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] The present invention relates to inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The present invention relates to novel pyridazin-3-ylphenol compounds useful as medicaments. Processes for the preparation of the compounds, pharmaceutical compositions containing said compounds, and methods for treating various diseases and disorders. and methods of using said compounds in the treatment of NLRP3-induced It also relates to their use in treating 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). and is also known as "pyrin domain-containing protein 3" (Inoue et al. l., Immunology, 2013, 139, 11-18). This gene is involved in the transcription of pyrimidine dehydrogenase (PDH) domain, nucleotide binding domain (NBD) and leucine-rich repeat (LR In response to sterile inflammatory danger signals, NLRs encode proteins that contain the . P3 is an adaptor protein that encodes the apoptosis-associated speck-like protein (ASC). and procaspase-1 to form the NLRP3 inflammasome. RP3 inflammasome activation then upregulates the inflammatory cytokine IL-1β (IL-1β). release of IL-1β and IL-18, resulting in dysregulation can cause abnormalities in many disease settings.

[0003] NLRP3 inflammasome activation normally involves two steps. TEPs are classified as pathogen-activating molecular patterns (PAMPs) or danger-activating molecular patterns (DAMs). P) is recognized by Toll-like receptors and induces nuclear factor kappa B (NF-κB)-mediated signaling. This in turn results in the activation of inactive NLRP3 and pro-IL-1β (proIL-1β). Upregulating the transcription of inflammasome-associated components, including IL-1β It is accompanied by priming signals such as preregulation (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). TEP regulates NLRP3 oligomerization and the expression of NLRP3, ASC, and procaspase-1. The subsequent assembly of the procaspase-1 caspases into the inflammasome complex. Triggers conversion to IL-1β 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). Summary of the Invention [Problem to be solved by the invention]

[0004] NLRP3 inflammasome activation is implicated in various inflammasome-associated diseases / disorders , immune disorders, inflammatory disorders, autoimmune disorders and autoinflammatory disorders, e.g. cryopyrin-associated peripheral inflammatory diseases, Autoinflammatory fever syndromes such as chronic acute myocardial infarction syndrome (CAPS) (Mortimer et al. Nature Immunol.2016,17(10),1176-1188); Sickle systemic lupus erythematosus (SLE); chronic liver disease, viral hepatitis, non-alcoholic Nonalcoholic fatty liver disease (NASH), alcoholic fatty liver disease, and alcoholic liver disease Liver-related diseases / disorders such as those listed in Petrasek et al. J. Clin. 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 (cartilage calcification), osteoarthritis (Ridker et al. .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), hemodialysis-related inflammation and diabetic Kidney-related complications of diabetes (type 1, type 2 and diabetes mellitus), also known as renal disease. Kidney-related diseases such as diabetic nephropathy (Shahzad et al. ney Int. 2015, 87, 74-84). Therefore, the involvement of the NLRP3 inflammasome in increased production of IL-1β and IL-18 is unclear. , disorders associated with neuroinflammation, such as brain infections, acute injuries, multiple sclerosis, Alzheimer's - and neurodegenerative diseases (Shao et al. Front. Pharmacol. 2013). 15,6,262); cardiovascular / metabolic disorders / diseases, e.g., cardiovascular risk reduction (CvRR) ), atherosclerosis, type I and type II diabetes and related complications (e.g., nephropathy , retinopathy), peripheral arterial 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, e.g. For example, acne vulgaris, hidradenitis suppurativa (Sweeney et al Br. J. Dermatol. 20 15,173,1361), asthma, sarcoidosis, age-related macular degeneration; cancer-related Diseases / disorders, e.g. myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), 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, 3204-18) and may be a factor in the onset and progression of various diseases. Those diseases / disorders that are immune or inflammatory in nature are usually difficult to diagnose efficiently. Most treatments focus on treating symptoms, slowing the progression of the disease / disorder, and slowing down, lifestyle changes and surgery as a last resort (e.g. atherosclerosis) Recent research has shown that the progression of the disease is related to the Linking mitochondrial dysfunction and NLRP3 activation in neuroinflammation-related diseases (Sarkar et al. 2017,3:30;Zhou et al Nature,2011,469,221 One of the main problems associated with mitochondrial modifiers is their poor metabolic stability. Therefore, selective and stable inhibition of neuroinflammation of this nature is Agents are needed (Lee et al Eur J.Org.Chem.2017,1 41,240).

[0005] Therefore, these inflammasome-related diseases / disorders as well as autoinflammatory fever syndromes, Cryopyrin-associated periodic syndromes (e.g., CAPS), sickle cell disease, chronic liver disease, non-alcoholic fatty liver disease, Nonalcoholic steatohepatitis (NASH), gout, hyperoxaluria, pseudogout (cartilage calcification), Related to type I / II diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammation Disorders (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease) ), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvR R), hypertension), sweat gland abscesses, wound healing and scarring, and cancer (e.g., colon cancer, lung cancer, Other conditions such as myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis, etc. To provide new and / or alternative treatments for NLRP3 inflammasomes, Inhibitors of this pathway are needed. [Means for solving the problem]

[0006] The present invention relates to a compound or a pharma- ceutically acceptable salt thereof, a pharmaceutical composition thereof, and a combination thereof. The present invention provides a compound that inhibits the NLRP3 inflammasome pathway. A method for treating or preventing a disease and / or disorder associated with 3, comprising administering to a subject person skilled in the art a compound of the present invention. and administering to a subject in need thereof an effective amount of the compound or a pharma- ceutical acceptable salt thereof. The present invention further provides a method comprising:

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

[0008] In one embodiment, the compound of formula (I): [ka] (In the formula, R 1 is Cl, CH3, -OCF3, or CF3; R 2 is H, halo, C1-C4 alkyl, or haloC1-C4 alkyl; R 3 , R 4 is H, CN, C1-C4 alkyl, or haloC1-C4 alkyl; Z is -O- or -NH-(CH2) n -wherein n is 0, 1, or 2; R 5 is C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl , -OH, halo, oxo, and -CO2H. or R 5 from halo, haloC1-C4 alkyl, C1-C4 alkyl, and -SO2NH2 Aryl or heterocyclic optionally substituted with 1 to 2 independently selected substituents is a aryl; or R 5 is independently selected from C1-C4 alkyl, halo, haloC1-C4 alkyl, and -OH. C3-C6 cycloalkyl optionally substituted with 1 to 3 selected substituents. or R 5 is -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl ), and one or more substituents independently selected from -N(C1-C4 alkyl)2 is a substituted C2-C6 alkyl or a pharma- ceutically acceptable salt thereof.

[0009] In another aspect, the present invention provides a therapeutically effective amount of a compound represented by formula (I) or or a pharma- ceutically acceptable salt thereof and one or more A pharmaceutical composition is provided that includes a pharma- ceutical carrier. The pharmaceutical composition is for use in treating NLRP3 activity. They are useful in the treatment of associated diseases and / or disorders.

[0010] In another aspect, the present invention provides a therapeutically effective amount of a compound represented by formula (I) or or a pharma- ceutically acceptable salt thereof and one or more Combinations, particularly pharmaceutical combinations, that include therapeutic agents are provided.

[0011] In another aspect, the present invention provides a composition disclosed herein for use as a medicament. Combinations, particularly pharmaceutical combinations, are provided.

[0012] In another aspect, the present invention relates to a disease or disorder, wherein NLRP3 signaling is a factor in said disease or disorder. Contributing to the pathology and / or symptoms and / or progression of a disease or disorder, A compound of formula (I) or a subformula thereof disclosed herein for use in or a pharma- ceutically acceptable salt thereof.

[0013] In another aspect, the present invention relates to a disease or disorder, wherein NLRP3 signaling is a factor in said disease or disorder. Contributing to the pathology and / or symptoms and / or progression of a disease or disorder The method comprises administering to said patient a therapeutically effective amount of a compound of formula (I) or a moiety thereof as disclosed herein. The method includes administering a compound of the formula or a pharma- ceutically acceptable salt thereof.

[0014] In another aspect, the present invention provides a method for inhibiting NLRP3 inflammasome activity in a subject requiring the inhibition of NLRP3 inflammasome activity. The method comprises administering to a subject having a tumor comprising administering to said subject a therapeutically effective amount of a compound of the formula (I) disclosed herein. I) or a subformula thereof, or a pharma- ceutically acceptable salt thereof, The method includes administering to a subject

[0015] Another aspect of the present invention is a compound of formula (I) or its derivatives disclosed herein as a medicament. or a pharma- ceutically acceptable salt thereof.

[0016] Another aspect of the present invention is a compound of formula (I) disclosed herein for use as a medicament. ) or a subformula thereof or a pharma- ceutically acceptable salt thereof.

[0017] Another aspect of the present invention is a method for treating inflammasome-associated diseases / disorders, immune diseases, and inflammatory diseases. , an autoimmune disease, or an autoinflammatory disease. The present invention relates to a compound of formula (I) or a subformula thereof, or a pharmaceutical composition thereof, for use in treating Also provided are physiologically acceptable salts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Therefore, the present invention provides a compound of formula (I): [ka] (In the formula, R 1 is Cl, CH3, -OCF3, or CF3; R 2 is H, halo, C1-C4 alkyl, or haloC1-C4 alkyl; R 3 , R 4 is H, CN, C1-C4 alkyl, or haloC1-C4 alkyl; Z is -O- or -NH-(CH2) n -wherein n is 0, 1, or 2; R 5 is C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl , -OH, halo, oxo, and -CO2H. or R 5 from halo, haloC1-C4 alkyl, C1-C4 alkyl, and -SO2NH2 Aryl or heterocyclic optionally substituted with 1 to 2 independently selected substituents is a aryl; or R 5 is independently selected from C1-C4 alkyl, halo, haloC1-C4 alkyl, and -OH. C3-C6 cycloalkyl optionally substituted with 1 to 3 selected substituents. or R 5 is -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl ), and one or more substituents independently selected from -N(C1-C4 alkyl)2 is a substituted C2-C6 alkyl The present invention provides a compound of the formula:

[0019] definition For purposes of interpreting this specification, the following definitions shall apply unless otherwise specified, as appropriate: Where applicable, terms used in the singular will also include the plural and vice versa.

[0020] As used herein and in the appended claims, in connection with the present invention (and in particular in the claims), The singular forms "a," "an," and "the" used in connection with the claims are "(the)" and similar terms are used unless or until the context clearly indicates. Unless expressly stated to the contrary, the terms "a," "the" and "the" should be construed as including both singular and plural referents. Thus, for example, reference to "a compound" includes one or more compounds. Includes references to things, etc.

[0021] As used herein, the term "C2-C6 alkyl" refers to an alkyl group consisting entirely of carbon atoms. It consists of a cyclic alkyl group and a hydrogen atom, does not contain unsaturation, has 2 to 6 carbon atoms, and is connected by a single bond. refers to a straight or branched hydrocarbon chain radical attached to the rest of the molecule through a cyclic alkyl group, as defined herein. The "C2-C6 alkyl" is a group having one or more substituents, preferably 1 to 13 substituents. More preferably, the alkyl group is optionally substituted with 1 to 8 substituents. The term "C1-C4 alkyl" should be interpreted accordingly. Examples of 2-C6 alkyl are ethyl, n-propyl, 1-methylethyl (isopropyl). , n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The present invention is not limited to these.

