5-fluoro-1-methylpiperidine-3-yl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidine-3-yl)amide (no)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amide (no)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidine-3-yl)amide (no)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidine-3-yl)ami (no)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5-fluoropiperidine-3-yl)amino)pyridazine-3-yl)- 3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoropiperidine-3-yl)aminopyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoropiperidine-3-yl)aminopyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoropiperidine-3-yl)amino)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoropiperidine-3-yl)aminopyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)py Ridazine-3-yl)amino)-1-methylpiperidine-3-ol; (3S,5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl Phenylpyridazine-3-ylamino-1-methylpiperidine-3-ol; (3R,5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl Phenylpyridazine-3-ylamino-1-methylpiperidine-3-ol; (3R,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl Phenylpyridazine-3-ylamino-1-methylpiperidine-3-ol; (3S,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl Phenylpyridazine-3-ylamino-1-methylpiperidine-3-ol; 2-(6-(((1-hydroxycyclopentyl)methyl)amino)pyridazine-3-i (Lu)-3-methyl-5-(trifluoromethyl)phenol; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-methylpyridazine-3-yl)amino)-1-methylpiperidine-2-one; 3-methyl-2-(5-methyl-6-(piperidine-3-ylamino)pyridazine-3- Il-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(5-methyl-6-(piperidine-3-ylamino)pyridadi (n-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(5-methyl-6-(piperidine-3-ylamino)pyridadi (n-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((1-ethylpiperidine-3-yl)amino)-5-methylpyridazine-3 -yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-ethylpiperidine-3-yl)amino)-5-methylpyridan Zin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((1-ethylpiperidine-3-yl)amino)-5-methylpyridan Zin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-methylpyridazine-3-yl)amino)-1-methylpiperidine-2-one; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)-4-methylpyridazine-3-yl)amino)-1-methylpiperidine-2-one ; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)-4-methylpyridazine-3-yl)amino)-1-methylpiperidine-2-one ; 4-(2-((6-(2-hydroxy-4,6-dimethylphenyl)pyridazine-3-i (Amino)ethyl)benzenesulfonamide; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-methylpyridazine-3-yl)amino)-1-methylpiperidine-1-oxide; (3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) (enyl)-4-methylpyridazine-3-yl)amino)-1-methylpiperidine-1-oxy Sid; (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) (enyl)-4-methylpyridazine-3-yl)amino)-1-methylpiperidine-1-oxy Sid; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-Methylpyridazine-3-yl)amino)-1-methylpiperidine 1-oxide TFA salt; (3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) (enyl)-4-methylpyridazine-3-yl)amino)-1-methylpiperidine-1-oxy Sid TFA salt; (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) (enyl)-4-methylpyridazine-3-yl)amino)-1-methylpiperidine-1-oxy Sid TFA salt; or a pharmaceutically acceptable salt thereof.

[0060] In Embodiment 11a, according to Embodiment 11, the present invention relates to formula (I) according to Embodiment 1, (II), (III), and (III-A) one of the compounds or their pharmaceutically acceptable compounds The salt to be provided is preferably selected from the following: (R)-2-(6-((1-ethylpiperidine-3-yl)amino)pyridazine-3-yl (Lu)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(4-methyl-6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidine-3-yl) Minopyridazine-3-yl-5-(trifluoromethyl)phenol; (R)-2-(6-((1-(2-hydroxyethyl)piperidine-3-yl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((1-isopropylpiperidine-3-yl)amino)pyridazine-3-yl )-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-(((1-ethylpyrrolidine-2-yl)methyl)amino)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5,5-difluoropiperidine-3-yl)amino)pyridazine-3-yl (Lu)-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-(trif (Pyromethyl)propyl)amino)pyridazine-3-yl)-5-(trifluoromethyl) ) Phenol; (R)-3-((1-ethylpiperidine-3-yl)amino)-6-(2-hydroxy- 6-Methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile; (R)-3-methyl-2-(6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(6-((1-(2-hydroxyethyl)piperidine-3-yl)amino) -5-methylpyridazine-3-yl)-3-methyl-5-(trifluoromethyl)pheno Ru; (R)-3-methyl-2-(6-((pyrrolidine-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; 2-(6-((2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl) -3-methyl-5-(trifluoromethyl)phenol; 2-(6-((2-(dimethylamino)-2-methylpropyl)amino)pyridazine-3 -yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpyrrolidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-methylpyrrolidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(2-hydroxy-2-methylpropoxy)pyridazine-3-yl)-3-methyl Tyl-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((piperidine-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((piperidine-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; (S)-2-(6-(((4,4-difluoropyrrolinidine-2-yl)methyl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-(((4,4-difluoropyrrolidine-2-yl)methyl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (Trans)-2-(6-((2-hydroxycyclopentyl)amino)pyridazine-3 -yl)-3-methyl-5-(trifluoromethyl)phenol; 3,5-Dichloro-2-(6-((2-hydroxyethyl)amino)pyridazine-3-i Phenol; 2-(6-((2-hydroxyethyl)amino)-5-(trifluoromethyl)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 3,5-Dichloro-2-(6-((2,2,2-trifluoroethyl)amino)pyridadi 0-3-yl)phenol; 3-Methyl-2-(6-((pyridine-2-ylmethyl)amino)pyridazine-3-yl )-5-(trifluoromethyl)phenol; 2-(6-((2-amino-2-methylpropyl)amino)pyridazin-3-yl)-3 -methyl-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((2-hydroxy-2-methylpropyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((cis-3-hydroxycyclobutyl)amino)pyridazine- 3-yl)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((trans-3-hydroxycyclobutyl)amino)pyridadi (n-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-(piperidine-3-ylamino)pyridazine-3-yl )-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-(((2-methylpyridine-3-yl)methyl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 5-Chloro-2-(6-(((2-methylpyridine-3-yl)methyl)amino)pyrida Zin-3-yl)-3-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((2-hydroxyethyl)amino)pyridazin-3-yl)- 5-(trifluoromethyl)phenol; (R)-5-chloro-3-fluoro-2-(6-((1-methylpiperidine-3-yl) Amino)pyridazine-3-yl)phenol TFA salt; (R)-2-(6-((1-methylpiperidine-3-yl)amino)pyridazine-3-yl (Lu)-3,5-bis(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-(((R)-1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA salt ; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)py Ridazine-3-yl)amino)piperidine-2-carboxylic acid; (R)-3-methyl-2-(6-((1-methylpiperidine-3-yl)oxy)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(pyrimidine-5-ylamino)pyridazin-3-yl)-5- (trifluoromethyl)phenol; 3,5-Dichloro-2-(6-(cyclopropylamino)pyridazine-3-yl)phen Ru; (R)-3,5-dichloro-2-(6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)phenol TFA salt; 3-methyl-2-(6-(pyridin-3-ylamino)pyridazine-3-yl)-5-( Trifluoromethylphenol; (R)-3,5-dimethyl-2-(6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)phenol; (R)-2-(4,5-dimethyl-6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)-5-(trifluoromethyl)phenol; (R)-3-chloro-2-(6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; (R)-5-methyl-2-(6-((1-methylpiperidine-3-yl)amino)-4- (Trifluoromethyl)pyridazine-3-yl)phenol; (R)-5-chloro-2-(6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-3-(trifluoromethyl)phenol; 2-(6-((1,3-dimethylpiperidine-3-yl)amino)pyridazine-3-yl )-3-methyl-5-(trifluoromethyl)phenol TFA salt; (R)-2-(6-((1-methylpiperidine-3-yl)amino)-4-(trifluor (Methyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-methyl Tylpyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methyl Tylpyridazine-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-( (trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl ) Phenol; 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)pyridazine-3-yl)amino)-1-methylpiperidine-2-one; (R)-2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino) Ridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)pyridazine-3-yl)amino)piperidine-2-one; 3-methyl-5-(trifluoromethyl)-2-(6-((6-(trifluoromethyl) Piperidine-3-yl)amino)pyridazine-3-yl)phenol; (R)-3-methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidi (-3-yl)amino)pyridazine-3-yl)-5-(trifluoromethyl)phenol Lu; (R)-3-methyl-2-(6-((1-methylpiperidine-3-yl)amino)-5- (Trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol Lu; (R)-2-(5-methyl-6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-( (Trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol ; 2-(6-(((cis)-3-hydroxy-3-(trifluoromethyl)cyclobutyl) Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol ; 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amide (no)-4-methylpyridazine-3-yl)phenol; 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amide (no)-4-(trifluoromethyl)pyridazine-3-yl)phenol; (R)-5-chloro-2-(6-((1-methylpiperidine-3-yl)amino)-4- (Trifluoromethyl)pyridazine-3-yl)phenol; (R)-5-chloro-2-(4-methyl-6-((1-methylpiperidine-3-yl) Minopyridazine-3-ylphenol; 2-(6-((2-hydroxy-2-methylpropyl)amino)-5-methylpyridazine -3-yl)3-methyl-5-(trifluoromethyl)phenol; 2-(6-((2-hydroxy-2-methylpropyl)amino)-4-methylpyridazine -3-yl)3-methyl-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-(piperidine-3-ylamino)pyridazine-3-yl )-5-(trifluoromethyl)phenol; 2-(6-((((2S,4S)-4-fluoropyrrolidine-2-yl)methyl)amino Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2S,4R)-4-fluoropyrrolidine-2-yl)methyl)amino Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-(6-(((4-methylmorpholine-3-yl)methyl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2- Methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)pheno HCl salt; 2-(6-((1-hydroxy-2-methylpropan-2-yl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidine-3- (yl)amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phen Knoll; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methyl Tylpyridazine-3-yl)-5-(trifluoromethoxy)phenol; (R)-2-(4-methyl-6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethoxy)phenol; 3-methyl-2-(6-(((8R,8aR)-octahydroindolidine-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((8S,8aS)-octahydroindolidine-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(6-(((1-(2-hydroxyethyl)piperidine-2-yl)methyl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Lu; (S)-2-(6-(((1-(2-hydroxyethyl)piperidine-2-yl)methyl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Lu; 3-methyl-2-(6-(((1S,2S,5S)-8-methyl-8-azabicyclo[3 .2.1] Octane-2-yl)amino)pyridazine-3-yl)-5-(trifluoro Methylphenol; 3-methyl-2-(6-(((1R,2R,5R)-8-methyl-8-azabicyclo[3 .2.1] Octane-2-yl)amino)pyridazine-3-yl)-5-(trifluoro Methylphenol; 2-(6-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabisic [3.2.1]octan-2-yl)amino)pyridazine-3-yl)-3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabisic [3.2.1]octan-2-yl)amino)pyridazine-3-yl)-3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((3R,6R)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl) Enol; 2-(6-(((3S,6S)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl) Enol; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)pyridazine-3-yl)amino)2-methylpropane-1,2-diol; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)pyridazine-3-yl)amino)2-methylpropane-1,2-diol; (1S,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro Methyl(phenyl)pyridazin-3-yl)amino(cyclopentan-1,2-diole Lu; (1R,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro Methyl(phenyl)pyridazin-3-yl)amino(cyclopentan-1,2-diole Lu; (S)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazine-3- Iyl-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazine-3- Iyl-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((2S,3S)-2-methylpiperidine-3-yl)amino Pyridazine-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((2R,3R)-2-methylpiperidine-3-yl)amino Pyridazine-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((R)-1-((S)-2-hydroxypropyl)piperidine-3-yl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Lu; 2-(6-(((R)-1-((R)-2-hydroxypropyl)piperidine-3-yl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Lu; 2-(6-(((3S,5S)-5-fluoropiperidine-3-yl)aminopyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoropiperidine-3-yl)amino)pyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidine-3-yl)amide (no)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidine-3-yl)amide (no)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidine-3-yl)amide (no)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidine-3-yl)ami (no)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoropiperidine-3-yl)aminopyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoropiperidine-3-yl)aminopyridadi (I-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (3S,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl Phenylpyridazine-3-ylamino-1-methylpiperidine-3-ol; 2-(6-(((1-hydroxycyclopentyl)methyl)amino)pyridazine-3-i (Lu)-3-methyl-5-(trifluoromethyl)phenol; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-methylpyridazine-3-yl)amino)-1-methylpiperidine-2-one; (R)-3-methyl-2-(5-methyl-6-(piperidine-3-ylamino)pyridadi (n-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(6-((1-ethylpiperidine-3-yl)amino)-5-methylpyridan Zin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nyl)-4-methylpyridazine-3-yl)amino)-1-methylpiperidine-2-one ; 4-(2-((6-(2-hydroxy-4,6-dimethylphenyl)pyridazine-3-i (Amino)ethyl)benzenesulfonamide; (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) (enyl)-4-methylpyridazine-3-yl)amino)-1-methylpiperidine-1-oxy Sid TFA salt; or a pharmaceutically acceptable salt thereof.

[0061] In Embodiment 11b, the present invention relates to a compound of formula (I) according to Embodiment 1 or its pharmaceutically appropriate properties. Regarding the permissible salts, the compound is 3-methyl-2-(5-methyl-6-((1-methyl methyl Peridine-3-yl)amino)pyridazine-3-yl)-5-(trifluoromethyl) It is an enol or a pharmaceutically acceptable salt thereof. In one example, the compound is (S)-3- Methyl-2-(5-methyl-6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3-yl)-5-(trifluoromethyl)phenol or its pharmaceutically acceptable It is a salt. In a preferred embodiment, the compound is (R)-3-methyl-2-(5-methyl- 6-((1-methylpiperidine-3-yl)amino)pyridazine-3-yl)-5-(to It is (ifluoromethyl)phenol or a pharmaceutically acceptable salt thereof.

[0062] In Embodiment 11c, the present invention relates to a compound of formula (I) according to Embodiment 1 or its pharmaceutically appropriate properties. Regarding the acceptable salts, the compound is 2-(4-methyl-6-((1-methylpiperidine-3 -yl)amino)pyridazine-3-yl)5-(trifluoromethyl)phenol or It is a pharmaceutically acceptable salt. In one example, the compound is (S)-2-(4-methyl -6-((1-methylpiperidine-3-yl)amino)pyridazine-3-yl)-5-( Trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof. A preferred embodiment. In the example, the compound is (R)-2-(4-methyl-6-((1-methylpiperidine-3- (Amino)pyridazine-3-yl)-5-(trifluoromethyl)phenol or the It is a pharmaceutically acceptable salt.

[0063] In Embodiment 11d, the present invention relates to a compound of formula (I) according to Embodiment 1 or its pharmaceutically appropriate properties. Regarding acceptable salts, the compound is 2-(6-((1-ethylpiperidine-3-yl)amine (no)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or It is a pharmaceutically acceptable salt. In one example, the compound is (S)-2-(6-((1 -Ethylpiperidine-3-yl)amino)pyridazine-3-yl)-3-methyl-5-( Trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof. A preferred embodiment. In the example, the compound is (R)-2-(6-((1-ethylpiperidine-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or the It is a pharmaceutically acceptable salt.

[0064] In Embodiment 11e, the present invention relates to a compound of formula (I) according to Embodiment 1 or its pharmaceutically appropriate properties. Regarding acceptable salts, the compound is 2-(6-((3-hydroxy-3-methylcyclobutyl (Amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)pheno It is a compound or a pharmaceutically acceptable salt thereof. In one example, the compound is 2-(6-((( Trans-3-hydroxy-3-methylcyclobutyl-amino)pyridazine-3-yl )-3-methyl-5-(trifluoromethyl)phenol or its pharmaceutically acceptable salt In a preferred embodiment, the compound is 2-(6-(((cis)-3-hydroxy- 3-Methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trif Luoromethylphenol or a pharmaceutically acceptable salt thereof.

[0065] In Embodiment 11f, the present invention relates to a compound of formula (I) according to Embodiment 1 or its pharmaceutically appropriate properties. Regarding acceptable salts, the compound is 2-(6-((3-hydroxycyclohexyl)amino Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or so It is a pharmaceutically acceptable salt of . In one example, the compound is 2-(6-(((1S,3R )-3-hydroxycyclohexyl)amino)pyridazine-3-yl)-3-methyl-5 -(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof. In one example: The compound is 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or so It is a pharmaceutically acceptable salt of . In one example, the compound is 2-(6-(((1S,3S )-3-hydroxycyclohexyl)amino)pyridazine-3-yl)-3-methyl-5 -(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof. Preferred one In the example, the compound is 2-(6-(((1R,3S)-3-hydroxycyclohexyl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno It is either ru or a pharmaceutically acceptable salt thereof.

[0066] In Embodiment 11g, the present invention relates to a compound of formula (I) according to Embodiment 1 or its pharmaceutically appropriate properties. Regarding acceptable salts, the compound is 5-((6-(2-hydroxy-6-methyl-4-( (Lifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidine -3-ol or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (3R, 5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phen Nylpyridazine-3-ylamino-1-methylpiperidine-3-ol or the drug thereof It is a scientifically acceptable salt. In one example, the compound is (3R,5R)-5-((6-( 2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazine-3- Il(amino)-1-methylpiperidine-3-ol or a pharmaceutically acceptable salt thereof In one embodiment, the compound is (3S,5S)-5-((6-(2-hydroxy-6-methyl Tyl-4-(trifluoromethyl)phenyl)pyridazine-3-yl)amino)-1-methyl Chilpiperidine-3-ol or a pharmaceutically acceptable salt thereof. In a preferred example: The compound is (3S,5R)-5-((6-(2-hydroxy-6-methyl-4-( (Lifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidine -3-ol or a pharmaceutically acceptable salt thereof.

[0067] In Embodiment 12, the present invention relates to formula (I) according to any one of Embodiments 1 to 11g, ( II), (III), and (III-A) a therapeutically effective amount of any one of the compounds or the Regarding pharmaceutical compositions comprising a pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers. ru.

[0068] In Embodiment 13, the present invention relates to formula (I) according to any one of Embodiments 1 to 11g, ( II), (III), and (III-A) a therapeutically effective amount of any one of the compounds or the This relates to combinations of pharmaceutically acceptable salts and one or more therapeutic agents.

[0069] In Embodiment 14, the present invention provides a therapeutically effective amount of formula (I) and (II) according to Embodiment 13. One of the compounds (III) and (III-A) or their pharmaceutically acceptable Regarding combinations containing salt, one or more therapeutic agents are farnesoid X receptor (FXR) Gonists; anti-lipidemia drugs; anti-fibrotic drugs; JAK inhibitors; anti-PD1 inhibitors, anti-LAG-3 inhibitors Drugs, checkpoint inhibitors including anti-TIM-3 inhibitors or anti-PDL-1 inhibitors; chemical Therapies, radiation therapy and surgical procedures; uric acid-lowering therapies; anabolic drugs and cartilage regeneration therapy. Methods; IL-17 blockade; complement inhibitors; Bruton's tyrosine kinase inhibitors (BTK inhibitors) ); Toll-like receptor inhibitors (TLR7 / 8 inhibitors); CAR-T therapy; antihypertensive agents; Resterol-lowering agents; leukotriene A4 hydrolase (LTAH4) inhibitors; SGLT 2 inhibitors; β2 agonists; anti-inflammatory agents; non-steroidal anti-inflammatory drugs ("NSAIDs"); a Acetylsalicylic acids (ASAs) including aspirin; paracetamol; regenerative therapy It is selected independently from the treatment of cystic fibrosis or atherosclerosis.

[0070] In one embodiment, the present invention is represented by Embodiments 1, 2, 3, 3a, 4, 5, 5a-5e, 6, 6 a~6c, 7, 7a~7d, 8, 8a, 9, 9a~9b, 10, 10a, 11, 11a~ Formulas (I), (II), (III) that follow one of 11g, 12, 13, and 14, Or administer a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof to the target. This relates to a method for inhibiting NLRP3 activity in a target, including the following.

[0071] In Embodiment 15, the present invention provides a method for use as a pharmaceutical product, using 1 to 11 g of each of the embodiments. One of the following equations (I), (II), (III), and (III-A) follows one of the following: The compound or a pharmaceutically acceptable salt thereof, or according to any one of embodiments 13 to 14. This relates to combinations. In particular, the present invention relates to embodiments 1 to 11 for use as a pharmaceutical. Any of the formulas (I), (II), (III), and (III-A) that follow one of g The present invention relates to one compound or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to NLRP3 According to any one of Embodiments 1 to 11 g for use as a pharmaceutical to inhibit the pathway One of the compounds of formulas (I), (II), (III), and (III-A), or This relates to a pharmaceutically acceptable salt of [the substance]. In another specific embodiment, the present invention is used as a pharmaceutical. This relates to a combination according to any one of embodiments 13 to 14 for the purpose of achieving this.

[0072] In Embodiment 16, the present invention relates to a disease or disorder in which NLRP3 signaling is performed In the treatment of diseases or disorders that contribute to the abnormality and / or symptoms and / or progression of a disease or disorder. Formulas (I), (II), and (I) according to any one of embodiments 1 to 11g for use in the above. (ii) and (III-A) a compound or a pharmaceutically acceptable salt thereof Regarding.

[0073] In Embodiment 17, the present invention relates to a disease or disorder in which NLRP3 signaling is performed To treat diseases or disorders that contribute to the abnormality and / or symptoms and / or progression of a disease or disorder. A method for which formula (I)(II), (II) is used according to any one of embodiments 1 to 11g. I) and (III-A) a therapeutically effective amount of the compound or its pharmaceutically acceptable amount The present invention relates to a method that includes administering a salt.

[0074] Embodiment 18 provides the present invention for use in accordance with Embodiment 16, as described in Embodiments 1-1 Formulas (I), (II), (III), and (III-A) which follow any one of 1g Treatment with any one of the compounds or its pharmaceutically acceptable salts or according to Embodiment 17 Regarding methods for this, diseases or disorders include inflammasome-related diseases / disorders, immune diseases. , inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as autoinflammatory fever syndrome (for example, Riopirin-associated periodic syndromes), liver-related diseases / disorders (e.g., chronic liver disease, urinary tract disease). Alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and Diseases related to inflammatory arthritis (e.g., gout, pseudogout (chondrocalcification)), Diseases related to the kidneys, such as osteoarthritis, rheumatoid arthritis, arthropathy (e.g., acute, chronic), and kidney-related diseases. (For example, hyperoxaluria, lupus nephritis, type 1 / type 2 diabetes and related complications (examples) For example, nephropathy, retinopathy, hypertensive nephropathy, inflammation associated with hemodialysis, and inflammation related to neuroinflammation. Diseases (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease) ), cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension) Atherosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), acute heart failure, inflammatory skin diseases (e.g., sweat gland abscess, acne), wound healing and Diseases / disorders related to scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer. (For example, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), bone marrow) Fibrosis) is selected from. In a particular aspect of Embodiment 16, the present invention relates to formula (I), (II ), (III), and (III-A) or any one of the pharmaceutically acceptable compounds thereof Regarding the salt, the disease or disorder is preferably autoinflammatory fever syndrome (e.g., CAPS), sickle Symptoms of erythrocytosis, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hyperscalculia Related to uric aciduria, gout, pseudogout (chondrocalcification), chronic liver disease, NASH, and neuroinflammation. Disorders (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease) ), atherosclerosis and cardiovascular risk (for example, reduced cardiovascular risk (CvR) R), hypertension, sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer) (Selected from myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis) .

[0075] In one embodiment, the present invention relates to inflammasome-related diseases / disorders, immune disorders, and inflammation. Sexually transmitted diseases, autoimmune diseases, or autoinflammatory diseases, such as autoinflammatory fever syndrome (e.g., cryo Pyrin-associated periodic syndromes), liver-related diseases / disorders (e.g., chronic liver disease, viral Alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic steatohepatitis Diseases related to inflammatory liver disease (e.g., gout, pseudogout (chondrocalcification)) Osteoarthritis, rheumatoid arthritis, arthropathy (e.g., acute, chronic), kidney-related diseases (e.g.) For example, hyperoxaluria, lupus nephritis, type 1 / type 2 diabetes and related complications (e.g.) (nephropathy, retinopathy), hypertensive nephropathy, inflammation associated with hemodialysis, and diseases related to neuroinflammation. (For example, multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), Cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, etc.) Arteriosclerosis telogen effluvium, type 1 and type 2 diabetes mellitus and related complications, peripheral artery disease (P AD), acute heart failure, inflammatory skin diseases (e.g., sweat gland abscesses, acne), wound healing and scarring Diseases / disorders related to formation, asthma, sarcoidosis, age-related macular degeneration, and cancer (e.g.) For example, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), bone marrow fibrillation Embodiments 1 to 11 g for use in the treatment of diseases or disorders selected from (symptoms) One of the following equations: (I), (II), (III), and (III-A) This relates to one compound or a pharmaceutically acceptable salt thereof. In a particular aspect of Embodiment 18, this The invention relates to one compound of any of the formulas (I), (II), (III), and (III-A). Or, with respect to a pharmaceutically acceptable salt thereof, the disease or disorder is preferably autoinflammatory fever syndrome. (e.g., CAPS), sickle cell disease, type 1 / type 2 diabetes and related complications (e.g., (nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (cartilage calcification), chronic liver disease, NA SH, disorders related to neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, nerve abnormalities) Sexually transmitted diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., heart Reduced cardiovascular risk (CvRR), hypertension, sweat gland abscesses, wound healing and scar formation, and Cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasm, leukemia, myelodysplastic syndrome (MDS), bone (Selected from myelofibrosis.)

[0076] In Embodiment 19, the present invention inhibits NLRP3 inflammasome activity, which is necessary. A method for performing an action on a subject that is described as such, and which is one of the embodiments 1 to 11 g. The effective therapeutic dose is one of the following formulas (I), (II), (III), and (III-A). To administer the compound or a pharmaceutically acceptable salt thereof to a subject in need. Regarding the method of inclusion.

[0077] In one embodiment, the present invention was a method for inhibiting NLRP3 activity in a subject. Embodiments 1, 2, 3, 3a, 4, 5, 5a-5e, 6, 6a-6c, 7, 7a-7d , 8, 8a, 9, 9a~9b, 10, 10a, 11, 11a~11g, 12, 13, and Treatments of formulas (I), (II), (III), and (III-A) that follow one of the 14 formulas Methods involving the administration of an effective amount of a compound or a pharmaceutically acceptable salt thereof to a subject .

[0078] In one embodiment, the present invention relates to inflammasome-related diseases / disorders, immune disorders, and inflammation. Sexually transmitted diseases, autoimmune diseases, or autoinflammatory diseases, such as autoinflammatory fever syndrome (e.g., cryo Pyrin-associated periodic syndromes, sickle cell disease, systemic lupus erythematosus (SLE), liver Related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic fatty liver disease) (NASH, alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis Related diseases (for example, gout, pseudogout (chondrocalcification), osteoarthritis, rheumatoid arthritis, acute Sexual or chronic arthritis, kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, diabetes) Diseases of nephropathy, hypertensive nephropathy, inflammation associated with hemodialysis, and diseases associated with neuroinflammation (for example) Multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease, cardiovascular system Metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis) Arteriosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), Acute heart failure, inflammatory skin diseases (e.g., sweat gland abscesses, acne), wound healing and scar formation, asthma Diseases / disorders related to respiration, sarcoidosis, age-related macular degeneration, and cancer (e.g., cancer (From intestinal cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis) A method for treating a selected disease or disorder, comprising embodiments 1, 2, 3, 3a, and 4. , 5, 5a~5e, 6, 6a~6c, 7, 7a~7d, 8, 8a, 9, 9a~9b, 10 Formula (I) follows one of the following: 10a, 11, 11a-11g, 12, 13, and 14. (II), (III), and (III-A) the therapeutically effective amounts of the compound or the pharmaceutically effective amount thereof The present invention relates to a method comprising administering a salt to a target, in particular, a disease or disorder, preferably This includes autoinflammatory fever syndrome (e.g., CAPS), sickle cell disease, type 1 / type 2 diabetes and related conditions. Related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (cartilage calcification) ), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infections) (Syndrome, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular disease Systemic risk factors (e.g., reduced cardiovascular risk (CvRR), hypertension), sweat gland abscesses, wound healing and scar formation, as well as cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplasia). The diagnosis is selected from the following: MDS (Myelofibrosis).

[0079] Depending on the selection of starting materials and procedures, the compound may take on one of the possible stereoisomer forms. As a mixture thereof, for example, as a pure optical isomer or depending on the number of chiral carbon atoms It exists as a stereoisomer mixture, such as a racemic mixture or a mixture of diastereoisomers. This invention allows for the creation of racemic mixtures, diastereomer mixtures and optically pure It is intended to include all such conceivable stereoisomers, including morphological ones. Optical activity ( The (R)- and (S)- stereoisomers were prepared using chiral synthons or chiral reagents. The compound may be divided or can be divided using conventional techniques. The compound contains a disubstituted cycloalkyl group. If present, the cycloalkyl substituent may have a cis or trans configuration. The tautomers of the same type are also intended to be included. The present invention is described herein as (r)- and It is represented as (s)- and does not change when reflected in a mirror, but by exchanging any two entities... It is also intended to include any pseudo-chiral carbon atoms that are reversed (PAC 1996, 68, 2 193,Basic terminology of stereochemistry IUPAC recommendations 1996).

[0080] As used herein, the term "salt" or "salts" " refers to an acid addition salt or base addition salt of the compound of the present invention. "Salt" specifically refers to "as a pharmaceutical product." Includes "acceptable salt". The term "pharmaceutically acceptable salt" refers to the biologically acceptable salt of the compound of the present invention. It retains its effectiveness and properties, and is not generally biologically or otherwise undesirable. Refers to salts. In many cases, the compounds of the present invention have an amino group and / or a carboxyl group or The presence of a similar group allows for the formation of salts of acids and / or bases.

[0081] Pharmacologically acceptable acid addition salts can be formed from inorganic and organic acids.

[0082] Inorganic acids that can induce salt formation include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. and other similar items.

[0083] Organic acids that can induce salt formation include, for example, acetic acid, propionic acid, glycolic acid, and syl acetic acid. Oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, ma Deulic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicyl This includes acids and other similar substances.

[0084] pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases.

[0085] Inorganic bases that can induce salts include, for example, ammonium salts and bases I-XI of the periodic table. It contains metals in column I. In one embodiment, the salt is sodium, potassium, ammonium, and Derived from calcium, magnesium, iron, silver, zinc, and copper, particularly suitable salts are ammonia Contains sodium, potassium, sodium, calcium, and magnesium salts.

[0086] Organic bases that can derive salts include, for example, primary, secondary, and tertiary amines, and ethers. Substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and others This includes similar substances. Certain organic amines include isopropylamine, benzathine, and corine. , diethanolamine, diethylamine, lysine, meglumine, piperazine and thor It contains metamine.

[0087] In another embodiment, the present invention relates to acetate, ascorbyl, adipine, and aspartate Benzoates, besilates, bromides / hydrobromides, bicarbonates / carbonates, bisulfates / sulfuric acid Salts, camphor sulfonates, caprinates, chlorides / hydrochlorides, chlortheophyllon Gluconate, citrate, ethane disulfonate, fumarate, gluceptate, gluconate Glucuronate, glutamate, glutarate, glycolate, hippurate, iodide Hydrogenates / iodides, isethionates, lactates, lactobionates, lauryl sulfates, Malate, maleate, malonate, mandelate, mesylate, methyl sulfate, m Zinate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, Oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrate Polyphosphate, polygalacturate, propionate, sebacinate, stearate, Sinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, Formulas (I), (II), (III) and in the form of trifluoroacetate or xinafoate. The present invention provides one of the compounds (III-A).

[0088] In another embodiment, the present invention relates to sodium, potassium, ammonium, calcium, magnesium Cium, iron, silver, zinc, copper, isopropylamine, benzathine, corinate, diethanol In the form of lyamine, diethylamine, lysine, meglumine, piperazine, or tromethamine salts. One of the compounds in formulas (I), (II), (III), and (III-A) provide.

[0089] Any formula shown herein represents the unlabeled and isotopically labeled forms of a compound. It is also intended that the isotope-labeled compound has one or more atoms with a selected atomic mass or Except for the point that it is exchanged with an atom having a mass number, it is represented by the formula shown herein. It has a structure that can be incorporated into the compound of the present invention, for example, hydrogen Contains isotopes.

[0090] Furthermore, certain isotopes, particularly deuterium (i.e.) 2 The incorporation of H or D is superior. Metabolic stability, for example, increased half-life in vivo, reduced required dosage, or a weaker therapeutic index. Alternatively, it may result in certain therapeutic benefits due to improvements in tolerability. In relation to this, Therefore, it is understood that deuterium is considered a substituent of the compound of formula (I). The concentration of deuterium This can be determined by the isotope enrichment coefficient. The term "isotope enrichment" as used herein refers to the isotope enrichment coefficient. The "contraction factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When the substituent in the compound of the invention is indicated to be deuterium, such a compound is less likely to At least 3500 (52.5% deuterium incorporated with each specified deuterium atom), At least 4000 (60% deuterium atom incorporation), at least 4500 (67.5%) (100% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least Also 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium) (Integrated), at least 6333.3 (95% deuterium incorporated), at least 646 6.7 (97% deuterium inclusion), at least 6600 (99% deuterium inclusion) ) or at least 6633.3 (99.5% deuterium inclusion) as specified in each It has an isotope enrichment factor for deuterium. The term "isotope enrichment factor" refers to the isotope enrichment factor for deuterium. It should be understood that this can be applied to any isotope, just as it is described. ru.

[0091] In another embodiment, the present invention relates to a compound of formula (I) as defined herein. [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula R 5 The following can be selected: [ka] R 5a , R 5b X, and m are as defined in Embodiments 5, 5a to 5e. R 5a and / or R 5b One or more hydrogen atoms present can be replaced by deuterium. (R, which is deuterium) 5a or R 5b (including). For example, but not limited to, deuterium It can be incorporated as follows: [ka]

[0092] In another embodiment, the present invention relates to a compound of formula (I) as defined herein. [ka] Or provide a pharmaceutically acceptable salt thereof, R 2 , R 3 , R 4 However, the next H, C1~C4 If selected from chloride or halo C1-C4 alkyl, one or more water molecules present in the group Elementary atoms can be replaced with deuterium. For example, but not limited to, deuterium is: It can be incorporated like this. [ka]

[0093] Other examples of isotopes that can be incorporated into the compounds of the present invention are, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 12 4 I, 125 Hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine such as I It contains isotopes. Therefore, the present invention, for example, 3 H and 14 Radioactive isotopes such as C Compounds incorporating one or more of the aforementioned isotopes, including the body or 2 H and 13 C etc. It should be understood that such compounds may contain non-radioactive isotopes. Isotope-labeled compounds are used in metabolic studies. 14 (by C) Study of reaction rates (for example, 2 H if Kuha 3 Positron emission tomography (P) including drug or substrate tissue distribution assays (P Detection techniques such as ET or single-photon emission computed tomography (SPECT) Alternatively, it is useful in image processing technology or in radiation therapy for patients. In particular, 18 F or mark The compound may be particularly desirable for PET or SPECT studies. Formula (I) or its Pharmacopoeia-acceptable salt isotope-labeled compounds are generally conventional techniques known to those skilled in the art. By means of the procedure, or by replacing the previously used unlabeled reagent with an appropriate isotope-labeled reagent Prepared by a process similar to that described in the attached examples and preparations. It is possible.

[0094] Pharmaceutical composition As used herein, the term “pharmaceutical composition” is suitable for oral or parenteral administration. The compound of the present invention comprising together with at least one pharmaceutically acceptable carrier in the form thereof or This refers to the pharmaceutically acceptable salt.

[0095] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutical composition This refers to a substance useful for the preparation or use of, for example, a suitable diluent that would be known to those skilled in the art. Solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption retarders. Agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, seasonings, This includes pigments and combinations thereof (e.g., Remington The Science) and Practice of Pharmacy, 22 nd Ed.Pharma (See ceutical Press, 2013, pp. 1049-1070) .

[0096] The term "therapeutic effective dose" of the compound in this invention refers to the biological or medical response of the subject. For example, it may induce a decrease or inhibition of enzyme or protein activity or symptoms. To induce remission, alleviate the condition, slow or delay the progression of the disease, or to treat the disease This refers to the amount of the compound of the present invention that would prevent, for example. In one non-limiting embodiment, the term The "therapeutic effective dose" is determined when administered to the target, by (1)(i) the NLRP3 pathway. (ii) related to NLRP3 activity, or (iii) related to NLRP3 activity ( A condition or disorder or disease characterized by (normal or abnormal) at least (2) Inhibit, prevent, and / or alleviate; or (2) activate NLRP3 (3) Reduces or inhibits the expression of NLRP3 ≤ refers to the amount of the compound of the present invention that is effective in inhibiting. In another non-limiting embodiment... The term "therapeutic effective amount" of the compound of the present invention refers to a quantity of cells, or tissues, or noncellular organisms. When administered to body substances or culture media, it at least partially reduces the activity of NLRP3. or inhibit; or at least partially reduce the expression of NLRP3 or This refers to the amount that is effective in inhibiting something.

[0097] As used herein, the term "subject" means a primate (e.g., human, male). Refers to a female, dog, rabbit, guinea pig, pig, rat, and mouse. In this embodiment, the subject is a primate. In yet another embodiment, the subject is a human.

[0098] As used herein, the terms “inhibit,” “inhibit,” or “inhibit” are used to mean “to inhibit.” "This refers to a reduction or suppression of a predetermined state, symptom or disorder or disease, or biological activity or This refers to a significant decrease in baseline activity for the process. For details, see NLRP3. Inhibition of the NLRP3 inflammasome pathway or inhibition of IL-1 beta and / or IL- It reduces the function of NLRP3 or the NLRP3 inflammasome pathway that induces the production of 18. This includes inactivating, destabilizing, and / or altering the distribution of NLRP3. This can be achieved by mechanisms that include, but are not limited to, transforming something. .

[0099] As used herein, the term "NLRP3" means, without limitation, nuclear Acids, polynucleotides, nucleotides, sense and antisense polynucleotides Chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice bodies It is intended to include riants, alleles, various species, and their active fragments.

[0100] As used herein, the term “to treat” any disease or disorder "To treat" or "treatment" means to alleviate or bring into remission a disease or disorder. (i.e., delaying the onset of the disease or at least one of its clinical symptoms) To suppress; or to include diseases or conditions that may not be identifiable to the patient. It reduces at least one physical parameter or biomarker associated with the disability. This refers to either causing or relieving the condition.

[0101] As used herein, the term “prevent” any disease or disorder "Prevention" or "prevention" means the preventive treatment of a disease or disorder; or disease or This refers to delaying the onset or progression of a disability.

[0102] As used herein, an object is a subject from which such an object is produced from such treatment. If one benefits from treatment in a physical, medical, or quality of life way, does that mean they "need" treatment? , or "I need it."

[0103] All methods described herein are, unless otherwise indicated herein. Or, unless the context clearly contradicts it, they can be performed in any suitable order. Any and all examples or exemplary expressions provided herein (e.g., "etc.") The use of terms such as ") is intended solely to further clarify the present invention and is not subject to a separate patent application. This does not limit the scope of the present invention.

[0104] Any chiral atom (e.g., carbon or other similar atoms) in the compound of the present invention is a racemic Alternatively, they may exist in enantiomerically rich configurations, such as (R)-, (S)-, or (R,S)-. This is possible. In one embodiment, each chiral atom has at least one (R)- or (S)- configuration. At least 50% enantiomer excess, at least 60% enantiomer excess, at least 7 0% enantiomer excess, at least 80% enantiomer excess, at least 90% mirror Enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer It has a high rate of excess body weight.

[0105] Therefore, as used herein, the compounds of the present invention are capable of considering steric differences. Taking one form of a morphogenetic isomer, rotational isomer, atropisomer, tautomer, or mixture thereof. For example, substantially pure geometric (cis or trans) stereoisomers can be formed, They may exist as astereomers, optical isomers (anti-isomers), racemates, or mixtures thereof. can.

[0106] Mixtures resulting from any stereoisomerism are based on the physicochemical differences of their constituent elements. , pure or substantially pure geometric isomers or optical isomers, diastereomers, racemates For example, separation can be achieved by chromatography and / or fractional crystallization.

[0107] The racemic mixture resulting from any of the compounds or intermediates of the present invention can be obtained by known methods For example, separation of diastereomer salts obtained by optically active acids or bases and optical activity It can be optically separated into oppositories by the liberation of acidic or basic compounds. In particular, salt The base component is therefore an optically active acid, such as tartaric acid, dibenzoyl tartaric acid, di Acetyl tartaric acid, di-O,O'-p-toluyl tartaric acid, mandelic acid, malic acid, or sodium tartaric acid The compound of the present invention is obtained by fractional crystallization of the salt formed by uno-10-sulfonic acid. It can be used to split into optical antiparallel bodies. The racemic product can be processed using chiral chromatography. For example, by high-performance liquid chromatography (HPLC) using chiral adsorbents. It can also be divided.

[0108] Method for synthesizing the compound of the present invention The compounds of the present invention are obtained by the route described in the following scheme or example, through formula (I It may be prepared according to the definition of the compound or its pharmaceutically acceptable salt. All methods described herein, unless otherwise indicated or clearly indicated in the context, are not otherwise specified. Unless otherwise specified, they may be performed in any suitable order. The use of any and all example or illustrative expressions provided (e.g., "such as") The purpose is solely to further clarify the present invention and the invention as separately claimed. This does not limit the scope. In the general method below, R 1 , R 2 , R 3 , R 4 , R 5 Halo and Z are as previously defined in the above embodiments, or scheme This applies only to the designations in the specified area. Unless otherwise specified, the starting materials must be commercially available or It is prepared by known methods.