[0022] As used herein, the term "haloC1-C4 alkyl" or "halogen "C1-C4 alkyl" means a group, as defined above, substituted by one or more halo radicals. Halogen refers to a C1-C4 alkyl radical as defined above. Examples of alkyl are trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl. 2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo bromo-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 a group of the formula -OR a of R refers to the radical a is a C1-C4 alkyl radical, as generally defined above Examples of "C1-C4 alkoxy" are methoxy, ethoxy, propoxy, isopropoxy, and alkoxy. Examples of alkoxy include, but are not limited to, butoxy, butoxy, and isobutoxy.

[0024] As used herein, the term "hydroxy C1-C4 alkyl" refers to a C1 C1-C4 alkyl radicals in which one of the hydrogen atoms is replaced by OH Examples of hydroxy C1-C4 alkyl are hydroxy-methyl, 2- Hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl, and 4- Including but not limited to hydroxy-butyl.

[0025] As used herein, the term "halogen" or "halo" refers to bromo, chloro, Refers to b, fluoro, or iodo.

[0026] As used herein, the term "heterocyclyl" or "heterocyclic" refers to a heterocyclic ring system having a ring structure of 3 A stable 5-membered ring having 1 to 24, preferably 4 to 16, and most preferably 5 to 10 ring atoms. 1 or 6-membered non-aromatic monocyclic, bicyclic or polycyclic ring radicals, preferably or 1 to 4, in particular 1 or 2, ring atoms are selected from, for example, oxygen, sulfur, and nitrogen; The remaining ring atoms are therefore carbon. The term excludes heteroaryl. Heterocyclic groups are selected from, for example, oxygen, sulfur, nitrogen, and the like. It can be attached to the remainder of the molecule through any selected heteroatom or carbon atom. Aryl can include, for example, fused or bridged rings and spiro rings. "Terocyclyl" refers to a cyclic ring system having one, two, or three heteroatoms selected from oxygen, nitrogen, and sulfur. Examples of monoheterocyclyls include dihydropyridine, ... Furanyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, di Hydropyranyl, oxathiolanyl, dithiolane, oxathianyl, thiomorpholino, o Xylanyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydro Furanyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl nyl, morpholino, piperazinyl, oxapinyl, oxazepanyl, oxatianyl, Thiepanyl, azepanyl, dioxepanyl, and diazepanyl are preferred. Heterocyclyl is morpholino, pyrrolidine, or piperidinyl. Examples of cryl include, for example, azabicyclooctanyl or octahydroindolizinyl. In the present invention, the term "heterocyclyl" substituted by an "OH" substituent also refers to a heterocyclyl. Heteroatoms, such as N or S, may be oxidized, e.g., heterocyclyl N-oxide, heterocyclyl Heterocyclyl S-oxide or heterocyclyl S-dioxide are obtained by Examples of heterocyclyl N-oxides include piperidinyl-N-oxides. Tylpyrrolidine 1-oxide. Heterocyclyl S-oxide or Heterocyclyl S-dioxide Examples of oxides are tetrahydro-2H-thiopyran-1-oxide, tetrahydro-2H- Thiopyran-1,1-dioxide, and tetrahydrothiophene-1-oxide.

[0027] As used herein, the term "heteroaryl" refers to any group containing nitrogen, oxygen, and sulfur. Yellow, a 5- or 6-membered aromatic ring containing 1, 2, 3, or 4 heteroatoms, A heteroaryl radical is a monocyclic ring radical. Examples of heteroaryl are furyl, pyrrolyl, thienyl, pyrazolyl, Imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl Zolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, or pyridyl, , but not limited to these.

[0028] As used herein, the term "C3-C6 cycloalkyl" refers exclusively to A stable monocyclic or bicyclic ring consisting of carbon and hydrogen atoms and having 3 to 10 carbon atoms. The term bicyclic cycloalkyl also refers to a s- or tricyclic saturated hydrocarbon radical. It also includes pyrobicyclic cycloalkyl. Examples of monocyclic C3-C6 cycloalkyl are cyclopro Cyclohexyl, cyclobutyl, cyclopentyl, and cyclohexyl. No. Bicyclic C3~C 10 Examples of cycloalkyl include bicyclo[1.1.1]pentane. However, this is not limited to this.

[0029] As used herein, the term "aryl" refers to an aryl group having 6 to 20 carbon atoms in the ring portion. Aryl refers to an aromatic hydrocarbon group that has 6 to 20 carbon atoms. In a preferred embodiment, the aryl is It is phenyl.

[0030] Unless otherwise specified, the term "compounds of the invention" refers to compounds of formula (I) and subformulas thereof, A compound of formula (II), a compound of formula (III), or a compound of formula (II IA) and their salts and all stereoisomers (diastereoisomers and isomers, rotamers, tautomers, and isotopically labeled compounds (including deuterium-substituted isomers). The term "compound of the invention" refers to one or more of the embodiments described below. "Compounds" refers to compounds as defined in any one of the above aspects.

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

[0032] In embodiment 1, the present invention relates to a compound of formula (I) or a pharmaceutical composition thereof, as described above. The present invention provides a physiologically acceptable salt thereof.

[0033] In embodiment 2, the present invention provides a compound of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, according to embodiment 1, In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is as defined in embodiment 1. do.

[0034] In embodiment 3, the present invention provides a compound of formula (III): [ka] or a pharma- ceutically acceptable salt thereof, according to embodiment 1, In the formula, n is 0, 1, or 2; R 1 , R 2 , R 3 , R 4 , and R 5 In embodiment 1 As defined in

[0035] In embodiment 3a, according to embodiment 3, the present invention provides a compound of formula (III-A): [ka] or a pharma- ceutically acceptable salt thereof, In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is as defined in embodiment 1. do.

[0036] In embodiment 4, the present invention relates to a compound of formula (I), (II) according to embodiment 1, 2, 3 or 3a. (III), (III-B), or a pharma- ceutically acceptable salt thereof. providing a salt, wherein R 5 is C1-C4 alkyl, halo C1-C4 alkyl, hydroxy 1 independently selected from C1-C4 alkyl, -OH, halo, oxo, and -CO2H is a mono- or bicyclic heterocyclyl optionally substituted with 1 to 2 substituents.

[0037] In embodiment 5, the present invention relates to a compound represented by formula (I), (II), (III) and (III-A) or a pharma- ceutically acceptable salt thereof; In the formula, R 5 is selected from: [ka] R 5a are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H. Selected; and R 5b is -OH, hydroxy C1-C4 alkyl, H, halo, oxo, independently selected from haloC1-C4 alkyl, and -CO2H; X is O or CH2 and m is 0 or 1.

[0038] In embodiment 5a, according to embodiment 5, the present invention provides a compound represented by formula (I), (II), (III) or a pharma- ceutically acceptable salt thereof, In the formula, R 5 is selected from: [ka] R 5a are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H. Selected; and R 5b is -OH, C1-C4 alkyl, hydroxy C1-C4 alkyl , H, halo, oxo, haloC1-C4 alkyl, and -CO2H; X is O or CH2; and m is 0 or 1.

[0039] In embodiment 5b, according to embodiments 5 and 5b, the present invention relates to a compound represented by formula (I), (II), ( III), and (III-A) or a pharma- ceutically acceptable salt thereof. wherein R 5 are as described herein above and are marked with "*" The configuration at the carbon atom to which Z is attached is (R) or (S). Preferably, Z is -NH-(C H2) n -, and when n=1 or 2, the configuration at the carbon marked with an "*" is (S). Preferably, Z is -O- or -NH-(CH2) n - and n=0 In some cases, the configuration at the carbon marked with an "*" is (R).

[0040] In embodiment 5c, in accordance with embodiments 5, 5a, and 5b, the present invention provides a compound represented by the formula (I), (I Any one of compounds of I), (III), and (III-A) or a pharma- ceutically acceptable salt thereof and providing a salt of formula R 5 is preferably selected from the following structures: [ka] R 5a are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H. Selected; and R 5b is -OH, C1-C4 alkyl, hydroxy C1-C4 alkyl , H, halo, oxo, haloC1-C4 alkyl, and -CO2H; and m is 0 or 1.

[0041] In embodiment 5d, according to embodiments 5, 5a, 5b and 5c, the present invention provides a compound of formula (I) (II), (III), and (III-A) or a pharmacopoeial compound thereof. Acceptable salts are provided, wherein R 5 is preferably selected from the following structures: [ka] R 5a are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H. Selected; and R 5b is -OH, C1-C4 alkyl, hydroxy C1-C4 alkyl , H, halo, oxo, haloC1-C4 alkyl, and -CO2H; and m is 0 or 1.

[0042] In embodiment 5e, according to embodiments 5, 5a, 5b, 5c, and 5d, the present invention provides a compound of formula Any one of the compounds (I), (II), (III), and (III-A) or a drug thereof and providing a physiologically acceptable salt thereof, wherein R 5 preferably has the structure: [ka] R 5a are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl, and H. It is selected.

[0043] In embodiment 6, the present invention relates to a compound of formula (I), (II) according to embodiment 1, 2, 3 or 3a. (III), (III-B), or a pharma- ceutically acceptable salt thereof. providing a salt, wherein R 5 is halo, haloC1-C4 alkyl, C1-C4 alkyl, and -SO2NH2 optionally substituted with 1 to 2 substituents independently selected from It is aryl or heteroaryl.

[0044] In embodiment 6a, according to embodiment 6, the present invention provides a compound represented by formula (I), (II), (III) or a pharma- ceutically acceptable salt thereof, In the formula, R 5 is preferably selected from the following structures: [ka] R 5c is independently selected from H, C1-C4 alkyl, and -SO2NH2; and s is 0, 1, or 2.

[0045] In embodiment 6b, according to embodiment 6, the present invention relates to a compound represented by formula (I), (II), (III) or a pharma- ceutically acceptable salt thereof, In the formula, R 5 is preferably selected from the following structures: [ka] R 5c is independently selected from H, C1-C4 alkyl, and -SO2NH2.

[0046] In embodiment 6c, in accordance with embodiments 6 and 6b, the present invention provides a compound represented by formula (I), (II), ( III), and (III-A) or a pharma- ceutically acceptable salt thereof. wherein R 5 is preferably selected from the following structures: [ka] R 5c is independently selected from H and C1-C4 alkyl.

[0047] In embodiment 7, the present invention relates to a compound of formula (I), (II) according to embodiment 1, 2, 3 or 3a. (III), (III-B), or a pharma- ceutically acceptable salt thereof. Provide salt, R 5 is C1-C4 alkyl, halo, haloC1-C4 alkyl, and -OH C3-C6 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from It is an alkyl.

[0048] In embodiment 7a, according to embodiment 7, the present invention provides a compound represented by formula (I), (II), (III) or a pharma- ceutically acceptable salt thereof, In the formula, R 5 is preferably C1-C4 alkyl, halo, haloC1-C4 alkyl, and Cyclopropane optionally substituted with 1 to 3 substituents independently selected from -OH cyclobutyl, cyclopentyl, or cyclohexyl.

[0049] In embodiment 7b, in accordance with embodiments 7 and 7a, the present invention relates to a compound represented by formula (I), (II), ( III), and (III-A) or a pharma- ceutically acceptable salt thereof. wherein R 5 is preferably selected from the following structures: [ka] R 5e , R 5e ', R 5d , R 5d ', and R 5f is H, C1-C4 alkyl, halo, Independently selected from haloC1-C4 alkyl, and -OH.