[0109] Reaction Scheme 1 The compounds of the present invention, as described herein, in Scheme 1 (below) The reaction sequence shown may also be used to prepare the appropriately substituted 3,6-dihalo Pyridazine (M1) typically ferments at high temperatures in the presence of a base, such as DIPEA. Between 50°C and 180°C (optionally under microwave irradiation), use an appropriate amine (M2a) and The reaction yields 6-halopyridazine-3amine (M3a) or a base, such as NaH. In the presence of , react with a suitable alcohol (M2b) at low temperature, typically 0°C, and 3 -Halo-6-alkoxypyridazine (M3b) is obtained. Both intermediates (M3a) or (M3b) is then suitable in a miscible solvent such as DME or dioxane. A palladium catalyst, such as Pd(PPh3)4, and an aqueous base, typically Na2CO3 or A suitable boronate in the form of boronic acid or boronic acid ester using NaHCO3. (M4), for example, with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane The compound of formula (I) or its pharmaceutically acceptable form is subjected to Suzuki's cross-coupling reaction. Salt is brought forth. [ka]

[0110] Reaction Scheme 2 Instead, the compounds of the present invention are as described herein, in scheme 2( The reaction sequence shown below may also be used to prepare the appropriately substituted product. 3,6-Dihalopyridazine (M1) is a miscible compound like DME or dioxane. In the solvent, a suitable palladium catalyst, such as Pd(PPh3)4 or XantPh os-Pd-G2 and aqueous bases, typically Na2CO3 or NaHCO3, are used. A suitable boronate (M4) in the form of a boronic acid or boronic acid ester, for example Suzuki's 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (PAS A) It is subjected to a Ross coupling reaction to obtain 3-halo-pyridazine (M5) or methyl Alternatively, like benzyl, which has a phenol protecting group P, boronate (M6) is the same. The reaction (pass B) yields the compound of formula 3-halo-pyridazine (M7). The interstitial (M5) is then typically formed at high temperatures in the presence of a base, such as DIPEA. Between 150°C and 180°C (optionally under microwave irradiation), use an appropriate amine (M2a). When reacted with, the compound of formula (I) or a pharmaceutically acceptable salt thereof is obtained. The intermediate (M7) is processed in the same way to obtain the protected form (M8), which is further The compound of formula (I) is subjected to typical cleavage treatments such as BBr3 or catalytic hydrogenation. Alternatively, a pharmaceutically acceptable salt thereof may be provided. [ka]

[0111] Reaction scheme 3 Instead, the compounds of the present invention are shown in Scheme 3 (below) as described herein. The reaction may be prepared in a specific order, thereby yielding a suitably substituted intermediate (M5). In aproton solvents such as toluene, a suitable palladium catalyst is needed, for example, PdCl 2(dppf) and a base, typically in the presence of LiOtBu, with a suitable amine (M2a) and The compound of formula (I) or its pharmaceutically acceptable form is subjected to the Buchwald amination reaction. Salt is brought forth. [ka]

[0112] The process is one of the following equations: (I), (II), (III), and (III-A) To prepare a compound or a pharmaceutically acceptable salt thereof, use the methods described herein. It can be extended to the extent described in Scheme 1, Scheme 2, or Scheme 3 above. Thus, depending on the starting material and the selected route, a person skilled in the art can determine a compound of formula (I) or the You should know how to prepare a pharmaceutically acceptable salt. The process is described in the experimental section below in this specification.

[0113] The present invention further includes any different processes of the present invention, obtained at any stage thereof. The interproduct is used as a starting material and the remaining steps are carried out, or the starting material reacts Under certain conditions, they are formed in situ, or the reaction components are their salts or optically pure It is used in the form of a substance. The compounds and intermediates of the present invention are generally known to those skilled in the art. They can also be converted to each other in accordance with the law.

[0114] In another embodiment, the present invention relates to the compound of the present invention or a pharmaceutically acceptable salt thereof and pharmaceutically The present invention provides a pharmaceutical composition comprising an acceptable carrier. In further embodiments, the composition is as described herein. It includes at least two pharmaceutically acceptable carriers, such as those described in the book. The pharmaceutical composition is administered orally, parenterally (for example, by injection, infusion, transdermal or topical administration). ) and can be formulated for specific routes of administration such as rectal administration. Local administration This may also relate to inhalation or intranasal application. The pharmaceutical composition of the present invention is in solid form (limited (including capsules, tablets, pills, granules, powders or suppositories) or liquids without the need for a solution. It can be prepared in various forms (including, without limitation, liquids, suspensions, or emulsions). The tablets are film-coated or It can be coated in the intestines. Typically, pharmaceutical compositions are a) Diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol Cellulose, cellulose, and / or glycine; b) Lubricants, such as silica, talc, stearic acid, its magnesium salt or calcium For tablets, further, c) Binders, such as magnesium aluminum silicate, starch paste, gelatin, etc. Laganth, methylcellulose, sodium carboxymethylcellulose and / or polymethylcellulose Nilpyrrolidone; as needed, d) Disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent agents Mixture; and e) Absorbents, colorants, flavorings, and sweeteners It is a tablet or gelatin capsule containing an active ingredient along with one or more of the above.

[0115] Method of use of the present invention NLRP3 induction in inflammatory responses associated with or resulting from many different disorders There is evidence regarding the roles of IL-1 and IL-18 in the development of IL-1 (Menu et al. C). Clinical and Experimental Immunology,2011 ,166,1-15;Strowig et al.Nature,2012,481, 278-286). NLRP3 mutations are a rare autoinflammatory disease known as CAPS. It was found to be the cause of sexually transmitted diseases (Ozaki et al. J. Inflamma) tion Research,2015,8,15-27;Schroder et a l.Cell,2010,140:821-832;Menu et al.Clini cal and Experimental Immunology,2011,166 CAPS is a genetic disorder characterized by relapsing fever and inflammation. It consists of three autoinflammatory disorders that are clinically interconnected. These diseases are, In order of increasing severity, these are: Familial Cold Autoinflammatory Syndrome (FCAS), Macklewells Syndrome. MWS (Membranous Neurocutaneous Arthritis Syndrome) and Chronic Infantile Neurocutaneous Arthritis Syndrome (CINCA; neonatal onset multiorgan inflammation). Sexually transmitted diseases (also known as NOMIDs) are all gain-of-function disorders of the NLRP3 gene. It has been shown to be caused by a mutation, which leads to increased secretion of IL-1 beta. LRP3 is used for septic arthritis, pyoderma gangrenosum and acne (PAPA), Sweet's syndrome, and chronic diseases. It has also been associated with many autoinflammatory diseases, including nonbacterial osteomyelitis (CNO) and acne vulgaris. (Cook et al.Eur.J.Immunol.,2010,40,595-6 53).

[0116] Many autoimmune diseases include multiple sclerosis, type 1 diabetes (T1D), psoriasis, and rheumatoid arthritis. Rheumatism (RA), Behçet's disease, Schnitzler syndrome, Macrophage activation syndrome (B raddock et al.Nat.Rev.Drug Disc.2004,3,1 -10;Inoue et al.Immunology,2013,139,11-1 8;Coll et al.Nat.Med.2015,21(3),248-55;S cott et al.Clin.Exp.Rheumatol.2016,34(1) ,88-93), systemic lupus erythematosus and its complications such as lupus nephritis (L u et al.J.Immunol.,2017,198(3),1119-29) Systemic sclerosis (Artlett et al. Arthritis Rheum. 2) It has been shown to be related to NLRP3, including 011, 63(11), 3563-74). NLRP3 is used for chronic obstructive pulmonary disease (COPD) and asthma (including steroid-resistant asthma). ), it has also been shown to play a role in many lung diseases, including asbestosis and silicosis (De Nardo et al.,Am.J. Pathol.,2014,184:42-54 ;Kim et al.Am.J.Respir.Crit.Care Med,201 7,196(3),283-97). NLRP3 is used in multiple sclerosis (MS) and parkinson's disease. Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, lung Brain injury originating from Streptococcal meningitis (Walsh et al. Nature Reviews, 2014,15,84-97; and Dempsey et al.Brain.Beha v.Immun.2017,61,306-16), intracranial aneurysm (Zhang et al.) al.J.Stroke and Cerebrovascular Dis.,201 5,24,5,972-9) and traumatic brain injury (Ismael et al. J. Neu Many of them include rotrauma.,2018,35(11),1294-1303). It was also suggested that it plays a role in the state of the central nervous system. NRLP3 activity is associated with type 2 diabetes. (T2D) and its organ-specific complications, atherosclerosis, obesity, gout, pseudogout Metabolic syndrome (Wen et al. Nature Immunology) y,2012,13,352-357;Duewell et al.Nature,2 010,464,1357-1361;Strowig et al.Nature,2 014,481,278-286) and non-alcoholic steatohepatitis (Mridha e Various studies including al.J.Hepatol.2017,66(5),1037-46) It has also been shown to be involved in metabolic diseases. Regarding NLRP3 via IL-1 beta. Its role is in atherosclerosis and myocardial infarction (van Hout et al. Eur.). Heart J.2017,38(11),828-36), heart failure (Sano et al. al.J.Am.Coll.Cardiol.2018,71(8),875-66), Aortic aneurysm and aortic dissection (Wu et al. Arterioscler. Thromb) Vase Biol., 2017, 37(4), 694-706) and other cardiovascular Bent (Ridker et al. N.Engl.J.Med., 2017, 377( This was also suggested in 12), 1119-31).

[0117] Other diseases shown to be associated with NLRP3 include both wet and dry age-related macular degeneration. (Doyle et al.,Nature Medicine,2012,18,7 91-798;Tarallo et al.Cell 2012,149(4),84 7-59), diabetic retinopathy (Loukovaara et al. halmol., 2017, 95(8), 803-8), Non-infectious uveitis and optic nerve Transinjury (Puyang et al. Sci. Rep. 2016, 6, 20998), etc. Eye diseases such as; including non-alcoholic steatohepatitis (NASH) and acute alcoholic hepatitis. Hepatic diseases (Henao-Meija et al. Nature, 2012, 482, 1 79-185); Contact hypersensitivity (bullous pemphigoid, etc. (Fang et al. J Der matol Sci.2016,83(2),116-23)), atopic dermatitis (N iebuhr et al. Allergy, 2014, 69(8), 1058-67) , sweat gland abscess (Alikhan et al.J.Am.Acad.Dermatol., 2009,60(4),539-61) and sarcoidosis (Jager et al .Am.J.Respir.Crit.Care Med.,2015,191,A58 16) Inflammatory reactions in the lungs and skin, including (Primiano et al. J.Imm) unol.2016,197(6),2421-33);Inflammatory response in the joints (Bra ddock et al.Nat.Rev.Drug Disc,2004,3,1-1 0); Amyotrophic lateral sclerosis (Gugliandolo et al.Int.J.Mol .Sci.,2018,19(7),E1992);Cystic fibrosis (Iannitti et al. Nat.Commun., 2016, 7, 10791); Stroke (Wals h et al.Nature Reviews,2014,15,84-97);Chronic Kidney disease(Granata et al.PLoS One 2015,10(3),eo i22272); and inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Braddo ck et al.Nat.Rev.Drug Disc,2004,3,1-10;N eudecker et al.J.Exp.Med.2017,214(6),173 7-52;Lazaridis et al.Dig.Dis.Sci.2017,62 (9), 2348-56) is included. The NLRP3 inflammasome responds to oxidative stress. It was found to be activated. NLRP3 has also been shown to be involved in inflammatory hyperalgesia. (Dolunay et al. Inflammation, 2017, 40, 36) 6-86).

[0118] 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.P LOS Pathogens 2017,13(2),e1006196).

[0119] NLRP3 has also been associated with the pathogenesis of many cancers (Menu et al. Clinica). l and Experimental Immunology,2011,166,1 -15). For example, some previous studies have shown that IL-1 is involved in cancer invasion, growth and metastasis. The role of IL-1 beta is suggested by canakinumab inhibition of IL-1 beta, which is randomized. In a double-blind, placebo-controlled clinical trial, the goal was to reduce the incidence of lung cancer and overall cancer mortality. This was shown (Ridker et al. Lancet., 2017, 390(1010 5), 1833-42). Inhibition of the NLRP3 inflammasome or IL-1 beta is also effective. It has been shown to inhibit the proliferation and migration of lung cancer cells in vitro (Wang et al. l. Oncol Rep., 2016, 35(4), 2053-64). NLRP3 The role of the flammosome is related to myelodysplastic syndrome, myelofibrosis, and other myeloproliferative neoplasms. and acute myeloid leukemia (AML) (Basiorka et al. Blood, 20 16,128(25),2960-75.) Furthermore, in gliomas (Li et a l.Am.J.Cancer Res.2015,5(1),442-9), pro-inflammatory Tumors of (Allen et al. J. Exp. Med. 2010, 207(5), 10 45-56;Hu et al.PNAS.,2010,107(50),21635- 40), Multiple Myeloma (Li et al. Hematology, 2016 21(3 ), 144-51) and squamous cell carcinoma of the head and neck (Huang et al. J. Exp. Various other studies, including .Clin.Cancer Res.,2017,36(1),116) This was suggested in the carcinogenesis of cancer. Activation of the NLRP3 inflammasome is associated with 5-fluorocarbon It has also been shown to mediate chemotherapy resistance in tumor cells to uracil (Feng et al.). al.J.Exp.Clin.Cancer Res.,2017,36(1),81) Activation of the NLRP3 inflammasome in peripheral nerves is associated with chemotherapy-induced neurogenic conditions. It can be a contributing factor to pain (Jia et al. Mol. Pain., 2017, 13, 1-1 1) NLRP3 is necessary for the efficient control of viruses, bacteria, and fungi. It was also indicated that...

[0120] Activation of NLRP3 leads to cellular pyroptosis, a characteristic that contributes to the emergence of clinical disease. It plays an important role in (Yan-gang et al. Cell Death a nd Disease,2017,8(2),2579;Alexander et a l.Hepatology,2014,59(3),898-910;Baldwin et al.J.Med.Chem.,2016,59(5),1691-1710;O zaki et al.J.Inflammation Research,2015, 8,15-27;Zhen et al.Neuroimmunology Neuro inflammation,2014,1(2),60-65;Mattia et a lJMed.Chem.,2014,57(24),10366-82;Satoh et al.Cell Death and Disease,2013,4,644 Therefore, NLRP3 inhibitors are effective in treating pyroptosis and pro-inflammatory sites from cells. It is expected that this will block the release of kine (e.g., IL-1 beta).

[0121] Formulas (I), (II), and (III) in free form or in pharmaceutically acceptable salt form. , and any one of (III-A), or a compound according to any one of the embodiments described above , or exemplary examples (for example, Ex001 to Ex104 disclosed herein) Compounds that conform to any one of the following have beneficial pharmacological properties, for example, provided in the following section. NRLP3 inhibitory properties against the NLRP3 pathway, as demonstrated by in vitro studies, for example. It exhibits these characteristics, and therefore is necessary for use as a therapeutic or research chemical, such as a tool compound. It can be done.

[0122] The compounds of the present invention are for inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, It may be useful in the treatment of symptoms selected from autoimmune or autoinflammatory diseases, for example If NLRP3 signaling contributes to abnormalities, and / or symptoms, and / or progression, and NLR Responding to P3 inhibition, and any one of Embodiments 1 to 19 or an exemplary embodiment of the present invention. According to any one of the examples (for example, Ex001 to Ex104 disclosed herein) Diseases, disorders, or conditions that can be treated or prevented according to the compound include the following: I. Inflammatory disorders, such as inflammation resulting from autoinflammatory diseases, and non-inflammatory disorders. Inflammation that occurs as a symptom, inflammation that results from infection, or trauma, injury, or autoimmunity Inflammation, including associated inflammation. Examples of inflammation that can be treated or prevented include, in relation to or This includes the resulting inflammatory response: (a) Contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, a Allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria Skin conditions such as rashes, erythema, or alopecia; (b) Osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis Inflammation, rheumatoid arthritis, juvenile chronic arthritis, crystal-induced arthropathy (e.g., pseudogout, gout) or Seronegative spondyloarthropathy (e.g., ankylosing spondylitis, psoriatic arthritis, or Reiter's syndrome) ) and other joint conditions; (c) Muscle conditions such as polymyositis or myasthenia gravis; (d) Inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcer, celiac disease, Enteritis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or shadows with little connection to the intestines. Food-related allergies that may cause allergic reactions (e.g., migraines, rhinitis, or eczema) The condition of the eel's gastrointestinal tract; (e) Chronic obstructive pulmonary disease (COPD), asthma (bronchial, allergic, endogenous, exogenous) or dust asthma, and especially late-onset asthma and airway hyperresponsiveness, which are chronic or persistent (including asthma), bronchitis, rhinitis (acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, Caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis, drug-induced rhinitis, membranous rhinitis, seasonal rhinitis (including, for example, hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF) , sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome, hypersensitivity pneumonitis or special Respiratory conditions such as autosomal interstitial pneumonia; (f) Atherosclerosis, Behçet's disease, vasculitis, or Wegener's granulomatosis What is the condition of the blood vessels? (g) Immune status, e.g., systemic lupus erythematosus (SLE), Sjögren's syndrome, all Physical sclerosis, Hashimoto's thyroiditis, type 1 diabetes, idiopathic thrombocytopenic purpura, or Graves' disease Autoimmune conditions such as illness; (h) Eye conditions such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (i) Neurological conditions such as multiple sclerosis or encephalomyelitis; (j) Acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infection, acute or This includes chronic parasitic infections, acute or chronic viral infections, and acute or chronic fungal infections. Infections, meningitis, hepatitis (types A, B, or C or other viral hepatitis), peritonitis, pneumonia, throat Skullitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, tuberculosis (mycobacteria) Mycobacterium tuberculosis, Mycobacterium avium Mycobacterium avium intracellulum are), Pneumocystis carinii pneumonia, orchitis / epididitis, Legionella, leprosy Influenza, influenza A, Epstein-Barr virus, viral encephalitis / aseptic meningitis or infections or infection-related conditions such as pelvic inflammatory disease; (k) Mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure Kidney conditions such as uremia or nephritis; (l) Lymphatic conditions such as Castleman disease; (m) High IgE syndrome, leprosy, familial hemophagocytic lymphohistiocytosis or graft pair A condition of the immune system or related conditions, such as host diseases; (n) Chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis Non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD) liver conditions such as alcoholic steatohepatitis (ASH) or primary biliary cirrhosis. status; (o) Cancers including those listed below in this specification; (p) burns, wounds, injuries, bleeding, or stroke; (q) Radiation exposure; and / or (r) Obesity; and / or (s) Pain such as inflammatory hyperalgesia; II. Inflammatory disorders, e.g., cryopyrin-associated periodic syndromes (CAPS), Maclewyn Ells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever ( FMF, neonatal-onset multiorgan inflammatory disease (NOMID), Magid syndrome, suppurative inflammatory bowel Adenitis, pyoderma gangrenosum and acne syndrome (PAPA), adult-onset Still's disease (AOSD), A2 Haploinsufficiency (HA2O), granulomatous arthritis in children (PGA), PLCG2-related antibody deficiency Immunomodulation disorders (PLAID), PLCG2-related autoinflammatory antibody deficiency immunomodulation disorders (APL Sideroblastic anemia (SIFD) with AID, B-cell immunodeficiency, periodic fever, and growth retardation, etc. 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 syndrome (APS), anti-synthetic enzyme antibody syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune Hepatitis epidemic, autoimmune oophoritis, autoimmune polyglandular endocrine insufficiency, autoimmune thyroiditis, celery Ack disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture syndrome, Graves' disease Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, systemic Lupus erythematosus, including systemic lupus erythematosus (SLE), and primary progressive multiple sclerosis (P) PMS, secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRM) Multiple sclerosis (MS), including S), myasthenia gravis, ocular clonus myoclonus syndrome (OMS), optic neuritis, oat thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary thyroiditis Cirrhosis of the liver, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, Treatable gouty arthritis, Reiter's syndrome, Sjögren's syndrome, systemic sclerosis, systemic connective tissue Arterial disorders, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, all Alopecia, Believes' disease, Chagas's disease, autonomic nervous system disorders, endometriosis, sweat gland abscess (HS) Interstitial cystitis, neurogenic myotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, cystitis Junitzler syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis, white blood Autoimmune diseases such as plaque or vulvar pain; IV. Lung cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), Langerhans cell histiocytosis ( LCH), myeloproliferative neoplasms (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndrome (MDS), acute Lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and promyelocytic leukemia (APML) Leukemia (including APL), adrenal carcinoma, anal carcinoma, basal cell and squamous cell carcinoma, cholangiocarcinoma Bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), Chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, intrauterine cancer Membrane cancer, esophageal cancer, Ewing family tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, Gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, glioma, Hodgkin lymphoma, Kaposi's sarcoma. cancer, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumor, and cutaneous T-cell lymphoma. Lymphoma, malignant mesothelioma, melanoma, Merkel cell carcinoma, multiple myeloma, nasal cavity cancer, and and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer and Oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma Salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymic cancer, Thyroid cancer including non-vascular thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenströmma Chloglobulinemia and cancers including Wilms' tumor; V. Viral infections (e.g., influenza virus, human immunodeficiency virus (HIV)) ), alphaviruses (such as chikungunyavirus and Ross River virus), flavivirus Viruses (such as dengue virus and Zika virus), herpesviruses (Epstein-B virus) (Viruses such as cytomegalovirus, varicella-zoster virus and KSHV), Pock Vaccinia virus (modified vaccinia virus Ankara) and Myxoma Viruses (such as Viruses), adenoviruses (such as adenovirus 5), or papillomaviruses. ), bacterial infections (for example, Staphylococcus aureus) s), Helicobacter pylori, Bacillus anthrax s anthracis), Bordetella pertussis, Burkholderia pseudomallei, Diphtheria bacillus (C) orynebacterium diphtheriae), Clostridium tetani (Clostri Clostridium botulinum (Clostridium dium tetani) m), Streptococcus pneumoniae, pyogenes Cocci (Streptococcus pyogenes), Listeria (Listeria) Haemophilus influenzae (Haemophilus monocytogenes), Haemophilus influenzae (Haemophilus insularis) fluenzae), Pasteurella multoc Ida), Shigella dysenteriae, Mycobacterium tuberculosis (Mycobacterium tuberculosis) Mycobacterium tuberculosis, Mycobacterium leprae um leprae), Mycoplasma pneumonitis ae), Mycoplasma hominis, Meningitis Neisseria meningitidis, Neisseria gonorrhoeae (onorrhoeae), Rickettsia ricketsi Legionella pneumophylla (ttsii) ila), Klebsiella pneumoniae, Pseudomonas aeruginosa Udomonas aeruginosa, Propionibacter *Treponema pallidum*, *Treponema spp.* Chlamydia trachomatis, Vibrio cholerae (V) Salmonella typhi (Salmonella typhi) Murium, Salmonella typhi, Borrelia burgundy Borrelia burgdorferi or Yersi Fungal infections (e.g., Candida species or Aspergillus) (derived from Nia pestis) Species-derived), protozoan infections (e.g., Plasmodium, Babesia, Gialida, Entoloma). (derived from the genera Amoebae, Leishmania, or Trypanosoma), Hellworm infections (e.g., swarming Infections including those caused by blood flukes, roundworms, tapeworms, or trematodes, as well as prion infections; VI. Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease Disease, cerebral malaria, brain injury resulting from pneumococcal meningitis, intracranial aneurysm, traumatic brain injury, multiple Central nervous system diseases such as sclerosis and amyotrophic lateral sclerosis; VII. Type 2 diabetes (T2D), atherosclerosis, obesity, gout and pseudogout, etc. Metabolic diseases such as; VIII. Hypertension, ischemia, reperfusion injury including ischemia-reperfusion injury after MI, and ischemic stroke. This includes stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, congestive heart failure, and Heart failure, including heart failure with preserved output, embolism, aneurysms, including abdominal aortic aneurysms, and cardiovascular risks. Cardiovascular diseases such as decreased cardiorespiratory rate (CvRR) and pericarditis, including Dressler syndrome; IX. Chronic obstructive pulmonary disease (COPD), allergic asthma, and steroid-resistant asthma Asthma, asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic Respiratory diseases, including pulmonary fibrosis; 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, nephrocalcemia, glomerulonephritis and kidney diseases, including diabetic nephropathy; XII. Diseases of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, horn Eye diseases including membrane infections, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma; XIII. Dermatitis such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, Skin lesions, sweat gland abscesses (HS), skin diseases caused by other cysts, and skin conditions including acne clusters. skin diseases; XIV. Lymphatic conditions such as lymphangitis and Castleman disease; XV. Mental disorders such as depression and mental stress; XVI. Graft-versus-host disease; XVII. Bone diseases, including osteoporosis and osteopetrosis; XVIII. Blood disorders, including sickle cell disease; XVIX. Allodynia including mechanical allodynia; and XVX. Individuals with germline or somatic nonsilent mutations in NLRP3 Any disease for which treatment has been determined.