[0050] In embodiment 7c, in accordance with embodiments 7, 7a, and 7b, the present invention provides a compound represented by the formula (I), (I Any one of compounds of I), (III), and (III-A) or a pharma- ceutically acceptable salt thereof and providing a salt of formula R 5 is preferably selected from the following structures: [ka] R 5d and R 5d ' is H, halo, haloC1-C4 alkyl, and C1-C4 alkyl; are selected independently.

[0051] In embodiment 7d, according to embodiments 7, 7a, 7b and 7c, the present invention provides a compound of formula (I) (II), (III), and (III-A) or a pharmacopoeial compound thereof. Acceptable salts are provided, wherein R 5 is preferably selected from the following structures: [ka] R 5d and R 5d ' is H, halo, haloC1-C4 alkyl, and C1-C4 alkyl; are selected independently.

[0052] In embodiment 8, the present invention relates to a compound of formula (I), (II), (II) or (II) according to embodiment 1, 2 or 3. The present invention provides a compound according to any one of the following formulas: In the formula, R 5 is -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1- C4 alkyl), and -N(C1-C4 alkyl)2 It is a C2-C6 alkyl substituted by a substituent.

[0053] In embodiment 8a, according to embodiment 8, the present invention provides a compound represented by formula (I), (II), (III) or a pharma- ceutically acceptable salt thereof, In the formula, R 5 is preferably selected from the following structures: [ka] R 5h -NH2, -OH, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl) The following two options are available:

[0054] In embodiment 9, the present invention relates to the method according to embodiments 1, 2, 3, 3a, 4, 5, 5a to 5e, 6, 6 Formula (I), (II) (I The present invention provides a compound according to any one of the following formulas: In the formula, R 2 and R 3 At least one of is H.

[0055] In embodiment 9a, according to embodiment 9, the present invention provides a compound represented by formula (I), (II), (III) or a pharma- ceutically acceptable salt thereof, In the formula, R 2 is halo, C1-C4 alkyl, or haloC1-C4 alkyl; and R 3 is H.

[0056] In embodiment 9b, according to embodiment 9, the present invention provides a compound represented by formula (I), (II), (III) or a pharma- ceutically acceptable salt thereof, In the formula, R 2 is H; and R 3 is CN, C1-C4 alkyl, or haloC1-C4 It is an alkyl.

[0057] In embodiment 10, the present invention relates to a compound represented by formula (I), (II), or (III) according to embodiments 1 to 9. or a pharma- ceutically acceptable salt thereof, In the formula, R 1 is -OCF3 or -CF3.

[0058] In embodiment 10a, according to embodiment 10, the present invention provides a compound represented by the formula (I), (II), (II The present invention provides a compound according to any one of the following formulas: In the formula, R 1 is CF3.