[0123] More specifically, the compounds of the present invention are useful in the treatment of the following conditions: Obtain: Inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or This is an autoinflammatory disease, such as autoinflammatory fever syndrome (e.g., cryopyrin-associated periodic syndromes). sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (for example) Chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcohol (Steatohepatitis and alcoholic liver disease), diseases related to inflammatory arthritis (e.g., gout, Pseudogout (chondrocalcification), osteoarthritis, rheumatoid arthritis, arthropathy (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, inflammation associated with hemodialysis), Diseases related to neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases) (e.g., Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk (C) vRR), hypertension, atherosclerosis, type 1 and type 2 diabetes and related conditions Comorbidities, peripheral artery disease (PAD), acute heart failure, inflammatory skin diseases (e.g., sweat gland abscess, rash) Related to 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) (MDS, myelofibrosis). In particular, autoinflammatory fever syndrome (e.g., CAPS), sickle cell anemia. Diabetes mellitus, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy), gout, pseudogout (Cartilage calcification), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis) (Severe brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis Diseases and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), sweat gland pus Surgery, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasm, leukemia, Myelodysplastic syndrome (MDS), myelofibrosis.

[0124] In particular, the compounds of the present invention or their pharmaceutically acceptable salts are preferably used in autoinflammatory fever symptoms. Group (e.g., CAPS), sickle cell disease, type 1 / type 2 diabetes and related complications (e.g.) (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (cartilage calcification), chronic liver disease, N ASH, disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, nerves) Degenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk factors (e.g., Reduced cardiovascular risk (CvRR), hypertension, sweat gland abscesses, wound healing and scar formation, and Cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasm, leukemia, myelodysplastic syndrome (MDS), bone It may be useful in the treatment of diseases or disorders selected from myelofibrosis.

[0125] Therefore, in a further aspect, the present invention relates to the therapy of formulas (I), (II), ( III) and (III-A), or any one of the embodiments described above. A compound according to one of the embodiments (i.e., according to any one of embodiments 1 to 11 g), or an example thereof. Any one of the embodiments (for example, Ex001 to Ex104 disclosed herein) The use of compounds or pharmaceutically acceptable salts thereof according to the method is provided. Further embodiments Therapies are selected from diseases that can be treated by inhibiting the NLRP3 inflammasome pathway. In another embodiment, the disease is appropriately related to the inflammasome, as listed above. Diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, for example, autoinflammation Fever-related syndromes (e.g., cryopyrin-associated periodic syndromes), sickle cell disease, systemic lupus erythema SLE (Systemic Lupus Erythematosus), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis) Non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease Diseases), diseases associated with inflammatory arthritis (e.g., gout, pseudogout (chondrocalcification), degenerative Arthritis, rheumatoid arthritis, arthropathy (e.g., acute, chronic), kidney-related diseases (e.g., high blood pressure) Oxaluria, lupus nephritis, type 1 / type 2 diabetes and related complications (e.g., nephropathy, Retinopathy, hypertensive nephropathy, inflammation associated with hemodialysis, diseases associated with neuroinflammation (for example) Multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease, cardiovascular system Metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis) Arteriosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), Acute heart failure, inflammatory skin diseases (e.g., sweat gland abscesses, acne), wound healing and scar formation, asthma Diseases / disorders related to respiration, sarcoidosis, age-related macular degeneration, and cancer (e.g., colon (Select from cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis) Selected. In particular, autoinflammatory fever syndrome (e.g., CAPS), sickle cell disease, type I / II Diabetes mellitus and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (Cartilage calcification), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis) (Severe brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis Diseases and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension), sweat gland pus Surgery, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasm, leukemia, Myelodysplastic syndrome (MDS), myelofibrosis.

[0126] Therefore, in a further embodiment, the present invention relates to a method for use in therapy, formula (I) One of the compounds (II), (III), and (III-A), or the aforementioned The method follows any one of the embodiments (i.e., any one of embodiments 1 to 11g). Compounds or exemplary embodiments (for example, Ex001-E disclosed herein) The present invention provides a compound or a pharmaceutically acceptable salt thereof that conforms to any one of the following (x104). In one embodiment, the therapy may be performed by inhibiting the NLRP3 inflammasome pathway. A disease is selected from the list above. In another embodiment, the disease is appropriately selected from the list above. Somole-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases For example, autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndromes), sickle cell anemia, Systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, Viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis and Alcoholic liver disease, diseases associated with inflammatory arthritis (e.g., gout, pseudogout (chondrolithiasis) (Calking), osteoarthritis, rheumatoid arthritis, arthropathy (e.g., acute, chronic), kidney-related diseases Patients (e.g., hyperoxaluria, lupus nephritis, type 1 / type 2 diabetes and related complications) For example, nephropathy, retinopathy, hypertensive nephropathy, inflammation associated with hemodialysis, and inflammation associated with neuroinflammation. Diseases that affect the brain (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease) Diseases, cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk ratio (CvRR), hypertension) Diseases, atherosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease Patients with PAD (Patient Adenopathy), acute heart failure, inflammatory skin diseases (e.g., sweat gland abscesses, acne), wound healing, and Diseases / disorders related to scarring, asthma, sarcoidosis, age-related macular degeneration, and cancer. (For example, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), bone marrow) The disease is selected from among fibrosis. In particular, autoinflammatory fever syndromes (e.g., CAPS) and sickle cell anemia. Type 1 / Type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, Gout, pseudogout (cartilage calcification), chronic liver disease, NASH, disorders associated with neuroinflammation (for example) (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atellite Arteriosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension) (e.g., hypertension), sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative cancer) These include tumors, leukemia, myelodysplastic syndrome (MDS), and myelofibrosis.

[0127] In another embodiment, the present invention treats diseases that are treated by inhibiting NLRP3. A method for determining the therapeutically effective dose, wherein the formulas (I), (II), (III), and (III-A) Any one of the compounds, or according to any one of the embodiments described above (i.e., implementation) Compound (according to any one of the 1-11 g values), or the example given (for example, the present invention A compound or the compound according to any one of Ex001 to Ex104) disclosed in the details The present invention provides a method comprising administering a pharmaceutically acceptable salt. In a further embodiment, disease The affected individuals include, appropriately, inflammasome-related diseases / disorders, immune disorders, and inflammation, as listed above. Sexually transmitted diseases, autoimmune diseases or autoinflammatory diseases, such as autoinflammatory fever syndrome (e.g., cryopreservoir). Phosphorus-related periodic syndromes, sickle cell disease, systemic lupus erythematosus (SLE), liver-related Related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic fatty liver disease) Related to NASH, alcoholic steatohepatitis and alcoholic liver disease, and inflammatory arthritis. Diseases that cause this (for example, gout, pseudogout (chondrocalcification), osteoarthritis, rheumatoid arthritis, arthritis) , for example, acute, chronic), kidney-related diseases (for example, hyperoxaluria, lupus nephritis, Type 1 / Type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hematology Inflammation associated with dialysis, diseases associated with neuroinflammation (e.g., multiple sclerosis, brain infections, Acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (for example, Reduced cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II Diabetes mellitus and related complications, peripheral artery disease (PAD), acute heart failure, inflammatory skin diseases (e.g., sweat gland abscess, 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, white blood cell carcinoma) The diagnosis is selected from blood disorders, myelodysplastic syndromes (MDS), and myelofibrosis. In particular, autoinflammatory fever. Symptoms (e.g., CAPS), sickle cell disease, type 1 / type 2 diabetes and related complications (e.g.) For example, nephropathy, retinopathy, hyperoxaluria, gout, pseudogout (cartilage calcification), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infections, acute injuries, neuropathy) Degenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk factors (e.g.) , reduced cardiovascular risk (CvRR), hypertension, sweat gland abscesses, wound healing and scar formation, and cancer (for example, colon cancer, lung cancer, myeloproliferative neoplasm, leukemia, myelodysplastic syndrome (MDS)), (Myelofibrosis)

[0128] In a further aspect, the present invention, as disclosed herein, provides NLRP3 infiltration Lamasome activity and / or NLRP3-induced IL-1 beta and / or NLRP3 induction In the treatment of diseases, disorders, or conditions substantially or completely mediated by sexual IL-18 Useful formulas are (I), (II), (III), and (III-A) The mixture or according to any one of the embodiments described above (i.e., any of embodiments 1 to 11g) Compounds (or according to one of the examples) or Ex disclosed herein A compound or a pharmaceutically acceptable salt thereof conforming to any one of the following (001-Ex104) is proposed. Provided herein. Some of the diseases, disorders, or conditions described herein are NLRP3. This occurs due to mutations in the gene, and in particular, leads to an increase in NLRP3 activity.

[0129] Therefore, in a further aspect, the present invention relates to a pharmaceutical product for the manufacture of formula ((I), (I I), (III), and (III-A) one of the compounds, or the aforementioned implementation A compound that follows any one of the states (i.e., any one of embodiments 1 to 11g), Alternatively, the exemplary embodiments (for example, Ex001 to Ex10 disclosed herein) 4) Provides the use of a compound or a pharmaceutically acceptable salt thereof according to any one of the following. In one embodiment, the medicine is for the treatment of a disease, and the disease is NLRP3 infection. It is treated by inhibiting the lamasomian pathway. In another embodiment, the disease is, Appropriately, inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, and autoimmune diseases. Or autoinflammatory diseases, such as autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndromes). ), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g.) For example, chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcohol Alcoholic steatohepatitis and alcoholic liver disease), diseases associated with inflammatory arthritis (e.g., gout) Pseudogout (chondrocalcification), osteoarthritis, rheumatoid arthritis, arthropathy (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, inflammation associated with hemodialysis) , diseases related to neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases) Diseases (e.g., Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., reduced cardiovascular risk) 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., sweat gland abscesses, 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) The disease is selected from the group (MDS, myelofibrosis). In particular, autoinflammatory fever syndromes (e.g., CAP) S) Sickle cell disease, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy) Hyperoxaluria, gout, pseudogout (chondrocalcification), chronic liver disease, NASH, neuroinflammation Related disorders (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease) Imer's disease), atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk) (CvRR, hypertension), sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer) These include lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), and myelofibrosis.

[0130] In another embodiment of the present invention, a disease or disorder treated by inhibition of the NLRP3 pathway 3-methyl-2-(5-methyl-6-((1-methylpiperine for use in treatment) (Zin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)pheno A ethanol or a pharmaceutically acceptable salt thereof is provided. In another embodiment of the present invention, NL (S) for use in the treatment of diseases or disorders treated by inhibition of the RP3 pathway -3-methyl-2-(5-methyl-6-((1-methylpiperidine-3-yl)amino) Pyridazine-3-yl)-5-(trifluoromethyl)phenol or its pharmaceutically acceptable A possible salt is provided. In a preferred embodiment of the present invention, inhibition of the NLRP3 pathway (R)-3-methyl-2-( 5-Methyl-6-((1-methylpiperidine-3-yl)amino)pyridazine-3-yl )-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof is provided. For example, diseases or disorders are, appropriately, diseases related to the inflammasome, as listed above. Disease / disorder, immune disease, inflammatory disease, autoimmune disease, or autoinflammatory disease, e.g., autoinflammation Fever syndromes (e.g., cryopyrin-associated periodic syndromes), sickle cell disease, systemic lupus erythematosus - SLE (Systemic Lupus Erythematosus), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, Non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease Diseases), diseases associated with inflammatory arthritis (e.g., gout, pseudogout (chondrocalcification), degenerative Arthritis, rheumatoid arthritis, arthropathy (e.g., acute, chronic), kidney-related diseases (e.g., high blood pressure) Oxaluria, lupus nephritis, type 1 / type 2 diabetes and related complications (e.g., nephropathy, Retinopathy, hypertensive nephropathy, inflammation associated with hemodialysis, diseases associated with neuroinflammation (for example) Multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease, cardiovascular system Metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis) Arteriosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), Acute heart failure, inflammatory skin diseases (e.g., sweat gland abscesses, acne), wound healing and scar formation, asthma Diseases / disorders related to respiration, sarcoidosis, age-related macular degeneration, and cancer (e.g., cancer (From intestinal cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis) Selected. In particular, the compounds of the present invention are used for autoinflammatory fever syndrome (e.g., CAPS), sickle cell death syndrome. Hematological disorders, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxalic acid Urinary tract disease, gout, pseudogout (chondrocalcification), chronic liver disease, NASH, and disorders related to neuroinflammation. (For example, multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), Atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR)) (e.g., hypertension), sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, bone cancer). Useful for treating myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), and myelofibrosis. That's fine.

[0131] In one embodiment of the present invention, the treatment of a disease or disorder that is treated by inhibiting the NLRP3 pathway 2-(4-methyl-6-((1-methylpiperidine-3-yl) for use in medical treatment )Amino)pyridazine-3-yl)-5-(trifluoromethyl)phenol or the drug thereof A scientifically acceptable salt is provided. In another embodiment of the present invention, the NLRP3 pathway is inhibited. (S)-2-(4-Me for use in the treatment of diseases or disorders treated by harm Tyl-6-((1-methylpiperidine-3-yl)amino)pyridazine-3-yl)-5 -(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof is provided. In preferred embodiments of the present invention, the disease or disorder treated by inhibition of the NLRP3 pathway. (R)-2-(4-methyl-6-((1-methylpiperidi for use in the treatment of (-3-yl)amino)pyridazine-3-yl)-5-(trifluoromethyl)phenol A pharmaceutically acceptable salt thereof is provided. For example, a disease or disorder is treated with the above-mentioned . Inappropriately, this refers to inflammasome-related diseases / disorders, immune disorders, inflammatory diseases, and autoimmune disorders. Epidemic diseases or autoinflammatory diseases, such as autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic fever syndromes). Syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders Harm (for example, chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), A Alcoholic steatohepatitis and alcoholic liver disease), diseases associated with inflammatory arthritis (for example) Gout, pseudogout (chondrocalcification), osteoarthritis, rheumatoid arthritis, arthropathy, for example, acute, Chronic kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II glucose) Diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, and conditions related to hemodialysis. Inflammation), diseases related to neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, nerves) Degenerative diseases (Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., cardiovascular risk) Decreased cerebrospinal fluid ratio (CvRR), hypertension, atherosclerosis, type 1 and type 2 diabetes, and related conditions. Related complications, peripheral artery disease (PAD), acute heart failure, inflammatory skin diseases (e.g., sweat gland disease) Abscesses, 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, myelodysplasia) The compounds of the present invention are selected from mesenteric syndromes (MDS, myelofibrosis). In particular, the compounds of the present invention are 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 Disorders related to disease, NASH, neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries) (e.g., neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk factors) For example, reduced cardiovascular risk (CvRR), hypertension, sweat gland abscesses, wound healing, and scar formation. Furthermore, cancer (for example, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS)) It may be useful in treating myelofibrosis.

[0132] In another embodiment of the present invention, a disease or disorder treated by inhibition of the NLRP3 pathway 2-(6-((1-ethylpiperidine-3-yl)amino) for use in treatment Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or the A pharmaceutically acceptable salt is provided. In another embodiment of the present invention, the NLRP3 pathway (S)-2-(6- ((1-ethylpiperidine-3-yl)amino)pyridazine-3-yl)-3-methyl- 5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof is provided. In preferred embodiments of the present invention, the disease or disorder treated by inhibition of the NLRP3 pathway. (R)-2-(6-((1-ethylpiperidine-3-I for use in the treatment of harm (Amino)pyridazine-3-yl)-3-methyl-5-(trifluoromethyl)pheno A ethanol or a pharmaceutically acceptable salt thereof is provided. For example, a disease or disorder is as described above. The list appropriately includes inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, and autoimmune diseases. Immune disorders or autoinflammatory diseases, such as autoinflammatory fever syndromes (e.g., cryopyrin-associated cycles) Sexual syndromes), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / Disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), Alcoholic steatohepatitis and alcoholic liver disease), diseases related to inflammatory arthritis (for example) For example, gout, pseudogout (chondrocalcification), osteoarthritis, rheumatoid arthritis, arthropathy, acute (chronic), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II) Diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, and hemodialysis-related conditions. (inflammation), diseases related to neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neuritis) Degenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., cardiovascular ribs) Decreased blood pressure rate (CvRR), hypertension, atherosclerosis, type 1 and type 2 diabetes, and Related complications include peripheral artery disease (PAD), acute heart failure, and inflammatory skin diseases (e.g., sweat). Adenomatous abscess, 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, myelodysplasia) The compounds of the present invention are selected from MDS (Myelofibrosis) and other related conditions. In particular, the compounds of the present invention are autoinflammatory Fever-related syndromes (e.g., CAPS), sickle cell disease, type 1 / type 2 diabetes and related complications. Diseases (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (cartilage calcification), chronic liver Diseases, NASH, and disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries) (Damage, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk ( For example, reduced cardiovascular risk (CvRR), hypertension, sweat gland abscesses, wound healing, and scar formation. Adult cancers and cancers (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MD)) It may be useful in treating S), myelofibrosis).

[0133] In another embodiment of the present invention, a disease or disorder treated by inhibition of the NLRP3 pathway 2-(6-((3-hydroxy-3-methylcyclobutyl) for use in treatment Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Or a pharmaceutically acceptable salt thereof is provided. In another embodiment of the present invention, NLRP 2-(6-) (((trans)-3-hydroxy-3-methylcyclobutyl)amino)pyridazine-3 -yl)-3-methyl-5-(trifluoromethyl)phenol or its pharmaceutically acceptable form A salt that can be used is provided. In a preferred embodiment of the present invention, inhibition of the NLRP3 pathway 2-(6-(((Sys)-3- Hydroxy-3-methylcyclobutyl)amino)pyridazine-3-yl)-3-methyl- 5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof is provided. For example, diseases or disorders are, appropriately, diseases related to the inflammasome / Disorders, immune disorders, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as autoinflammatory fever syndrome. Group syndromes (e.g., cryopyrin-associated periodic syndromes), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic liver disease) Non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease. Diseases associated with inflammatory arthritis (e.g., gout, pseudogout (chondrocalcification), osteoarthritis, Rheumatoid arthritis, arthropathy (e.g., acute, chronic), kidney-related diseases (e.g., hyperoxalic acid Urinary urinary tract infections, lupus nephritis, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy) (e.g., hypertensive nephropathy, inflammation associated with hemodialysis), diseases associated with neuroinflammation (e.g., multiple Sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic Diseases / Disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis) Diabetes mellitus, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), acute heart failure (All), inflammatory skin diseases (e.g., sweat gland abscesses, acne), wound healing and scar formation, asthma, monkey Coidosis, age-related macular degeneration, and cancer-related diseases / disorders (e.g., colon cancer, lung cancer) (Selected from myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis) In particular, the compounds of the present invention are effective in treating autoinflammatory fever syndrome (e.g., CAPS), sickle cell disease, and I Type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout , pseudogout (chondrocalcification), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., Multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease, atheroma Arteriosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk ratio (CvRR), hypertension) ), sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms). It may be useful in treating leukemia, myelodysplastic syndrome (MDS), and myelofibrosis.

[0134] In another embodiment of the present invention, a disease or disorder treated by inhibition of the NLRP3 pathway 2-(6-((3-hydroxycyclohexyl)amino) phosphate for use in treatment Ridazine-3-yl)-3-methyl-5-(trifluoromethyl)phenol or the drug thereof A scientifically acceptable salt is provided. In another embodiment of the present invention, the NLRP3 pathway is inhibited. 2-(6-(((1S for use in the treatment of diseases or disorders treated by harm) ,3R)-3-hydroxycyclohexyl)amino)pyridazine-3-yl)-3-meth A ru-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof is provided. In another embodiment of the present invention, a disease or disorder is treated by inhibition of the NLRP3 pathway. 2-(6-(((1R,3R)-3-hydroxycyclo for use in the treatment of harm Hexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl) A phenol or a pharmaceutically acceptable salt thereof is provided. In another embodiment of the present invention, For use in the treatment of diseases or disorders treated by inhibition of the NLRP3 pathway 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol or its pharmaceutically acceptable A possible salt is provided. In a preferred embodiment of the present invention, inhibition of the NLRP3 pathway 2-(6-(((1R,3S for use in the treatment of diseases or disorders that are treated) )-3-hydroxycyclohexyl)amino)pyridazine-3-yl)-3-methyl-5 -(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof is provided. For example, diseases or disorders are listed above, and appropriately, diseases / disorders related to inflammasomes. Harm, immune disorders, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as autoinflammatory fever syndrome. (For example, cryopyrin-associated periodic syndromes), sickle cell disease, systemic lupus erythematosus ( SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic liver disease) Non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease, inflammation Diseases related to symptomatic arthritis (e.g., gout, pseudogout (chondrocalcification), osteoarthritis, etc.) Rheumatoid arthritis, arthropathy (e.g., acute and chronic), kidney-related diseases (e.g., hyperoxaluria) Diseases, lupus nephritis, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy), Hypertensive nephropathy, inflammation associated with hemodialysis, diseases related to neuroinflammation (e.g., multiple sclerosis) (Chemical diseases, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases) Diseases / Disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis) Diabetes mellitus, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), acute heart failure ), inflammatory skin diseases (e.g., sweat gland abscesses, acne), wound healing and scar formation, asthma, sarcoma Diseases / disorders related to idosis, age-related macular degeneration, and cancer (e.g., colon cancer, lung cancer, The diagnosis is selected from myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), and myelofibrosis. In particular, the compounds of the present invention are used in autoinflammatory fever syndrome (e.g., CAPS), sickle cell disease, and type I. Type II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, Pseudogout (cartilage calcification), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple (Cellular sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis Arteriosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR), hypertension) , sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, It may be useful in treating leukemia, myelodysplastic syndrome (MDS), and myelofibrosis.

[0135] In another embodiment of the present invention, a disease or disorder treated by inhibition of the NLRP3 pathway 5-((6-(2-hydroxy-6-methyl-4-(truffles for use in treatment) Luoromethyl)phenyl)pyridazine-3-yl)amino)-1-methylpiperidine-3 -ol or a pharmaceutically acceptable salt thereof is provided. In another embodiment of the present invention, For use in the treatment of diseases or disorders treated by inhibition of the NLRP3 pathway ( 3R,5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl )phenyl)pyridazin-3-yl)amino)-1-methylpiperidine-3-ol or A pharmaceutically acceptable salt thereof is provided. In another embodiment of the present invention, NLRP3 (3R, 5R) for use in the treatment of diseases or disorders treated by obstruction of pathways. -5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Pyridazine-3-yl)amino)-1-methylpiperidine-3-ol or its pharmaceutically A suitable salt is provided. In another embodiment of the present invention, inhibition of the NLRP3 pathway (3S,5S)-5-((6 -(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazine- 3-yl)amino)-1-methylpiperidine-3-ol or its pharmaceutically acceptable Salt is provided. In a preferred embodiment of the present invention, treatment is performed by inhibiting the NLRP3 pathway. (3S,5R)-5-((6-(2- Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl (amino)-1-methylpiperidine-3-ol or a pharmaceutically acceptable salt thereof is provided. For example, diseases or disorders are, as listed above, appropriately related to inflammasomes. Diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, for example, autoinflammation Fever-related syndromes (e.g., cryopyrin-associated periodic syndromes), sickle cell disease, systemic lupus erythema SLE (Systemic Lupus Erythematosus), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis) Non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease Diseases), diseases associated with inflammatory arthritis (e.g., gout, pseudogout (chondrocalcification), degenerative Arthritis, rheumatoid arthritis, arthropathy (e.g., acute, chronic), kidney-related diseases (e.g., high blood pressure) Oxaluria, lupus nephritis, type 1 / type 2 diabetes and related complications (e.g., nephropathy, Retinopathy, hypertensive nephropathy, inflammation associated with hemodialysis, diseases associated with neuroinflammation (for example) Multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease, cardiovascular system Metabolic diseases / disorders (e.g., reduced cardiovascular risk (CvRR), hypertension, atherosclerosis) Arteriosclerosis, type 1 and type 2 diabetes and related complications, peripheral artery disease (PAD), Acute heart failure, inflammatory skin diseases (e.g., sweat gland abscesses, acne), wound healing and scar formation, asthma Diseases / disorders related to respiration, sarcoidosis, age-related macular degeneration, and cancer (e.g., colon (Select from cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis) In particular, the compounds of the present invention are selected for autoinflammatory fever syndrome (e.g., CAPS) and sickle cell anemia. Cystic dysplasia, type 1 / type 2 diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria Diseases, gout, pseudogout (chondrocalcification), chronic liver disease, NASH, disorders related to neuroinflammation ( For example, multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease, A Atherosclerosis and cardiovascular risk (e.g., reduced cardiovascular risk (CvRR)), Hypertension, sweat gland abscesses, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, bone marrow cancer). It is useful in treating proliferative tumors, leukemia, myelodysplastic syndrome (MDS), and myelofibrosis. It is possible.

[0136] The pharmaceutical composition or combination of the present invention provides approximately 1 to 100 units for approximately 50 to 70 kg of subject matter. 0 mg of active ingredient or approximately 1-500 mg, or approximately 1-250 mg, or approximately 1-1 Unit dose of the active ingredient: 50 mg, or approximately 1-100 mg, or approximately 1-50 mg This may be the case. The therapeutically effective dosage of a compound, pharmaceutical composition, or combination thereof is the target Depending on the species, weight, age, and individual condition, disability or disease, or the severity of the treatment being provided It exists. A physician, clinician, or veterinarian of ordinary skill can prevent, treat, or inhibit the progression of a disorder or disease. The effective amount of each active ingredient needed to cause harm can be easily determined.

[0137] The characteristics of the above-mentioned dosages apply to mammals such as mice, rats, dogs, monkeys, or The extracted organs, tissues, and preparations are conveniently used in in vitro and in vivo trials. It can be proven in this way. The compounds of the present invention are in the form of a liquid preparation, for example, an aqueous solution, in vitro. In vivo, it can be administered enterally, parenterally, or, conveniently, intravenously, for example, as a suspension. It can be applied in liquid or aqueous solution. The dosage in vitro is approximately 10 -3 Morin Degrees ~10 -9 It can range across molar concentrations. The therapeutically effective dose in vivo depends on the route of administration. Depending on the individual, the dosage can range from approximately 0.1 to 500 mg / kg or from approximately 1 to 100 mg / kg. .

[0138] Combination products and therapies of the present invention "Combination" refers to a fixed combination or combination of administration in a single medication unit. This refers to the compounds and combination partners of the present invention (for example, other drugs described below). The agents (also called "therapeutic agents" or "coagents") are administered simultaneously, separately, or within a time frame. They can be administered separately, and especially within these timeframes, the combination partners can work together. For example, they exhibit synergistic effects. A single component may be contained in one kit or packaged separately. It may be possible to administer one or both of the components (e.g., powder or liquid) in the desired dose before administration. It may be reduced or diluted. The terms "simultaneous administration" and "combined administration" as used herein "Combination" or other similar items require the selected combination partner. It is intended to include administration to a single target (e.g., a patient), and the active ingredient is the same It is intended to include treatment regimens that are not necessarily administered by the same route or simultaneously. As used herein, the term "combination of pharmaceuticals" refers to a mixture of two or more therapeutic agents. or resulting from combinations, fixed and unfixed combinations of therapeutic agents This refers to a product containing both. The term "combination of pharmaceuticals" as used herein means: Fixed or non-fixed combinations in a single medication unit form or This refers to a kit of components for a combination of medications, where two or more therapeutic agents are administered simultaneously and separately. It may be administered in separate doses within a time frame, and in particular, depending on the time frame, The partners are cooperative, for example, exhibiting synergistic effects. The term "fixed combination" refers to a therapeutic approach. The therapeutic agent, for example, the compound and combination partner of the present invention, together constitute a single entity or dosage. This means that the drug is administered to all patients simultaneously in this form. The term "unfixed combination" is used. "The therapeutic agent, for example, the compound of the present invention and its combination partner, together constitute a separate entity and And, administered to patients simultaneously, in parallel or sequentially, without any specific time limit, such This means that the patient's body receives therapeutically effective levels of the two compounds. The latter also applies to cocktail therapy, for example, the administration of three or more therapeutic agents.

[0139] The term “combination of therapies” refers to a combination of therapies used to treat a medical condition or disorder as described in this disclosure. This refers to the administration of two or more therapeutic agents. Such administration involves single agents having a fixed ratio of active ingredients. This includes the simultaneous administration of these therapeutic agents in virtually the same time, such as in a single capsule. Instead, such administration is carried out in multiple or separate containers for each active ingredient. This includes simultaneous administration in, for example, tablets, capsules, powders, and liquids. Powders and / or The liquid formulation may be reduced or diluted to the desired dose before administration. In addition, such administration is almost This also includes the use of each type of therapeutic agent simultaneously or sequentially at different times. In some cases, the treatment regimen may involve the use of drugs to treat the conditions or disorders described herein. This combination will likely yield beneficial results.

[0140] The compounds of the present invention are administered simultaneously with, or before or after, one or more other therapeutic agents. The compounds of the present invention are obtained by the same or different routes of administration, separately from other active substances. They can be administered together in the same pharmaceutical composition. The therapeutic agent may be, for example, a chemical compound, a peptide The compound is an antibody, antibody fragment, or nucleic acid, which is therapeutically active or is a compound of the present invention. When administered to patients in combination with [another substance], it enhances therapeutic activity.

[0141] In one embodiment, the present invention provides preparations for simultaneous, separate, or sequential use in therapy. As a combination of objects, any of the following equations: (I), (II), (III), and (III-A) A preparation comprising one compound or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent. The product is provided. In one embodiment, the therapy is for a disease or condition mediated by NLRP3. It is a treatment. Products provided as a combination of preparations are together in the same pharmaceutical composition. in which any one of the compounds of formula (I), (II), (III), and (III-A) or its pharmaceutically acceptable salt and other therapeutic agents or in a separate form, such as a kit. In this case, one of the compounds of formulas (I), (II), (III), and (III-A) The composition includes a pharmaceutically acceptable salt thereof and other therapeutic agents.

[0142] In one embodiment, the present invention relates to formulas (I), (II), (III), and (III-A) Any one of the compounds or its pharmaceutically acceptable salts or any of the embodiments described above A compound or the following according to one of the embodiments (i.e., according to any one of embodiments 1 to 11g) Provides a combination of pharmaceuticals containing pharmaceutically acceptable salts and other therapeutic agents. The combination of pharmaceuticals includes a pharmaceutically acceptable carrier, as described above. That's good too.

[0143] In one embodiment, the present invention provides a kit comprising two or more distinct pharmaceutical compositions, and pharmaceutical At least one of the compositions is a compound of formula (I), (II), (III), and (III-A). Any one of the compounds or its pharmaceutically acceptable salts or any one of the embodiments described above Compounds or their pharmaceuticals according to one of the embodiments (i.e., according to any one of embodiments 1 to 11g) It contains a suitable acceptable salt. In one embodiment, the kit is a container, a separate bottle, or The kit includes means for holding the composition separately, such as separate foil wrappers. One example is the blister packing commonly used for packaging tablets, capsules, and other similar items. It's a tarpak.

[0144] The kit of the present invention is used to administer different dosage forms, such as oral and parenteral medications. To administer separate compositions at a certain interval or to dose-set separate compositions relative to each other It can be used. To facilitate compliance, the kit of the present invention is typically administered Includes instructions for use.

[0145] In the therapeutic combination of the present invention, the compound of the present invention and other therapeutic agents are the same or different. It can be manufactured and / or formulated by a manufacturer. Furthermore, the compounds of the present invention and other therapeutic agents Therapeutic drugs (i) before launching a combination product to physicians (for example, the compound of the present invention and other therapeutic drugs) In the case of a kit containing a therapeutic agent; (ii) Immediately before administration by the physician himself (or under the guidance of the physician) (iii) For example, during the sequential administration of the compound of the present invention and other therapeutic agents, the patient himself may administer them together It can be a combination of therapies.

[0146] Therefore, the present invention relates to the treatment of diseases or conditions mediated by NLRP3. , one of the compounds of formulas (I), (II), (III), and (III-A) or The use of pharmaceutically acceptable salts is provided, and the medicine is prepared for administration with another therapeutic agent. The present invention also provides another treatment for diseases or conditions mediated by NLRP3. The use of therapeutic drugs is also provided, and the medicines are of formulas (I), (II), (III), and (III-A). Any one of the compounds or its pharmaceutically acceptable salts or any of the embodiments described above A compound or drug according to one of the embodiments (i.e., according to any one of embodiments 1 to 11g) It is administered with a scientifically acceptable salt.

[0147] The present invention also relates to a method for treating diseases or conditions mediated by NLRP3. Any of the following formulas for use: (I), (II), (III), and (III-A) One compound or a pharmaceutically acceptable salt thereof, or according to any one of the embodiments described above. (i.e., according to any one of embodiments 1 to 11 g) the compound or its pharmaceutically acceptable The acceptable salts are also provided, any of formulas (I), (II), (III), and (III-A). or one compound or a pharmaceutically acceptable salt thereof or any one of the embodiments described above The compound or its pharmaceutically acceptable (i.e., according to any one of embodiments 1 to 11 g) The acceptable salts are prepared for administration with other therapeutic agents. This invention also relates to NLRP3 Another treatment for use in methods for treating diseases or conditions mediated by We also provide other therapeutic agents, including those of formulas (I), (II), (III), and (III-A). Any one of the compounds or its pharmaceutically acceptable salts or any one of the embodiments described above A compound or drug according to one of the embodiments (i.e., according to any one of embodiments 1 to 11g) Prepared for administration with scientifically acceptable salts. The present invention is also mediated by NLRP3. Formulas (I) and (II) for use in methods for treating the disease or condition being treated. ), (III), and (III-A) or any one of the compounds thereof that is pharmaceutically acceptable The salt is prepared according to any one of the embodiments described above (i.e., according to Embodiments 1 to 11g) We also provide compounds (following either one of them) or pharmaceutically acceptable salts thereof, formula (I), (I I), (III), and (III-A) any one of the compounds or their pharmaceutically acceptable The salt to be used or according to any one of the embodiments described above (i.e., Embodiments 1 to 11 g) A compound (following any one of the following rules) or a pharmaceutically acceptable salt thereof may be administered together with another therapeutic agent. The present invention also provides for the treatment of diseases or conditions mediated by NLRP3. We also provide other therapeutic agents for use in the method, other therapeutic agents are formulas (I), (II), (III), and (III-A), one of the compounds or their pharmaceutically acceptable A salt or according to any one of the embodiments described above (i.e., any of embodiments 1 to 11g) It is administered with a compound (or one thereof) or a pharmaceutically acceptable salt thereof.

[0148] The present invention also provides a formula (I) for treating diseases or conditions mediated by NLRP3. ), (II), (III), and (III-A) - one of these compounds or drugs thereof A scientifically acceptable salt or according to any one of the embodiments described above (i.e., Embodiment 1~ The use of the compound or a pharmaceutically acceptable salt thereof (according to any one of 11g) is also provided. The patient has been treated previously (e.g., within 24 hours) with another therapeutic agent. , a separate treatment for diseases or conditions mediated by the NLRP3 inflammasome pathway The use of therapeutic agents is also provided, and patients are given formulas (I), (II), (III), and (III- A) any one of the compounds or pharmaceutically acceptable salts thereof or the embodiments described above A compound that follows either one of the embodiments (i.e., one of embodiments 1 to 11g) It has been treated previously (e.g., within 24 hours) with a pharmaceutically acceptable salt.

[0149] In one embodiment, other therapeutic agents are inframaso, as disclosed herein. Diseases / disorders related to the immune system, immune diseases, inflammatory diseases, autoimmune diseases, or the treatment of autoinflammatory diseases. It is a useful therapeutic agent in medical treatment.

[0150] In one embodiment, other therapeutic agents useful in the combination of therapies include farnesoid X. (FXR) agonist; anti-lipidemia drug; anti-fibrotic drug; JAK inhibitor; checkpoint Inhibitors; chemotherapy, radiotherapy and surgical procedures; uric acid-lowering therapies; anabolic drugs and Cartilage regeneration therapy; IL-17 blockade; complement inhibitors; Bruton's tyrosine kinase inhibitors ( BTK inhibitors; Toll-like receptor inhibitors (TLR7 / 8 inhibitors); CAR-T therapy; anti Antihypertensive drugs; cholesterol-lowering drugs; leukotriene A4 hydrolase (LTAH4) inhibitors Agents; SGLT2 inhibitors; β2 agonists; anti-inflammatory agents; non-steroidal anti-inflammatory drugs (NSA) ID); Acetylsalicylic acid drugs (ASA) including aspirin; Paracetamol; Regenerative medicine Treatment by law; treatment of cystic fibrosis; and treatment of atherosclerosis are selected from the following: ru.

[0151] Suitable leukotriene A4 hydrolase (LTA4) for use in combination H) Inhibitors are described in International Publication No. 2015 / 092740 (Agent Reference Number PA) This includes, but is not limited to, the compounds disclosed in T056044-WO-PCT. do not have.

[0152] Suitable sodium-dependent glucose transporter 2 (SG) for use in combination LT2) inhibitors are specified in U.S. Patent No. 8,163,704 (Agent Reference Number PAT05 3854-WO-PCT), International Publication No. 2011 / 048112, International Publication Pamphlet No. 2011 / 048148 or International Publication No. 2010 / 128152 This includes, but is not limited to, the compounds disclosed in the brochure.

[0153] Suitable β2 agonists for use in combination include alformoterol, Bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol Dopexamine, Fenoterol, Formoterol, Hexoprenaline, Ibuterol Isoethalin, Isoprenaline, Levosalbutamol, Mabuterol, Meladrin Metaprotenelol, Noromilol, Orciprenaline, Pirbuterol, Procatero Leproterol, Ritodrine, Rimoterol, Salbutamol, Salmefamol Salmeterol, cybenadette, sothenerote, sulfonterol, terbutaline, thia Lamid, Tulobuterol, GSK-597901, GSK-159797, GSK-67 8007, GSK-642444, GSK-159802, HOKU-81, (-)-2 -[7(S)-[2(R)-hydroxy-2-(4-hydroxyphenyl)ethylamino ]-5,6,7,8-tetrahydro-2-naphthyloxy]-N,N-dimethylacetate Midohydrochloride monohydrate, carmoterol, QAB-149 and 5-[2-(5,6-diethyl Ruindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quino Phosphate-2-one, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy )propyl]sulfonyl]ethyl]amino]ethyl]-2(3H)-benzothiazolon, 1-(1-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl) )-2-methyl-2-butylaminoethanol, 1-[3-(4-methoxybenzylamine]ethanol [Mino)-4-hydroxyphenyl]-2-[4(1-benzimidazolyl)-2-methyl -2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1 ,4-benzoxazine-8-yl]-2-[3-(4-N,N-dimethylaminophenicol [Lu)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3 -Oxo-4H-1,4-benzoxazine-8-yl]-2-[3-(4-methoxyf [ethanol](enyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy -3-oxo-4H-1,4-benzoxazine-8-yl]-2-[3-(4-n-bu [Tyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5 -hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl]-2-{4- [3-(4-methoxyphenyl)-1,2,4-triazole-3-yl]-2-methyl -2-butylaminoethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylethanol) Ropyraminobutyl)-2H-1,4-benzoxazine-3-(4H)-one, 1-(4 (-amino-3-chloro-5trifluoromethylphenyl)-2-tert-butylamino ) Ethanol, 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenicol This includes (Lu)-2-(tert-butylamino)ethanol and combinations thereof, Not limited to these, each of these can be optionally selected as a racemic mixture, enantiomer, or dias. It is in the form of a teleomer or a mixture thereof, and further optionally, a pharmacologically compatible acid. This is a form of salting.