[0059] In embodiment 11, the present invention relates to a compound represented by formula (I), (II), (III) and the like according to embodiment 1. and (III-A) or a pharma- ceutically acceptable salt thereof, The object is selected from the following: 2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3 -Methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)pyridine Dazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxycyclohexyl)amino)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-(((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-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pi ridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)a (amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)a (amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((1-isopropylpiperidin-3-yl)amino)pyridazin-3-yl )-3-Methyl-5-(trifluoromethyl)phenol; 2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazine-3- yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5,5-difluoropiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-(trifluoro (fluoromethyl)propyl)amino)pyridazin-3-yl)-5-(trifluoromethyl ) phenol; 3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy-6-methyl 4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile; (S)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy- 6-Methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile; (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy- 6-Methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile; 3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methyl Tylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino) -5-Methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno rule; (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino) -5-Methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno rule; 3-Methyl-2-(6-((pyrrolidin-2-ylmethyl)amino)pyridazin-3-yl (trifluoromethyl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((pyrrolidin-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(6-((pyrrolidin-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-methylpyrrolidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(2-hydroxy-2-methylpropoxy)pyridazin-3-yl)-3-methyl ethyl-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazin-3-yl (trifluoromethyl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; (S)-2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((2-hydroxycyclopentyl)amino)pyridazin-3-yl)-3- Methyl-5-(trifluoromethyl)phenol; (cis)-2-(6-((2-hydroxycyclopentyl)amino)pyridazin-3-yl (trifluoromethyl)-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)pyridazin-3-yl l) phenol; 2-(6-((2-hydroxyethyl)amino)-5-(trifluoromethyl)pyridazinone (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 3,5-Dichloro-2-(6-((2,2,2-trifluoroethyl)amino)pyridazine (3-yl)phenol; 3-Methyl-2-(6-((pyridin-2-ylmethyl)amino)pyridazin-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)pyridazin-3-yl (trifluoromethyl)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((trans-3-hydroxycyclobutyl)amino)pyridazine (3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)-5- (Trifluoromethyl)phenol; (R)-3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl )-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl )-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 5-Chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridin di-3-yl)-3-(trifluoromethyl)phenol; 3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-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-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol; (S)-5-Chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl) Amino)pyridazin-3-yl)phenol; (R)-5-Chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl) Amino)pyridazin-3-yl)phenol; 5-Chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol TFA salt; (S)-5-Chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl) Amino)pyridazin-3-yl)phenol TFA salt; (R)-5-Chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl) Amino)pyridazin-3-yl)phenol TFA salt; 2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3 ,5-Bis(trifluoromethyl)phenol; (S)-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3,5-bis(trifluoromethyl)phenol; (R)-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3,5-bis(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-(((S)-1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-(((R)-1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazine (3-methyl-5-(trifluoromethyl)phenol TFA salt; 2-(4,5-dimethyl-6-(((S)-1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA salt ; 2-(4,5-dimethyl-6-(((R)-1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA salt ; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridine ridazin-3-yl)amino)piperidine-2-carboxylic acid; 3-Methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(pyrimidin-5-ylamino)pyridazin-3-yl)-5- (Trifluoromethyl)phenol; 3,5-Dichloro-2-(6-(cyclopropylamino)pyridazin-3-yl)pheno rule; 3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine (3-yl)phenol; (S)-3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol; (R)-3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol; 3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine (3-phenyl)phenol TFA salt; (S)-3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol TFA salt; (R)-3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol TFA salt; 3-Methyl-2-(6-(pyridin-3-ylamino)pyridazin-3-yl)-5-( (trifluoromethyl)phenol; 3,5-Dimethyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine (3-yl)phenol; (S)-3,5-Dimethyl-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol; (R)-3,5-Dimethyl-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol; 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazine (3-yl)-5-(trifluoromethyl)phenol; (S)-2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-3-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-3-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 5-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl) (fluoromethyl)pyridazin-3-yl)phenol; (S)-5-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4- (Trifluoromethyl)pyridazin-3-yl)phenol; (R)-5-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4- (Trifluoromethyl)pyridazin-3-yl)phenol; 5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-3-(trifluoromethyl)phenol; (S)-5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-3-(trifluoromethyl)phenol; (R)-5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-3-(trifluoromethyl)phenol; 2-(6-((1,3-dimethylpiperidin-3-yl)amino)pyridazin-3-yl )-3-Methyl-5-(trifluoromethyl)phenol; 2-(6-((1,3-dimethylpiperidin-3-yl)amino)pyridazin-3-yl )-3-Methyl-5-(trifluoromethyl)phenol TFA salt; 2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl )pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoro (trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoro (trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-5-methylpyridine (diphenyl-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 Tylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridine di-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4 -Methylpyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methyl Tylpyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-5-(trifluoromethyl) (trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phen Le; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-5 -(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pyridazin-3-yl til)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-( (trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pyridazin-3-yl ) phenol; 2-(6-((3-hydroxycyclohexyl)amino)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-(((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)pyridine ridazin-3-yl)amino)-1-methylpiperidin-2-one; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)pyridazin-3-yl)amino)-1-methylpiperidin-2-one; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)pyridazin-3-yl)amino)-1-methylpiperidin-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)pyridine ridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino)pyridine ridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridine Ridazin-3-yl)amino)piperidin-2-one; (S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)pyridazin-3-yl)amino)piperidin-2-one; (R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)pyridazin-3-yl)amino)piperidin-2-one; 3-Methyl-5-(trifluoromethyl)-2-(6-((6-(trifluoromethyl) Piperidin-3-yl)amino)pyridazin-3-yl)phenol; 3-Methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidine-3- yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidinyl) (3-amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol Le; (R)-3-Methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidinyl) (3-amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol Le; 3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5-(trifluoromethyl) (fluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5- (Trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)pheno Le; (R)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5- (Trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)pheno Le; 2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl) (trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4 -(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)pheno rule; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-( (Trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol ; 2-(6-((3-hydroxy-3-(trifluoromethyl)cyclobutyl)amino)pyridine ridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-(trifluoromethyl)cyclobutene (amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno rule; 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- Methylpyridazin-3-yl)phenol; 5-Chloro-2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl) Amino)-4-methylpyridazin-3-yl)phenol; 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amine (o)-4-methylpyridazin-3-yl)phenol; 5-Chloro-2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4- (Trifluoromethyl)pyridazin-3-yl)phenol; 5-Chloro-2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl) Amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol; 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amine (o)-4-(trifluoromethyl)pyridazin-3-yl)phenol; 5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl) (fluoromethyl)pyridazin-3-yl)phenol; (S)-5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4- (Trifluoromethyl)pyridazin-3-yl)phenol; (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4- (Trifluoromethyl)pyridazin-3-yl)phenol; 5-Chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pi ridazin-3-yl)phenol; (S)-5-Chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)a (amino)pyridazin-3-yl)phenol; (R)-5-chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)a (amino)pyridazin-3-yl)phenol; 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-(piperidin-3-ylamino)pyridazin-3-yl)-5- (Trifluoromethyl)phenol; (S)-3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl )-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl )-5-(trifluoromethyl)phenol; 2-(6-(((4-fluoropyrrolidin-2-yl)methyl)amino)pyridazine-3 -yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2S,4S)-4-fluoropyrrolidin-2-yl)methyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2R,4S)-4-fluoropyrrolidin-2-yl)methyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2R,4R)-4-fluoropyrrolidin-2-yl)methyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2S,4R)-4-fluoropyrrolidin-2-yl)methyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-(((4-methylmorpholin-3-yl)methyl)amine Pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(6-(((4-methylmorpholin-3-yl)methyl)amine Pyridazin-3-yl)-5-(trifluoromethyl)phenol; (rac)-3-Methyl-2-(6-(((4-methylmorpholin-3-yl)methyl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropane propyl)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 rule; (R)-3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2- Methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)pheno rule; 3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropane (propyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol HC 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)piperidin-3-yl)a (amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidine-3- yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenyl Knoll; (R)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidine-3- yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenyl Knoll; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridine di-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 Tylpyridazin-3-yl)-5-(trifluoromethoxy)phenol; 2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethoxy)phenol; (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethoxy)phenol; (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethoxy)phenol; 3-Methyl-2-(6-((octahydroindolizin-8-yl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((8R,8aR)-octahydroindolizin-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((8R,8aS)-octahydroindolizin-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((8S,8aR)-octahydroindolizin-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((8S,8aS)-octahydroindolizin-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Le; 2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Le; 3-Methyl-2-(6-((8-methyl-8-azabicyclo[3.2.1]octane-2 -yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((1S,2S,5S)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro Methyl)phenol; 3-Methyl-2-(6-(((1S,2R,5S)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro Methyl)phenol; 3-Methyl-2-(6-(((1S,2R,5R)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro Methyl)phenol; 3-Methyl-2-(6-(((1S,2S,5R)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro Methyl)phenol; 3-Methyl-2-(6-(((1R,2R,5S)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro Methyl)phenol; 3-Methyl-2-(6-(((1R,2S,5S)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro Methyl)phenol; 3-Methyl-2-(6-(((1R,2S,5R)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro Methyl)phenol; 3-Methyl-2-(6-(((1R,2R,5R)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro Methyl)phenol; 2-(6-((8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octa (2-amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl) l) phenol; 2-(6-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenyl)-2-hydroxyethyl 2-[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol; 2-(6-(((1R,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenyl ... 2-[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol; 2-(6-(((1R,2S,5R)-8-(2-hydroxyethyl)-8-azabicyclo[4.2.1.2]phenyl)-2-hydroxyethyl 2-[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol; 2-(6-(((1R,2R,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenyl)-1,2-dihydro-1,2-trimethylphenyl 2-[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol; 2-(6-(((1S,2S,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenyl)-1,2-dihydro-1,2-tri ... 2-[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol; 2-(6-(((1S,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenyl)-1,2-dihydro-1,2-tri ... 2-[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol; 2-(6-(((1S,2R,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenyl)-1,2-dihydro-1,2-tri ... 2-[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol; 2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenyl)-1,2-dihydro-1,2-tri ... 2-[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol; 2-(6-((6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,6R)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan phenol; 2-(6-(((3S,6R)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan phenol; 2-(6-(((3R,6S)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan phenol; 2-(6-(((3S,6S)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan phenol; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridine ridazin-3-yl)amino)-2-methylpropane-1,2-diol; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridine ridazin-3-yl)amino)cyclopentane-1,2-diol; (1S,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Le; (1S,2R,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Le; (1S,2S,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Le; (1S,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Le; (1R,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Le; (1R,2S,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Le; (1R,2R,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Le; (1R,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Le; (S)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazine-3- yl)-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- yl)-3-methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((2-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((2S,3S)-2-methylpiperidin-3-yl)amino )pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((2R,3S)-2-methylpiperidin-3-yl)amino )pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((2S,3R)-2-methylpiperidin-3-yl)amino )pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((2R,3R)-2-methylpiperidin-3-yl)amino )pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((2-hydroxypropyl)piperidin-3-yl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Le; 2-(6-(((S)-1-((R)-2-hydroxypropyl)piperidin-3-yl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Le; 2-(6-(((S)-1-((S)-2-hydroxypropyl)piperidin-3-yl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Le; 2-(6-(((R)-1-((R)-2-hydroxypropyl)piperidin-3-yl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Le; 2-(6-((5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)- 3-Methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoropiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoropiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)- 3-Methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoropiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoropiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridine ridazin-3-yl)amino)-1-methylpiperidin-3-ol; (3S,5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol; (3R,5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol; (3R,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol; (3S,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol; 2-(6-(((1-hydroxycyclopentyl)methyl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-Methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one; 3-Methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazine-3- yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazin (3-yl)-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazin (3-yl)-5-(trifluoromethyl)phenol; 2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridazine-3 -yl)-3-methyl-5-(trifluoromethyl)-phenol; (S)-2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridine di-3-yl)-3-methyl-5-(trifluoromethyl)-phenol; (R)-2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridine di-3-yl)-3-methyl-5-(trifluoromethyl)-phenol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-Methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one ; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one ; 4-(2-((6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl) l)amino)ethyl)benzenesulfonamide; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-Methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide; (3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)fluor) (phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxy Sid; (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)fluor) (phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxy Sid; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-Methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide TFA salt; (3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)fluor) (phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxy Cid TFA salt; (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)fluor) (phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxy Cid TFA salt; or a pharma- ceutically acceptable salt thereof.