[0154] Suitable cartilage regeneration therapies for use in combination are described in International Publication No. 2014 / 13. In pamphlet No. 8687 (agent case number PAT055625-WO-PCT) Disclosed ANGPTL3 peptide mimetic or International Publication No. 2015 / 175487 Cartilage disclosed in Fret (Agent case number PAT055940-WO-PCT) This includes, but is not limited to, activating factors.

[0155] Suitable checkpoint inhibitors for use in combination are anti-PD1 inhibitors. This includes, but is not limited to, anti-LAG-3 inhibitors, anti-TIM-3 inhibitors, and anti-PDL-1 inhibitors. No. Suitable anti-PD1 inhibitors are described in International Publication No. 2015 / 112900. This includes, but is not limited to, the antibody molecules disclosed in [the relevant document]. Suitable anti-LAG-3 inhibitors The agent is an antibody molecule disclosed in International Publication No. 2015 / 138920. This includes, but is not limited to, suitable anti-TIM-3 inhibitors, as described in International Publication No. 2015 / 11. This includes, but is not limited to, the antibody molecules disclosed in Pamphlet No. 7002. The anti-TIM-3 inhibitor described in International Publication No. 2015 / 117002 The disclosed antibody molecules include, but are not limited to, those disclosed. Suitable anti-PDL1 inhibitors are internationally publicly available. This includes antibody molecules disclosed in Pamphlet No. 2016 / 061142, but Not limited to this.

[0156] Suitable Toll-like receptor inhibitors (TLR7 / 8 inhibitors) for use in combination The agent contains the compounds disclosed in International Publication No. 2018 / 04081. However, it is not limited to this.

[0157] A suitable FXR agonist for use in combination is obeticholic acid (Iwa (Loose OCA, Intercept), GS9674, Elafibranol (GFT505) ), GW4064, UPF987, FXR-450, fexalamine, methyl cholate, Methyl deoxycholate, 5β-coranaic acid, 7α,12α-diol 5β-coranaic acid, NI HS700, Marcantine A, Marcantine E, MFA-1 INT767 (International Publication No. Also known as 6α-ethyl-CDCA, as disclosed in pamphlet No. 2014 / 085474. (commonly known as), MET409 (Metacrine), EDP-305 (Enanta), 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoro Methoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabisic [3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6 -Carboxylic acid (also known as tropifexol) or its pharmaceutically Permissible salts or disclosed in International Publication No. 2012 / 087519 Compounds or chemicals disclosed in International Publication No. 2015 / 069666 This includes, but is not limited to, blended products.

[0158] Suitable JAK inhibitors for use in combination include ruxolitinib, This is not limited to this.

[0159] Suitable NSAIDs for use in combination are aceclofenac and acemeta. Syn, acetylsalicylic acid, alclofenac, aluminoprofen, amfenac, Ampiroxicam, Antremethine guayl, Anilolac, Anthraphenine, Azapro Pason, Benolilate, Belmoprofen, Vindalito, Bromfenac, Bucloxic Acid Bucolome, Bufexamac, Bumadizone, Butibufen, Butixylat, Carbasara Calcium triglycerides, caprophene, choline magnesium trisalicylate, celecoxib, Nmethacin, Synnoxicam, Clidanac, Clobuzalit, Deboxameth, Dexibpro Fen, dexketoprofen, diclofenac, diflunisal, droxicam, erte Nak, enfenamic acid, etersalat, etodrug, etofenamate, etoricoxy Bu, feclobuzon, felbinac, fenbufen, fenclofenac, fenop Lofen, Fentiazac, Feprazinol, Feprazon, Flobufen, Floctate Fenine, flufenamic acid, fluphenisal, flunoxaprofen, flurbiprof Flurbiprofen axetyl, flofenac, fluprofen, glucamethasone ibuprofen, ibufenac, ibuprofen, indobufen, indomethacin, indomethacin Farnesil, Indoprofen, Isoxepac, Isoxicam, Ketoprofen, Ke Trolac, Lobenzarit, Lonazolac, Lornoxicam, Loxoprofen, Lumira Coxib, meclofenamime, meclofen, mefenamic acid, meloxicam, mesalazine Miroprofen, mofezolac, nabumetone, naproxen, niflumic acid, orsaladi Oxaprozin, Oxypinac, Oxyfenbutazone, Parecoxib, Phenyl Butazone, perbiprofen, pimeprofen, pyrazolac, pyriloxicam, pilpro Fen, Pranoprofen, Priferon, Prinomod, Proglumatacin, Procason , protidinic acid, lofecoxib, romazarit, salicylamide, salicylic acid, sal Mystein, sarnasedin, sarsalat, sulindac, sudoxicam, suprofen, Talniflumart, Tenidap, Tenosal, Tenoxicam, Tepoxaline, Chiaprof Tinamide, thirnoprofen albamel, thymegazin, thinolysine, thiopinac Tolfenamic acid, tolmetin, ufenamate, valdecoxib, xymoprofen, This includes, but is not limited to, zaltoprofen, zoliprofen, and combinations thereof. .

[0160] Suitable BTK inhibitors include, for example, ibrutinib and acalabrutinib (ACP-196). Evobrutinib; Fenebrutinib; Tirabrutinib (ONO-4059, GS-40 59); Zanubrutinib (BGB-3111), spebratinib (CC-292, AVL) -292), Posertinib (HM-71224, LY3337641), Becabrutinib (SN-062), BM-986142;BMS986195;PRN2246;PRN 1008, M7583, CT1530, BIIBO68, AC-0058TA, ARQ- 531, TAK-020, TG1701 or International Publication No. 2015 / 079417 pamphlet Lett, International Publication No. 2015 / 083008, International Publication No. 2015 / 11 Pamphlet No. 0923, International Publication No. 2014 / 173289, International Publication Pamphlet No. 2012 / 021444, International Publication Pamphlet No. 2013 / 081016 Lett, International Publication No. 2013 / 067274, International Publication No. 2012 / 17 Pamphlet No. 0976, International Publication No. 2011 / 162515, U.S. Patent Specification in Patent Publication No. 2017 / 119766, International Publication No. 2016 / 065226 Fret, U.S. Patent No. 9,688,676, International Publication No. 2016 / 201280 Pamphlet No. 2017 / 059702, U.S. 9,6 Specifications No. 30,968, U.S. Patent Application Publication No. 2014 / 0256734, International Patent Pamphlet No. 2017 / 118277, International Publication No. 2014 / 039899 Fret, International Publication No. / 16 / 105531, International Publication No. 2018 / 00 Pamphlet No. 5849, International Publication No. 2013 / 185082, or J This is described in .Med.Chem.,2016,59(19),9173-9200. It contains compounds that are particularly interesting. Of particular interest are the BTK inhibitors, as described in International Publication No. 2014 / 0398. The compound of Example 31 described in Pamphlet No. 99, Journal of M edicinal chemistry,2016,59(19),9173-9200 The following structure is described as compound 14f: [ka] The compound; the implementation described in U.S. Patent Application Publication No. 2017 / 119766 The compound in Example 2 is described in International Publication No. 2016 / 065226. [ka] The compound of Example 223, or the compound in International Publication No. 2016 / 201280, Compound 1, described in International Publication No. 2017 / 059702, is described in the brochure. Compound 1 listed or described in International Publication No. 2017 / 118277 Contains compound 1 listed; or a pharmaceutically acceptable salt thereof.

[0161] Another particularly interesting finding is that BTK inhibitors are mentioned in International Publication No. 2015 / 079417. Compounds listed in the frets, for example, N-(3-(5-((1-acryloylase Thidin-3-yl)oxy)-6-aminopyrimidine-4-yl)-5-fluoro-2- Methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6- Amino-5-((1-propioloylazetidine-3-yl)oxy)pyrimidine-4- Iyl-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluoroben Zuamide; N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy Pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl -2-Fluorobenzamide; N-(3(6-amino-5-(2-(N-methylpropyl Allamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl )-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-( 2-(N-methylbuta-2-inamide)ethoxy)pyrimidine-4-yl)-5-flu Oro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-( 3-(6-amino-5-(2-(N-ethylacrylamide)ethoxy)pyrimidine-4 -yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobe N-(3-(6-amino-5-(2-(N-(2-fluoroethyl)acrylate) Luamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)- 4-Cyclopropyl-2-Fluorobenzamide; (S)-N-(3-(6-Amino-5 -(2-(buta-2-inamide)propoxy)pyrimidine-4-yl)-5-fluoro (-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N -(3-(6-amino-5-(2-(N-methylbuta-2-inamide)propoxy) Limidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -Fluorobenzamide, and N-(3-(6-amino-5-(3-(N-methyl acrylate Luamide (propoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl) Contains -4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof . [Examples]

[0162] Examples of the present invention This disclosure is further illustrated by the following examples and synthesis schemes, which are part of this disclosure. This shall be limited in scope or intent to the specific procedures described herein. Examples are provided to illustrate certain embodiments of the disclosure. It should be understood that this does not mean that the scope is limited. Various other embodiments, variations thereof, and equivalents that can be associated with this disclosure are in line with the spirit and / It is further understood that it may be used without departing from the scope of the attached claims. It should.

[0163] The compounds of this disclosure may be prepared by methods known in the art of organic synthesis. In all methods, protecting groups for sensitive or reactive groups are in accordance with the general principles of chemistry. Therefore, it is understood that protecting groups can be used as needed. Protecting groups are standard methods in organic synthesis. It is treated according to (TWGreen and PGMWuts (2014)P rotective Groups in Organic Synthesis,5t (h edition, John Wiley & Sons). These materials are directly applicable to those skilled in the art. It is removed at a convenient stage in compound synthesis using a method that will be revealed later.

[0164] Unless otherwise specified, reagents and solvents were obtained and used from private suppliers.

[0165] The chemical name is from CambridgeSoft's ChemBioDraw Ultra v1. It was generated using 4.

[0166] Temperatures are expressed in degrees Celsius. Unless otherwise specified, evaporation is performed under reduced pressure. Typically, this is performed at approximately 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of the final product, intermediates, and starting materials can be determined using standard analytical methods, such as trace analysis and spectroscopy. The properties are confirmed by methods such as MS, IR, and NMR. The abbreviations used are those used in this technical field. It is common in that context.

[0167] Abbreviation Acetic acid (ACOH) ASC (Apoptosis-Related Speck-like Protein) BINAP (2,2'-bis(diphenylphosphin)-1,1'-binaphthyl) BippyPhos 5-(di-tert-butylphosphino)-1',3',5'-to Riphenyl-1'H-1,4-bipirazole Boc tert-butyloxycarbonyl CAPS (Cryopyrin-Associated Periodic Syndrome) DAMP Dangerous Activation Molecular Pattern DIAD (Diisopropyl Azodicarboxylate) DIPEA N-diisopropylethylamine DME 1,2-Dimethoxyethane DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) dppf 1,1'-bis(diphenylphosphin)ferrocene HCl ethyl acetate EtOH Ethanol h time HCl (hydrogen chloride) HTRF Homogeneous Time-Resolved Fluorescence Hz / MHz Hertz / Megahertz I C 50 Half of the maximum inhibitory concentration IL-1β Interleukin-1 beta IR infrared LC-MS Liquid Chromatography-Mass Spectrometry LPS (Lipopolysaccharide) derived from Escherichia coli O111:B4 LRR Leucine Rich Repeat M moles mCPBA 3-chloroperbenzoic acid MEK Methyl ethyl ketone; Butan-2-one MeOH methanol min mL / L (milliliters / liter) mmol millimol NASH (Non-Alcoholic Steatohepatitis) NBD (Nucleotide Binding Site) Domain NLR NOD-like receptor NMP 1-methylpyrrolidine-2-one NMR nuclear magnetic resonance PAD (Peripheral Artery Disease) PAMP Pathogen Activation Molecular Pattern Pd / C Palladium Carbon PMA 13-Polubyl myristate 12-acetic acid ppm parts per million RP inverse phase RPMI Roswell Park Memorial Institute RT Room temperature in Celsius Rt retention time SFC Supercritical Fluid Chromatography SLE (Systemic Lupus Erythematosus) TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) TMEDA N,N,N',N'-Tetramethylethane-1,2-diamine TMS Tetramethylsilane TNF-α Tumor necrosis factor-α UPLC (Ultra High Performance Liquid Chromatography) XantPhos-Pd-G2 Chloro[(4,5-bis(diphenylphosphino)-9 ,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]paradiul Mu (II)

[0168] Analysis details • NMR: Measurement is performed using tetramethylsilane (TMS) as an internal standard or And, Bruker Ultrashield (trademark) 400 (400MHz) or Br Bruker Ascend (trademark) (400MHz) or Bruker cryo sys The analysis was performed using a TEM (600 MHz) spectrometer. The chemical shift (δ) was obtained from the TMS to the low magnetic field. It was reported in pm, and the spectral splitting pattern is singleline (s), doubleline (d), tripleline (t). ), quadruple lines (q), quint lines (quint), hept lines (sept), multiple lines, undivided or overlapping Multiple signals (m) and broad signals (br) are shown. Deuterated solvents are indicated in parentheses. Dimethyl sulfoxide (δ 2.50 ppm), methanol (δ 3.31 ppm), and Loloform (δ 7.26 ppm) and other solvents with a chemical shift are NMR spectroscopy This is as shown in the data. • LC-MS: System: Waters Acqu with Waters SQ detector ity UPLC. Column: Acquity HSS T3 1.8μm 2.1×50 mm, column temperature: 60℃. Gradient: 5-98% for 1.4 minutes. B, A = water + 0.05% formic acid +3.75 mM ammonium acetate, B = acetonitrile + 0.04% formic acid, flow rate: 1.0 mL / min. Mass spectrometry results are reported as the mass-to-charge ratio.

[0169] Preparative separation method • Flash column chromatography system: System: Teledyne ISCO, CombiFlash (registered trademark) Rf. Column: Pre-packed RediSep RF cartridge. The samples were typically adsorbed onto isolute. • Achiral reversed-phase (RP) chromatography: System: Gilson Autopurification LC System Sunfire C18 5um 30×100mm column Detection: Gilson UV / VIS 155 Detector Column temperature: RT Eluent A: Water + 0.1% TFA Eluent B: Acetonitrile Flow rate: 30mL / min gradient:

[0170] [Table 1]

[0171] • Chiral normal-phase chromatography: System: Gilson Autopurification LC System Detection: Gilson UV / VIS-155 Detector Column temperature: RT

[0172] • Achiral supercritical fluid chromatography (SFC): System: Waters SFC-100 SFC System Detection: Waters 2998 PDA Detector Waters 3100 Mass Detector Eluent A: CO2 Eluent B: As described in the examples.

[0173] • Chiral supercritical fluid chromatography (SFC): System: Waters SFC-100 SFC System Detection: Waters 2998 PDA Detector Waters 3100 Mass Detector Eluent A: CO2 Eluent B: As described in the examples.

[0174] All starting materials, constituent units, reagents, acids, etc., used to synthesize the compounds of the present invention The base, dehydrating agent, solvent, and catalyst are commercially available or organically known to those skilled in the art. It can be produced by synthetic methods.

[0175] Synthesis of intermediates Synthesis of Boronate Intermediates 3-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) -yl)-5-(trifluoromethyl)phenol and 5-chloro-2-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl Chil(phenol), IntB001 [ka] (1) 3-chloro-2-iodo-5-(trifluoromethyl)phenol and 5-chloro -2-iodo-3-(trifluoromethyl)phenol, IntB002 [ka] 3-chloro-5-(trifluoromethyl)phenol (10g) in 150mL of toluene A mixture of (50.9 mmol) and sodium hydride (2.44 g, 102 mmol) The mixture was stirred at 0°C for 30 minutes. Iodine (12.9g, 50.9mmol) was then added. The solution was stirred at 0°C for 3 hours. The reaction mixture was then acidified with concentrated HCl, and 4- A final pH of 5 was obtained. It was extracted with carboxylic acid, and the organic layer was washed with water and brine, and N The crude mixture of positional isomers was dried with a2SO4, filtered, and evaporated. Used in the application. LC-MS: Rt=1.10 and 1.12 min; MS m / z 32 0.9[MH]-.

[0176] (2) 5-Chloro-1-(ethoxymethoxy)-2-iodo-3-(trifluoromethyl )benzene and 1-chloro-3-(ethoxymethoxy)-2-iodo-5-(trifluorescein Methylbenzene, IntB003 [ka] (Chloromethoxy)ethane (7.25 mL, 62.5 mmol) in 70 mL of DMF IntB002 (16g, 49.6 mmol) and CS2CO3 (16.2g, 49.6 (chloromethoxymethylammonium) was added to the suspension. The reaction mixture was stirred at RT for 18 hours. Add 2.88 mL (24.8 mmol) of ethane and continue stirring for 24 hours. The suspension was filtered through Celite, the filtrate was evaporated, and the title compound was obtained as a mixture of positional isomers. The following was obtained and used in the next step without further purification: LC-MS:Rt= 1.37 and 1.38 min.

[0177] (3) 2-(2-chloro-6-(ethoxymethoxy)-4-(trifluoromethyl)phen Nyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-(4- Chloro-2-(ethoxymethoxy)-6-(trifluoromethyl)phenyl)-4,4, 5,5-Tetramethyl-1,3,2-Dioxaborolane, IntB004 [ka] In 60 mL of 1,4-dioxane, IntB003 (11.9 g, 31.3 mmol) 4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane (9.08 mL, 62 The solutions of 0.5 mmol) and NET3 (13.08 mL, 94 mmol) were perfused with nitrogen. Pd(OAc)2 (0.35g, 1.56mmol) and biphenyl-2-yl - Dicyclohexylphosphan (1.1g, 3.13 mmol) was added, resulting in The mixture was stirred at 80°C for 3 hours. Pd(OAc)2(0.35g, 1.56mmo l) was added and heating continued for 13 hours. The reaction mixture was cooled to RT and saturated with NH4C. The oil was washed with solution, water, and brine to obtain an orange-colored oil. The crude product was then treated with cyclohexane and Use ¼ (0%~100%) for column chromatography with silica gel. Therefore, the compound was purified, and the title compound was obtained as a mixture of positional isomers. LC-MS: Rt=1.4 3 min.

[0178] (4) 3-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxavorola (-2-yl)-5-(trifluoromethyl)phenol and 5-chloro-2-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(triflu Oromethylphenol, IntB001 In 25 mL of CH2Cl2, IntB004 (8.5 g, 22.34 mmol) and TF Purge solution A (25.8 mL, 670.2 mmol) with nitrogen and stir at 0°C for 1 hour. The mixture was washed with saturated NH4Cl solution, water, and brine. The organic layer was Na2SO4 It was dried, filtered, and evaporated to obtain an orange oil. The crude product was then mixed with cyclohexane and Using ¼ (0%~5%), column chromatography with silica gel is performed. The compound was purified, and the title compound was obtained as a mixture of positional isomers. LC-MS: Rt=1.23m in and 1.28 min; MS m / z 321.1[MH]-.

[0179] (2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid, In tB005 [ka] (1) 3-methyl-5-(trifluoromethyl)phenol, IntB006 [ka] LiOH (26.5g, 630.33mmol), Pd2(dba)3 (3.85g, 4.20 mmol) and BippyPhos (4.25 g, 8.40 mmol) are used in 5 1,4-dioxane in 00 mL and 1-bromo-3-methyl-5-( It was added to a solution of trifluoromethylbenzene (50 g, 210.11 mmol). The reaction mixture was purged with nitrogen and heated at 100°C for 16 hours. The reaction mixture was cooled to RT. The filtrate was then filtered through a Celite® pad and washed with Â. The material was washed with 1.5 M HCl, dried with Na2SO4, filtered, and evaporated. Crude material. Using petroleum ether and ¼ (0%~15%), column chromatography was performed using silica gel. The title compound was obtained as a yellow oil by purification using matrix imaging. 1 1H NMR (40 0MHz,CDCl3)δ(ppm)7.01(s,1H),6.88(s,1H),6 .82(s,1H),5.11(br s,1H),2.36(s,3H).LC-MS :Rt=0.95min;MS m / z 175.0[MH]-.

[0180] (2) 2-iodo-3-methyl-5-(trifluoromethyl)phenol, IntB00 7 [ka] In 370 mL of toluene, an ice-cold solution of IntB006 (13.03 g, 74 mmol) was added. NaH (dispersed in 60% mineral oil, 5.92g, 148 mmol) was added. The suspension was divided into 3 Stir at 0°C for 0 minutes, then gradually add iodine (18.77g, 74 mmol) in portions. The mixture was added and stirred for 3 hours. The mixture was diluted with water and acidified with 2M HCl until the pH was 5. The organic layer was converted and extracted with siRNA. The organic layer was washed with brine, dehydrated with Na2SO4, and filtered. It was evaporated. The crude product was treated with cyclohexane and ¼ (5% to 100%). The oil was purified by column chromatography using Ricagel (220g) and presented as a yellow oil. The target compound was obtained. 1 H NMR(400MHz,CDCl3)δ(ppm)7.08-7 .04(m,2H),5.74(s,1H),2.50(s,3H).LC-MS:Rt =1.11 min; MS m / z 301.0 [MH]-.