[0060] In embodiment 11a, according to embodiment 11, the present invention provides a compound according to embodiment 1 of formula (I), Any one of the compounds (II), (III), and (III-A) or a pharma- ceutical approved derivatives thereof and the compound is preferably selected from the following: (R)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin (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-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)a (amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((1-isopropylpiperidin-3-yl)amino)pyridazin-3-yl )-3-Methyl-5-(trifluoromethyl)phenol; (S)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5,5-difluoropiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-(trifluoro (fluoromethyl)propyl)amino)pyridazin-3-yl)-5-(trifluoromethyl ) phenol; (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy- 6-Methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile; (R)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino) -5-Methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno rule; (R)-3-Methyl-2-(6-((pyrrolidin-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-methylpyrrolidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(2-hydroxy-2-methylpropoxy)pyridazin-3-yl)-3-methyl ethyl-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; (S)-2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino) Pyridazin-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)pyridazin-3-yl l) phenol; 2-(6-((2-hydroxyethyl)amino)-5-(trifluoromethyl)pyridazinone (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 3,5-Dichloro-2-(6-((2,2,2-trifluoroethyl)amino)pyridazine (3-yl)phenol; 3-Methyl-2-(6-((pyridin-2-ylmethyl)amino)pyridazin-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)pyridazine (3-yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl )-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 5-Chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridin di-3-yl)-3-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-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-methylpiperidin-3-yl) Amino)pyridazin-3-yl)phenol TFA salt; (R)-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3,5-bis(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-(((R)-1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA salt ; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridine ridazin-3-yl)amino)piperidine-2-carboxylic acid; (R)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(pyrimidin-5-ylamino)pyridazin-3-yl)-5- (Trifluoromethyl)phenol; 3,5-Dichloro-2-(6-(cyclopropylamino)pyridazin-3-yl)pheno rule; (R)-3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol TFA salt; 3-Methyl-2-(6-(pyridin-3-ylamino)pyridazin-3-yl)-5-( (trifluoromethyl)phenol; (R)-3,5-Dimethyl-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol; (R)-2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-5-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4- (Trifluoromethyl)pyridazin-3-yl)phenol; (R)-5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-3-(trifluoromethyl)phenol; 2-(6-((1,3-dimethylpiperidin-3-yl)amino)pyridazin-3-yl )-3-Methyl-5-(trifluoromethyl)phenol TFA salt; (R)-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoro (trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-methyl Tylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methyl Tylpyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-( (trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pyridazin-3-yl ) 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)phenyl) Nyl)pyridazin-3-yl)amino)-1-methylpiperidin-2-one; (R)-2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino)pyridine ridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)pyridazin-3-yl)amino)piperidin-2-one; 3-Methyl-5-(trifluoromethyl)-2-(6-((6-(trifluoromethyl) Piperidin-3-yl)amino)pyridazin-3-yl)phenol; (R)-3-Methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidinyl) (3-amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol Le; (R)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5- (Trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)pheno Le; (R)-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-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)amine (o)-4-methylpyridazin-3-yl)phenol; 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amine (o)-4-(trifluoromethyl)pyridazin-3-yl)phenol; (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4- (Trifluoromethyl)pyridazin-3-yl)phenol; (R)-5-chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)a (amino)pyridazin-3-yl)phenol; 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-(piperidin-3-ylamino)pyridazin-3-yl )-5-(trifluoromethyl)phenol; 2-(6-((((2S,4S)-4-fluoropyrrolidin-2-yl)methyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2S,4R)-4-fluoropyrrolidin-2-yl)methyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (rac)-3-Methyl-2-(6-(((4-methylmorpholin-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)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenyl Knoll; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methyl Tylpyridazin-3-yl)-5-(trifluoromethoxy)phenol; (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethoxy)phenol; 3-Methyl-2-(6-(((8R,8aR)-octahydroindolizin-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((8S,8aS)-octahydroindolizin-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Le; (S)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Le; 3-Methyl-2-(6-(((1S,2S,5S)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro Methyl)phenol; 3-Methyl-2-(6-(((1R,2R,5R)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro Methyl)phenol; 2-(6-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenyl)-2-hydroxyethyl 2-[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol; 2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenyl)-1,2-dihydro-1,2-tri ... 2-[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol; 2-(6-(((3R,6R)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan phenol; 2-(6-(((3S,6S)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan phenol; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol; (1S,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Le; (1R,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Le; (S)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazine-3- yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazine-3- yl)-3-methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((2S,3S)-2-methylpiperidin-3-yl)amino )pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((2R,3R)-2-methylpiperidin-3-yl)amino )pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Le; 2-(6-(((R)-1-((R)-2-hydroxypropyl)piperidin-3-yl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Le; 2-(6-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoropiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoropiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)pyridazine (3-yl)-3-methyl-5-(trifluoromethyl)phenol; (3S,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol; 2-(6-(((1-hydroxycyclopentyl)methyl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-Methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one; (R)-3-Methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazin (3-yl)-5-(trifluoromethyl)phenol; (R)-2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridine di-3-yl)-3-methyl-5-(trifluoromethyl)-phenol; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one ; 4-(2-((6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl) l)amino)ethyl)benzenesulfonamide; (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)fluor) (phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxy Cid TFA salt; or a pharma- ceutically acceptable salt thereof.