[0181] (3) 2-iodo-1-methoxy-3-methyl-5-(trifluoromethyl)benzene, IntB008 [ka] K2CO3 (24g, 172.22 mmol) in 300mL of anhydrous acetone, iodide Chill (8.1 mL, 129.13 mmol), and IntB007 (26 g, 86.09 A mixture of mmol was stirred at RT for 5 hours. It was then filtered, and the filtrate was evaporated. The residue is dissolved in CH2Cl2, washed with water, dried with Na2SO4, and filtered. The compound was evaporated to obtain the title compound as an off-white solid. 1 1H NMR (400MHz, CDCl3)δ(ppm)7.15(s,1H),6.84(s,1H),3.93(s ,3H),2.54(s,3H).

[0182] (4)2-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-4, 4,5,5-Tetramethyl-1,3,2-Dioxaborolane, IntB009 [ka] Pinacolborane (50.5 mL, 348.03 mmol), biphenyl-2-yl Dicyclohexylphosphan (2.44g, 6.96mmol), Pd(OAc)2(1 (0.55g, 6.96 mmol), and NET3 (48.5mL, 348.03 mmol) In 300 mL of anhydrous 1,4-dioxane (300 mL), IntB008 (22 g, 6 It was added to a 9.61 mmol solution. The reaction mixture was purged with nitrogen and left at 100°C for 16 hours. It was heated to [temperature]. After it cooled to RT, it was passed through a Celite® pad. The solution was filtered and washed with ethyl acetate. The filtrate was evaporated, and the residue was separated from petroleum ether and EtO Purification using Ac (0%~10%) by column chromatography on silica gel. The title compound was obtained as an off-white solid. 1 1H NMR (400MHz, CDC) l3)δ(ppm)7.02(s,1H),6.85(s,1H),3.84(s,3H ), 2.40 (s, 3H), 1.40 (s, 9H).

[0183] (5) (2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid IntB005 BBr3 (1M in CH2Cl2, 95 mL, 94.86 mmol) was incubated at 0°C for 150 ml. Add IntB009 (12g, 37.95 mmol) to L of anhydrous CH2Cl2 solution. The reaction mixture was stirred at 0°C for 30 minutes. After this, in order to maintain the pH at approximately 9, It was carefully poured into approximately 250 mL of 10% NaOH solution. The resulting mixture was CH Washed with 2Cl2. Separated the aqueous layer and adjusted the pH to 5 with 1.5M HCl. Precipitated the solid. It is then filtered, washed with petroleum ether, dried under vacuum, and left as an off-white solid. The title compound was obtained. 1 1H NMR (400MHz, CD3OD) δ (ppm) 6.9 4(s,1H),6.82(s,1H),2.29(s,3H).MS(ESI):m / z 219.8[MH]-

[0184] 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2) -yl)-5-(trifluoromethyl)phenol, IntB010 [ka] (1) 1-(ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl) Benzene, IntB011 [ka] (Chloromethoxy)ethane (3.35 g, 35.50 mmol) in 30 mL of dried DM IntB007 (8.50g, 28.10 mmol) and CS2CO3 (9.17g) The mixture was added dropwise to a white suspension of 28.10 mmol. The reaction mixture was then allowed to evaporate to dryness for 2 minutes. The mixture was stirred for RT. The crude product was treated with cyclohexane and toluene (0%~5%). The compound was purified by column chromatography using silica gel to obtain the title compound. LC- MS:Rt=1.39min.

[0185] (2) 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phen Nyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, IntB01 2 [ka] In 60 mL of 1,4-dioxane, IntB011 (10 g, 27.80 mmol), 4 ,4,5,5-tetramethyl-[1,3,2]dioxaborolane (20.15 mL, 13 Purge the solutions of 9 mmol) and NEt3 (28.6 mL, 205 mmol) with nitrogen. Pd(OAc)2 (0.81g, 3.61mmol) and biphenyl-2-yl Add dicyclohexylphosphan (2.33 g, 6.66 mmol) and mix the contents until 18 It was stirred at 80°C for 2 hours. Then it was cooled to RT, diluted with HCl, and saturated with NH4. The mixture was washed with Cl, water, and brine. The organic layer was dried with Na2SO4, filtered, and evaporated. The crude product is processed using cyclohexane and CH2Cl2 (0%~20%), and silica gel. The title compound was obtained by purification by column chromatography at LC-MS: Rt= 1.40 min.

[0186] (3) 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxavorola (2-yl)-5-(trifluoromethyl)phenol, IntB010 TFA (44.9 mL, 583 mmol) in 250 mL of CH2Cl2 at 0°C. It was gradually added to a solution of ntB012 (7.00 g, 19.43 mmol). (Reaction mixture) The mixture was stirred at 0°C for 20 minutes and then evaporated. The resulting oil was then treated with cyclohexane and Using CH2Cl2 (0%~100%), column chromatography with silica gel. The title compound was obtained by purification using the following method. 1 1H NMR (400MHz, DMSO-d6)δ (ppm)9.80(s,1H),6.92(s,1H),6.82(s,1H),2. 30(s,3H),1.30(s,12H).LC-MS:Rt=1.38min;MS m / z 301.1[MH]-

[0187] 3,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxavorola (2-yl)phenol, IntB013 [ka] (1) 2-iodo-3,5-dimethylphenol, IntB014 [ka] Dissolve 3,5-dimethylphenol (1 g, 8.2 mmol) in 40 mL of toluene. It was then cooled to 0°C. NaH (dispersed in 60% mineral oil, 655 mg, 16.4 mmol) Add the mixture in separate portions, stir the mixture at 0°C for 20 minutes, then at RT for 10 minutes, and finally re It was then cooled to 0°C. Iodine (2.08g, 8.2 mmol) was then added in portions and stirred. Stirring was continued for 30 minutes. The reaction mixture was quenched by adding 0.5M HCl, and E Extraction was performed with tOAc. The combined organic extracts were washed with water and brine, and dehydrogenated with Na2SO4. The mixture was diluted with water, filtered, and evaporated. The crude product was then treated with n-heptane and toluene (0%~20%). The sample was used and purified by column chromatography on silica gel (100g), followed by... Using n-heptane and ا(5%), a second (fixed composition) was performed, and off-white The title compound was obtained as a solid form of whitet. 1 1H NMR (400MHz, DMSO-d6) δ(ppm)10.07(s,1H),6.60(s,1H),6.51(s,1H), 2.30(s,3H),2.15(s,3H).LC-MS:Rt=1.03min;M S m / z 246.9[MH]-

[0188] (2) 1-(ethoxymethoxy)-2-iodo-3,5-dimethylbenzene, IntB0 15 [ka] In 6 mL of DMF, a solution of IntB014 (660 mg, 2.66 mmol) is added, along with CS2 CO3 (867 mg, 2.66 mmol) was added, followed by (chloromethoxy)ethane ( 311 μL (3.35 mmol) was added. The reaction mixture was stirred overnight at RT, and then water was added. It was then quenched and extracted with ethyl acetate. The combined organic extract was dried with Na2SO4. The mixture was dried, filtered, and evaporated. The crude product was then diluted with n-heptane and toluene (0%~10%). Using this method, the sample was purified by column chromatography with silica gel (50g), resulting in a yellow color. The title compound was obtained as an oil. 1 1H NMR (400MHz, DMSO-d6) δ (ppm )6.82(s,1H),6.74(s,1H),5.27(s,2H),3.69(q ,2H),2.35(s,3H),2.23(s,3H),1.13(t,3H).LC -MS:Rt=1.36min;MS m / z 307.2[M+H] +

[0189] (3) 2-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-4,4,5,5 -Tetramethyl-1,3,2-dioxaborolane, IntB016 [ka] In 2.5 mL of 1,4-dioxane, IntB015 (393 mg, 1.28 mmol) Add 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (373 μL) to the solution. (2.57 mmol) and NEt3 (537 μL, 3.85 mmol) were added, via The sample was purged with nitrogen. Pd(OAc)2 (14.4 mg, 64 μmol) and biphenyl Added ru-2-yl-dicyclohexylphosphan (45 mg, 0.128 mmol). The vial was sealed and heated at 80°C overnight. The reaction mixture was cooled to RT and diluted with water. It was then quenched and extracted with ethyl acetate. The combined organic extract was dried with Na2SO4. The mixture was dried, filtered, and evaporated. The crude product was then diluted with n-heptane and toluene (0%~20%). Using this method, the sample was purified by column chromatography with silica gel (50g) and was colorless. The title compound was obtained as an oil. 1 1H NMR (400MHz, DMSO-d6) δ (ppm )6.63(s,1H),6.60(s,1H),5.13(s,2H),3.64(q ,2H),2.23(s,3H),2.20(s,3H),1.29(s,12H),1 .12(t,3H).LC-MS:Rt=1.36min;MS m / z 307.2[ M+H] +

[0190] (4) 3,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxa Bororan-2-yl)phenol, IntB013 A solution of IntB016 (486 mg, 1.59 mmol) in 25 mL of CH2Cl2. The mixture was cooled to -30°C, and TFA (611 μL, 7.94 mmol) was gradually added. After a short time, the reaction was quenched at -30°C by adding water. The mixture was dissolved in 1M NaHCO3. The solution was neutralized by adding liquid and extracted twice with CH2Cl2. The combined organic extract was then used. The title compound was dried with Na2SO4, filtered, and evaporated to obtain a yellow oil. It was used without further purification. 1 1H NMR (400MHz, DMSO-d6)δ (ppm)8.72(s,1H),6.43(s,1H),6.38(s,1H),2. 24(s,3H),2.16(s,3H),1.30(s,12H).LC-MS:Rt =1.37min;MS m / z 249.2[M+H] +

[0191] (2-methoxy-4,6-dimethylphenyl)boronic acid, IntB017 [ka] 1-Methoxy-3,5-dimethylbenzene (1.04 mL, 7.34 mmol) and T MEDA (2.44 mL, 16.15 mmol) is dissolved in 16 mL of Et2O, and then nitrogen is used. Cooled to 0-5°C under normal conditions. n-BuLi(1.6M in hexane, 10.1 mL, 16 0.15 mmol) was added dropwise to a colorless solution while maintaining the temperature below 10°C. The results were as follows: The resulting yellow suspension was stirred at RT for 1 hour, and then cooled to -78°C. B(OMe)3 (1.15 mL, 10.28 mmol) should be kept at a temperature below -70°C. Then, it was added over a period of about 4 minutes. Stirring was continued at -78°C for 20 minutes, and then the reaction mixture was added. The mixture was heated overnight to RT. It was then quenched by adding water and diluted to pH 1 with 4M HCl. The mixture was acidified. The mixture was extracted three times with CH2Cl2, and the combined organic extract was evaporated. The residue was dissolved in MeOH and washed twice with n-heptane. The lower MeOH layer was evaporated. The title compound was obtained as a yellow semi-solid. LC-MS: Rt=0.74min; MS m / z 180.9[M+H] +

[0192] (2,4-dichloro-6-hydroxyphenyl)boronic acid and 3,5-dichloro-2-( 4,4,5,5-Tetramethyl-1,3,2-Dioxaborolan-2-yl)phenol IntB018 [ka] (1) 3,5-Dichloro-2-iodophenol, IntB019 [ka] NaH (dispersed in 60% mineral oil, 1.472g, 36.8 mmol) was incubated under nitrogen at 0°C. 30 mL of dry toluene contains 2.00 g of 3,5-dichlorophenol (12.27 mmol) The solution was divided and added to (1). The resulting mixture was heated to RT and stirred for 30 minutes. Mixed. The suspension was then cooled to 0°C, and iodine (2.49 g, 9.82 mmol) was added. It was added very slowly. The reaction mixture was stirred at 0°C for 1.5 hours, then 1M HCl was added. Quenched by adding [ingredient] and extracted with CH2Cl2. The organic extract was washed with brine and Na [ingredient]. Dehydrated with 2SO4, filtered, and evaporated. The crude product was treated with n-heptane and toluene (0%). Purification using ~50% silica gel by column chromatography (50g). The title compound was obtained as a yellow solid. 1 1H NMR (400MHz, DMSO-d6) )δ(ppm)11.32(s,1H),7.14(d,1H),6.81(d,1H) .LC-MS:Rt=1.09min;MS m / z 287.0[MH]-

[0193] (2) 1,5-Dichloro-3-(ethoxymethoxy)-2-iodobenzene, IntB0 20 [ka] (Chloromethoxy)ethane (1.004 g, 10.62 mmol) in 25 mL of DMF IntB019 (2.8g, 8.43mmol), and CS2CO3 (2.75g, 8 The suspension of 0.43 mmol was stirred at RT for 22 hours. The reaction mixture was dissolved by adding water. The layers were separated. The aqueous layer was extracted with CH2Cl2, and the combined organic extract was treated with Na2 The crude product was dried with SO4, filtered, and evaporated. n-heptane and toluene (0%) Using ~25%, the purity is measured by column chromatography with silica gel (100g). The compound was prepared and obtained as a brown solid. 1 1H NMR (400MHz, DMSO-d 6)δ(ppm)7.39(d,1H),7.13(d,1H),5.39(s,2H) ,3.69(q,2H),1.14(t,3H).

[0194] (3) 2-(2,4-dichloro-6-(ethoxymethoxy)phenyl)-4,4,5,5 -Tetramethyl-1,3,2-dioxaborolane, IntB021 [ka] In 15 mL of 1,4-dioxane, IntB020 (2.7 g, 7.78 mmol), 4 ,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1M in THF, 15. 56 mL, 15.56 mmol), and NET3 (3.25 mL, 23.34 mmol) The solution was purged with nitrogen for 30 minutes. Then, Pd(OAc)2(87 mg, 0.38 9 mmol) and biphenyl-2-yl-dicyclohexylphosphane (273 mg, 0 (0.778 mmol) was added, and the mixture was stirred at 80°C for 20 hours. The reaction mixture was saturated. Quenched by adding NH4Cl and separated the layers. The organic layer was washed with water and brine, and then It was evaporated to obtain an orange oil. The crude product was mixed with n-heptane and toluene (0%~ Using 20%, column chromatography with silica gel (100g) was performed. Then, using n-heptane and toluene (0%~5%), and silica gel (50g) The title compound was obtained as a pale yellow solid after purification by a second chromatography procedure. 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.17(d,1H),7. 11(d,1H),5.26(s,2H),3.64(q,2H),1.31(s,12 H), 1.12(t,3H).

[0195] (4) (2,4-dichloro-6-hydroxyphenyl)boronic acid and 3,5-dichloro- 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Knoll, IntB018 A solution of IntB021 (880 mg, 2.54 mmol) in 10 mL of CH2Cl2. The mixture was cooled to 0°C. TFA (3.91 mL, 50.7 mmol) was added, and the reaction mixture was analyzed. The mixture was stirred at 0°C for 1 hour. The mixture was quenched by adding saturated NH4Cl. The layers were separated. The organic extracts were separated and washed with water and brine. The solvent was evaporated, and the title compound was prepared as a mixture. The obtained solution was used without purification. LC-MS: Rt = 0.76 min and 1. 32 min; MS m / z 205.0 [MHz] and 289.0 [MHz + MHz] +

[0196] 3-Chloro-5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxy Saborolan-2-yl)phenol and 5-chloro-3-fluoro-2-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, IntB0 twenty two [ka] A mixture of positional isomers was prepared starting from 3-chloro-5-fluorophenol as described above. As described, it was synthesized in the same way as IntB018. LC-MS: Rt=1.25min .

[0197] (2-Hydroxy-4,6-bis(trifluoromethyl)phenyl)boronic acid, IntB 023 [ka] (2-methoxy-4,6-bis(trifluoromethyl)) in 10 mL of CH2Cl2 In a solution of nylboronic acid (500 mg, 1.736 mmol), BBr3 was added at 0°C under nitrogen. 1 M (8.68 mL, 8.68 mmol) of CH2Cl2 was added dropwise. The result The pale orange solution was heated to RT and stirred for 17 hours. The reaction mixture was then cooled in ice water (approximately 3 The solution was poured into 0 mL of water, and the pH was adjusted to 10 by adding 2 M NaOH. The aqueous layer was then separated. Then, the pH is acidified to 1 by adding 2M HCl, followed by CH2Cl2 and then Ânda Extraction was performed using [method]. The combined organic extracts were dried with Na2SO4, filtered, and evaporated. The crude product was prepared using CH2Cl2 and MeOH (0%~5%), and silica gel (25g). The title compound was purified by column chromatography and obtained as a beige solid. . LC-MS: Rt=0.81min; MS m / z 273.1[MH]-

[0198] Synthesis of 6-halo-pyridazine-3-amine intermediates (R)-6-chloro-N-(1-ethylpiperidine-3-yl)pyridazine-3-amine IntP024 [ka] 3,6-dichloropyridazine (3g, 20.13 mmol) and ( in 80 mL of NMP In a solution of R)-1-ethylpiperidine-3-amine (5.24 g, 22.15 mmol) Add DIPEA (17.59 mL, 101 mmol) and allow the reaction mixture to stand for 48 hours. The mixture was stirred at 0°C. It was then cooled to RT, poured into water, and extracted twice with Depositphotos. The combined organic layers were washed with brine, dehydrated with Na2SO4, filtered, and evaporated. The crude product was subjected to coloration using silica gel with CH2Cl2 and MeOH (0%~10%). The title compound was obtained by purification using LC-MS. LC-MS:Rt= 0.42 min; MS m / z 241.2 [M+H] +

[0199] (R)-6-chloro-N-(1-methylpiperidine-3-yl)pyridazine-3-amine IntP025 [ka] 4 mL of NMP contains 3,6-dichloropyridazine (500 mg, 3.26 mmol), ( R)-1-methylpiperidine-3-amine (379 mg, 3.32 mmol), and DI A mixture of PEA (505 mg, 3.91 mmol) was heated at 150°C for 4 hours. The mixture was cooled to RT and evaporated to dryness. The residue was dissolved in siRNA and Na2CO3 was added. Washed with saturated solution. The aqueous layer was extracted three more times with HCl. Combined organic extraction The substance is dried with Na2SO4, filtered, and evaporated to obtain a dark orange oil, and this Using MeOH (0%~10%) containing CH2Cl2 and 5% NH4OH, The title compound was obtained by purification using column chromatography on a 50g gel. 1 H NMR(600MHz,DMSO-d6)δ(ppm)7.34(d,1H),7 .00(d,1H),6.92(d,1H),4.03-3.93(m,1H),2.9 0-2.70 (m, 1H), 2.58-2.51 (m, 1H) overlap with DMSO signal. 2.19(s,3H),2.12-1.87(m,2H),1.84-1.75(m,1 H),1.74-1.64(m,1H),1.57-1.47(m,1H),1.37- 1.23(m,1H).LC-MS:Rt=0.34min;MS m / z 227.2 [M+H] +

[0200] (R)-6-chloro-N-(1-methylpiperidine-3-yl)-4-(trifluoromethyl (Tyl)pyridazine-3-amine, IntP026 and (R)-6-chloro-N-(1-amine (Tylpiperidine-3-yl)-5-(trifluoromethyl)pyridazine-3-amine, I ntP027 [ka] 3,6-dichloro-4-(trifluoromethyl)pyridazine in 5 mL of 1-butanol (3.4g, 15.67mmol), (R)-1-methylpiperidine-3-amine (2. 468 mL, 18.80 mmol), and DIPEA (8.21 mL, 47.0 mmol) The solution of ) was heated at 110°C for 20 hours. The reaction mixture was evaporated, and the crude product was prepared by CH2C Using l2 and MeOH (0%~10%), column chromatography was performed on silica gel (220g). Purified and separated by tography. IntP026 (first eluted) or IntP0 The fractions containing 27 (the second to elute) were combined separately and evaporated. Both products were then produced. Next, the organic extracts were individually partitioned between CH2Cl2 and 1M NaOH. The title compound Int was dried with a2SO4, filtered, and evaporated, respectively, to obtain a brown oil. P026 and IntP027 were obtained as a pale yellow solid. IntP026 (first to be eluted): 1 H-NMR (400 MHz, DMSO-d6) δ(p pm)7.91(s,1H),6.22(d,1H),4.44-4.27(m,1H) ,2.69-2.55(m,1H),2.42-2.28(m,1H),2.18(s, 3H, m, overlap with 2H), 1.71-1.58 (m, 3H), 1.56-1.43 (m, 1H).LC-MS:Rt=0.52min;MS m / z 295.1[M+H] + IntP027 (second to elute): 1 1H NMR (400MHz, DMSO-d6) δ( ppm)7.50(d,1H),7.39(s,1H),4.12-4.02(m,1H ),2.79-2.64(m,1H),2.46-2.37(m,1H),2.17(s (overlaps with 3H,m,1H), 2.08-1.98(m,1H), 1.81-1.63(m ,2H),1.58-1.46(m,1H),1.43-1.30(m,1H).LC- MS:Rt=0.59min;MS m / z 295.1[M+H] +

[0201] cis-((6-chloro-4-(trifluoromethyl)pyridazine-3-yl)amino)- 1-Methylcyclobutan-1-ol, IntP028 and cis-((6-chloro-5- (Trifluoromethyl)pyridazin-3-yl)amino)-1-methylcyclobutane-1 - All, IntP029 [ka] 3,6-dichloro-4-(trifluoromethyl)pyridazine in 5 mL of 1-butanol (1g, 4.61 mmol), cis-3-amino-1-methylcyclobutan-1-ol Hydrochloride (0.698g, 5.07mmol), and DIPEA (2.415mL, 13. A solution of 83 mmol was heated in a microwave apparatus at 180°C for 1 hour. Reaction mixing The material was partitioned between siRNA and a 10% NaHCO3 solution. The organic extract was washed with brine. The mixture was then dehydrated with Na2SO4, filtered, and evaporated. The crude product was then mixed with CH2Cl2 and MeOH. Using (0%~10%), column chromatography was performed with silica gel (40g). It was purified and separated. The product-containing fractions were combined separately, evaporated, and each was brown. The title compound IntP028 (first to elute) is an oil with a certain characteristic, and In is a pale yellow solid. tP029 (the second to elute) was obtained. IntP028 (first to be eluted): 1 H-NMR (400 MHz, DMSO-d6) δ(p pm)7.87(s,1H),6.91(d,1H),4.94(s,1H),4.19 -4.01(m,1H),2.44-2.35(m,2H),2.19-2.10(m, 2H),1.27(s,3H).LC-MS:Rt=0.82min;MS m / z 2 82.1[M+H] + IntP029 (second to elute): 1 1H NMR (400MHz, DMSO-d6) δ( ppm)7.83(d,1H),7.24(s,1H),5.06(s,1H),4.0 2-3.87(m,1H),2.46-2.37(m,2H),1.99-1.88(m ,2H),1.27(s,3H).LC-MS:Rt=0.82min;MS m / z 282.1[M+H] +

[0202] (R)-6-chloro-4-methyl-N-(1-methylpiperidine-3-yl)pyridazine -3-amine, IntP030 and (R)-6-chloro-5-methyl-N-(1-methyl Piperidine-3-yl)pyridazine-3-amine, IntP031 [ka] 3,6-dichloro-4-methylpyridazine (1.02 g, 6.26 mg) in 5 mL of NMP (mol), (R)-1-methylpiperidine-3-amine (0.986 mL, 7.51 mm A solution of (18.77 mmol) and DIPEA (3.28 mL, 18.77 mmol) was subjected to microwave irradiation. The mixture was heated under injection at 180°C for 2 hours. The reaction mixture was almost completely evaporated, and the residue was converted to CH2Cl2. The mixture was partitioned with 1M NaOH. The organic layer was washed with brine, dehydrated with Na2SO4, and filtered. Then, it was evaporated. The crude product was used with CH2Cl2 and MeOH (0%~20%), and silica Purified by column chromatography using Kagel (40g), with positional isomers in a ratio of approximately 1:3. The title compound was obtained as a mixture of the following. This mixture was further purified by chiral SFC. Separation (column: ChiralPak AY, 250×30mm, 5μm; 38℃, elution) Agent B: 35% EtOH + 0.1% NH4OH, Flow rate: 50 mL / min, Pressure: 100 bar (Cycle time: 8 minutes), the title compound IntP030 is shown as an orange oil. IntP031 (eluted secondly) was obtained as a brown solid (first eluted) and then as a brown solid. IntP030 (first to be eluted): 1 H-NMR (400 MHz, CDCl3) δ (ppm )6.99(s,1H),4.97(br s,1H),4.50-4.42(m,1H ),2.69-2.38(m,3H),2.25(s,3H),2.18-2.25(m ,1H)2.13(s,3H) overlap,1.89-1.77(m,1H),1.74-1 .67(m,1H),1.61-1.51(m,2H).LC-MS:Rt=0.40m in;MS m / z 241.1[M+H] + IntP031 (second to elute): 1 ¹H NMR (400 MHz, CDCl3) δ(pp) m)6.52(s,1H),5.13(br s,1H),4.08-3.97(m,1 H),2.65-2.33(m,3H),2.32-2.24(m,1H)2.26(s ,3H) and 2.25(s,3H) overlap, 1.75-1.69(m,1H), 1.69 -1.52(m,3H).LC-MS:Rt=0.43min;MS m / z 241. 1[M+H] +

[0203] Instead, the substituted pyridazine intermediate IntP030 is regioselective as described below. Prepared using root.

[0204] (R)-6-chloro-4-methyl-N-(1-methylpiperidine-3-yl)pyridazine -3-amine, IntP030 [ka] (1) 6-Chloro-2-(4-methoxybenzyl)-5-methylpyridazine-3(2H) -On, IntP032 [ka] 6-Chloro-4-methylpyridazine-3(2H)-one (25g, 173mmol), 1-(bromomethyl)-4-methoxybenzene (36.5g, 182 mmol), K2C O3 (47.8g, 346mmol), and Bu4NBr (2.79g, 8.65mmol) l) was dissolved in 300 mL of acetonitrile. The mixture was heated to 90°C, and 2.2 Stirred for 5 hours. Cool the mixture to RT and filter through a Celite® pad. The filtrate was evaporated to dryness under reduced pressure to obtain the title compound as a brown oil, which was then further refined. It was used in the next step without being prepared. LC-MS:=0.98min;MS m / z 265.1[M+H] +

[0205] (2)(R)-2-(4-methoxybenzyl)-5-methyl-6-((1-methylpiperyl Zin-3-yl)amino)pyridazine-3(2H)-one, IntP033 [ka] In 300 mL of dry toluene, IntP032 (30.5 g, 115.3 mmol), ( R)-1-methylpiperidine-3-amine (15g, 131 mmol), and CS2CO The mixture of 3 (75g, 231 mmol) was purged with nitrogen for 5 minutes. Then, Pd(O Ac)2 (1.3g, 5.79 mmol) and BINAP (8g, 12.85 mmol) The ingredients were added in order, and the reaction mixture was stirred under reflux for 3 hours. It was then cooled to RT, and C The filtrate was filtered using an elite® pad. The filtration cake was washed with toluene. The filtrate was then filtered. The compound is evaporated to dryness under reduced pressure to obtain the title compound as a brown oil, which is then further purified. It was used without any problems. LC-MS: Rt=0.51min; MS m / z 343.5[M+H ] +

[0206] (3)(R)-5-methyl-6-((1-methylpiperidine-3-yl)amino)pyrida Zin-3(2H)-on, IntP034 [ka] IntP033 (39.4g, 115 mmol) was dissolved in 250 mL of TFA. The dark brown mixture was stirred under reflux for 2 days. The reaction mixture was evaporated to dryness. The residue was then 2 It was dissolved in 00 mL of acetonitrile and 5 mL of water, and then evaporated again to dryness. The resulting black oil was dispersed with Et2O. The supernatant was removed, and the remaining brown oil was removed under high vacuum. The compound was dried to obtain the title compound, which was used without further purification. LC-MS :Rt=0.19 / 0.25min(injection peak);MS m / z 223 .2[M+H] +

[0207] (4)(R)-6-chloro-4-methyl-N-(1-methylpiperidine-3-yl)pyri Dazin-3-amine, IntP030 [ka] POCl3 (250 mL) in 250 mL of dry acetonitrile IntP034 (3 8.7 g was added to a 115 mmol solution, and the mixture was heated under reflux for 2.5 days. The mixture was cooled to RT and evaporated to dryness. The black oily residue was removed in 200 mL of acetone. It was dissolved in nitrile. This solution was added dropwise to an ice-cold saturated solution of Na2CO3 (significantly disintegrated). (Thermal). The pH was adjusted to >12 by adding 30% NaOH. This black mixture The solution was evaporated to dryness and then treated with a 1:1 mixture of CH2Cl2 and MeOH. This black suspension was stirred in RT for 30 minutes. Then, Celite (registered trademark) was added. Filter the filtered cake through a pad (standard), and add CH2Cl2 and MeOH (approximately 500 mL). The sample was further washed with a 1:1 mixture of ). The filtrate was evaporated to dryness and presented as a black solid. The compound was obtained and used without further purification. LC-MS: Rt=0.43m in;MS m / z 241.1[M+H] +

[0208] cis-((6-chloro-4-methylpyridazine-3-yl)amino)-1-methylcyclo Butan-1-ol, IntP035, and cis-((6-chloro-5-methylpyridazine -3-yl)amino)-1-methylcyclobutan-1-ol, IntP036 [ka] 1.9 mL of 1-butanol contains cis-3-amino-1-methylcyclobutan-1-O (309 mg, 2.392 mmol), 3,6-dichloro-4-methylpyridazine (3 (00 mg, 1.840 mmol), and DIPEA (1.3 mL, 7.36 mmol) The solution was heated in a microwave apparatus at 180°C for 90 minutes. The reaction mixture was evaporated. The orange crude oil was partitioned between RINKAN and a 2M Na2CO3 solution. The exudate was washed with brine, dehydrated with Na2SO4, filtered, and evaporated. The crude product was converted to CH2C Using l2 and MeOH (0%~5%), column chromatography was performed using silica gel (40g). The product was purified and separated by Raffy. The product-containing fractions were combined separately and evaporated. The title compound IntP035 (first to elute) is a beige solid, and the white compound is... IntP036 (the second to elute) was obtained as a solid. IntP035 (first to be eluted): 1 H-NMR (400 MHz, CDCl3) δ (ppm )7.02(s,1H),4.38(br s,1H),4.32-4.20(m,1H ),2.77-2.63(m,2H),2.11(s,3H),2.09-2.00(m ,2H),1.96(s,1H),1.45(s,3H).LC-MS:Rt=0.58 min;MS m / z 228.1[M+H] + IntP036 (second to elute): 1 ¹H NMR (400 MHz, CDCl3) δ(pp) m)6.52-6.47(m,1H),5.81-5.69(m,1H),3.91-3 .76(m,1H),2.76(s,1H),2.72-2.63(m,2H),2.2 9(d,3H),2.18-2.08(m,2H),1.43(s,3H).LC-MS :Rt=0.58min;MS m / z 228.1[M+H] +

[0209] cis-((6-chloropyridazine-3-yl)amino)-1-methylcyclobutane-1- All, IntP037 [ka] 8 mL of 1-butanol contains 3,6-dichloropyridazine (1 g, 6.71 mmol), cis-3-amino-1-methylcyclobutan-1-ol (0.970g, 7.05mm) A solution of (1 ol) and DIPEA (4.1 mL, 23.49 mmol) is microwaved. The mixture was heated at 180°C for 1 hour. The reaction mixture was poured over water and extracted three times with toluene. The combined organic extracts were washed with brine, dehydrated with Na2SO4, filtered, and evaporated. The crude product is dispersed in acetonitrile for 20 minutes, filtered, and washed again with acetonitrile. The title compound was obtained as a beige solid. 1 H-NMR (400MHz, DMSO-d 6) δ(ppm) 7.33 (overlapping d, 1H and br s, 1H), 6.84 (d, 1H ),4.98(s,1H),3.91-3.78(m,1H),2.42-2.34(m ,2H),1.96-1.86(m,2H),1.26(s,3H).LC-MS:Rt =0.53min;MS m / z 214.1[M+H] +

[0210] (1S,3R)-3-((6-chloropyridazine-3-yl)amino)cyclohexane- 1-All, IntP038 [ka] 3,6-Dichloropyridazine (100 mg, 0.671 mmol), (1S,3R)- 3-aminocyclohexane-1-ol (102 mg, 0.671 mmol), and DI A solution of PEA (0.352 mL, 2.014 mmol) was heated in a microwave oven for 1 hour. It was heated to 180°C. The residue was dissolved in toluene and washed with saturated NaHCO3 and brine. The solution was purified, dried with Na2SO4, filtered, and evaporated. CH2Cl2 and MeOH (0%) Column chromatography using silica gel (12g) with ~10% adhesion The title compound was obtained as a solid of the same sex. LC-MS: Rt=0.55min; MS m / z 228.1[M+H] +

[0211] (R)-3-chloro-6-((1-methylpiperidine-3-yl)oxy)pyridazine, IntP039 [ka] 1 mL of 1,4-dioxane contains 150 mg of 3,6-dichloropyridazine (1.0 mm (ol) and (R)-3-hydroxy-1-methylpiperidine (128 mg, 1.1 mmol) l) Add NaH (60% of mineral oil, 161 mg, 4.0 mmol) gradually to the ice-cold mixture. The suspension was then stirred at 0°C for 1 hour. Next, water was carefully added to quench it. The solution was acidified with 1M HCl. The aqueous layer was separated, washed with siRNA, and then saturated with Na2C. The solution was made basic by adding an O3 solution and extracted with dimethyl alcohol. The organic extract was evaporated and the crude solution was removed. The product was prepared using CH2Cl2 and MeOH (0%~20%) and silica gel (25g). The title compound was obtained as a colorless oil by purification using column chromatography. 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.76(d,1H),7.31 (d,1H),5.22-5.14(m,1H),2.90-2.82(m,1H),2 .48-2.43 (m, 1H) overlaps with DMSO signal, 2.24-2.19 (m, 1H) ),2.17(s,3H),2.14-2.05(m,1H),2.02-1.92(m ,1H),1.79-1.72(m,1H),1.55-1.50(m,2H).LC- MS:Rt=0.36min;MS m / z 228.2[M+H] +

[0212] The following pyridazine intermediates (IntP) are used with the corresponding 3,6-dihalopyridazine and appropriate Using an amine, prepare the solution in the same manner as described above, and optionally continue with the deprotection step. .

[0213] [Table 2]

[0214] [Table 3]

[0215] [Table 4]

[0216] [Table 5]

[0217] [Table 6]

[0218] [Table 7]

[0219] [Table 8]

[0220] [Table 9]

[0221] Further modification of piperazine intermediates: 1-((R)-3-((6-chloropyridazine-3-yl)amino)piperidine-1-yl (L) Propane-2-ol, IntP105 [ka] IntP100 (200 mg, 0.621 mmol), K2CO3 (429 mg, 3 (0.11 mmol) and 1-chloropropan-2-ol (0.23 mL, 1.86 mmol) Before adding (1), it was dissolved in 2 mL of DMF. The yellow suspension was left at 100°C for 4.5 hours. Next, the mixture was stirred at 120°C for 1.5 hours. The mixture was cooled to RT and diluted with a small amount of water. The compound was purified by achiral reverse-phase HPLC, yielding the title compound as a pale yellow solid. LC- MS:Rt=0.40min;MS m / z 271.2[M+H] +

[0222] (R)-1-(3-((6-chloropyridazine-3-yl)amino)piperidine-1-yl (Lu)-2-methylpropan-2-ol, IntP106 [ka] The title compound was prepared using IntP100 and 1-chloro-2-methylpropan-2-ol. Using the same procedure as described above, IntP105 was synthesized. LC-MS: Rt=0.47min; MS m / z 285.3[M+H] +

[0223] Synthesis of selected amines for the above intermediates (R)-2-(3-aminopiperidine-1-yl)ethane-1-ol dihydrochloride IntA107 [ka] (1) tert-butyl(R)-(1-(2-hydroxyethyl)piperidine-3-yl ) Carbamate, IntA108 [ka] 100 mL of acetonitrile contains tert-butyl(R)-piperidine-3-ylcarb Mate (10g, 49.9mmol), 2-bromoethane-1-ol (6.24g, 4 A suspension of 9.9 mmol) and Na2CO3 (10.58 g, 100 mmol) is prepared in two separate containers. The mixture was stirred at RT for several days. The suspension was filtered, and the solid was washed several times with acetonitrile. The filtrate was evaporated. The residue was then used with CH2Cl2 and MeOH (0%~10%). The compound was purified by column chromatography using silica gel to obtain the title compound. LC- MS:Rt=0.40min;MS m / z 245.1[M+H] +

[0224] (2)(R)-2-(3-aminopiperidine-1-yl)ethane-1-oldihydro Lorido, IntA107 A solution of IntA108 (10.0 g, 40.9 mmol) in 20 mL of CH2Cl2. , treated with 4M HCl in 1,4-dioxane (40.9 mL, 164 mmol). The mixture was stirred at RT for 3 hours. The precipitate was filtered and sterilized several times with 1,4-dioxane. The sample was washed and dried overnight at 60°C under high vacuum to obtain the title compound. LC-MS:R t=0.15min; MS m / z 145.2[M+H] +

[0225] 1-(tert-butyl)2-methyl5-aminopiperidine-1,2-dicarboxylate T, IntA109 [ka] (1) 1-(tert-butyl)2-methyl5-hydroxypiperidine-1,2-dical Boxylate, IntA110 [ka] 1-tert-butyl-2-methyl5-oxopiperidine-1,2-dicarboxylate Dissolve (500 mg, 1.943 mmol) in 15 mL of MeOH and cool to 0°C. Rejected. NaBH4 (73.5 mg, 19.43 mmol) was added in separate doses. 3 hours After stirring, half of the MeOH was removed under reduced pressure. The residue was diluted with Depositphotos, and 0.5 The organic extracts were subsequently washed with M HCl, 0.5 M NaOH, and brine. The mixture was dried in 4, filtered, and evaporated to obtain the title compound as a colorless oil. (Diastereomer) The mixture was used without further purification. 1 H-NMR (400 MHz, DMSO) -d6)δ(ppm)4.95(d,1H),4.70-4.54(m,1H),3.9 7-3.84(m,1H),3.68 and 3.67(2s(diastereomer),3H) ,3.42-3.29(m,2H),2.11-2.05(m,1H),1.85-1. 72(m,1H), 1.72-1.58(m,1H), 1.41 and 1.36(2s(ji Astereomer), 9H), 1.04-0.94(m,1H).

[0226] (2) 1-(tert-butyl)2-methyl5-azidopiperidine-1,2-dicarboxy Silate, IntA111 [ka] Dissolve IntA110 (526 mg, 1.927 mmol) in 10 mL of toluene. , PPh3 (1.064g, 4.06mmol) and Zn(N3)2 (468mg, 1 The mixture was treated with 0.521 mmol) by RT. To this mixture, DIAD (0.789 mL, 4.06 mmol) was then added dropwise. After stirring at RT for 4 hours, the reaction mixture was heated to a high temperature. The solution was filtered through iodine and washed with ammonium. The filtrate was evaporated, and the crude product was obtained as n-heptane. And using ¼ (10%~80%), column chromatography with silica gel (50g) The title compound was obtained as a mixture of diastereomers by purification using Graph. 1 H- NMR(400MHz,DMSO-d6)δ(ppm)4.88-4.63(m,1H) ,4.05-3.90(m,2H),3.68(s,3H),3.19-2.97(m, 1H),1.99-1.78(m,2H),1.72-1.63(m,1H),1.55 -1.47 (m, 1H), 1.41, and 1.39 (2s (diastereomer), 9H).

[0227] (3) 1-(tert-butyl)2-methyl5-aminopiperidine-1,2-dicalk Silate, IntA109 Pd / C (159 mg, 0.15 mmol, 10% Pd content) in 10 mL MeOH In the suspension, add IntA111 (426 mg, 1.498 mmol) in 30 mL of MeOH. The solution was added. The mixture was hydrogenated at atmospheric pressure for 1 hour at RT. The mixture of diastereomers was filtered through a (registered trademark) pad and washed with alkyl substances. To obtain the title compound as a physical substance, the filtrate was evaporated and used without further purification. 1 H-NMR(400MHz,DMSO-d6)δ(ppm)4.75-4.5(m,1H ),3.65(s,3H),3.59-3.52(m,1H),3.31(s,2H), 3.15-2.86(m,2H),2.16-2.02(m,1H),1.82-1.7 Overlaps with 1(m,1H), 1.49-1.40(m,2H), and 1.38(s,9H).

[0228] Synthesis of the Examples Example Ex001 (R)-2-(6-((1-ethylpiperidine-3-yl)amino)pyridazine-3-yl (Lu)-3-methyl-5-(trifluoromethyl)phenol [ka] IntP024 (770 mg, 1.663 mmol) and IntB010 (754 mg) Dissolve 2.495 mmol of (2.495 mmol) in 8 mL of 1,4-dioxane and prepare 2 M Na2CO2 3 (0.25 mL, 0.499 mmol) was added. Then Pd(Ph3P)4(9 Add 6 mg (0.083 mmol), purge the reaction mixture with nitrogen for 5 minutes, and then, The mixture was stirred at 120°C for 1 hour under microwave irradiation. The reaction mixture was poured into water and toluene was added. It was extracted twice. The combined organic extracts were evaporated, and the residue was divided into CH2Cl2 and Me Purification using OH (0%~10%) by column chromatography on silica gel. And thus, the title compound was obtained. 1 1H NMR (600MHz, DMSO-d6) δ(p pm)10.14(s,1H),7.22(d,1H),7.10(d,1H),7.0 4(d,1H),6.88(d,1H),6.75(d,1H),4.07(s,1H) ,2.97(s,1H),2.37(s,3H),2.13(s,3H),2.08-1 .83(m,3H),1.78-1.67(m,1H),1.60-1.48(m,1H ),1.39-1.27(m,1H),1.01(t,3H).LC-MS:Rt=0. 42 min; MS m / z 241.3 [M+H] +

[0229] Example Ex002 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridadi (-3-yl)-3-methyl-5-(trifluoromethyl)phenol [ka] 1 mL of DME and 1 mL of water containing In...

Claims

1. A pharmaceutical composition for treating a disease or disorder in which NLRP3 signaling contributes to the abnormality, and / or symptoms, and / or progression of the disease or disorder, comprising the following formula: 【Transformation 5】 Use of the compound or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises the compound or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

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