[0061] In embodiment 11b, the present invention relates to a compound of formula (I) according to embodiment 1 or a pharma- ceutical thereof. With respect to acceptable salts, the compound is 3-methyl-2-(5-methyl-6-((1-methylpi (peridin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)furan In one embodiment, the compound is (S)-3- Methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin 5-(trifluoromethyl)-5-(diphenyl-3-yl)phenol or its pharma- ceutically acceptable salt In one preferred embodiment, the compound is (R)-3-methyl-2-(5-methyl- 6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trimethylpyridazin-3-yl) (trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof.

[0062] In embodiment 11c, the present invention relates to a compound of formula (I) according to embodiment 1 or a pharma- ceutical thereof. With respect to acceptable salts, the compound is 2-(4-methyl-6-((1-methylpiperidine-3 -yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol or and pharma- ceutically acceptable salts thereof. In one embodiment, the compound is (S)-2-(4-methylphenyl)-2-(4-phenylphenyl)-1,1-dihydro-2-(4-methyl ... -6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-( (trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof. In the example, the compound is (R)-2-(4-methyl-6-((1-methylpiperidine-3-yl) (3-amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol or its It is a pharma-ceutically acceptable salt.

[0063] In embodiment 11d, the present invention relates to a compound of formula (I) according to embodiment 1 or a pharma- ceutical thereof. With respect to acceptable salts, the compound may be 2-(6-((1-ethylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or and pharma- ceutically acceptable salts thereof. In one embodiment, the compound is (S)-2-(6-((1 -ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-( (trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof. In an example, the compound is (R)-2-(6-((1-ethylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or its It is a pharma-ceutically acceptable salt.

[0064] In embodiment 11e, the present invention relates to a compound of formula (I) according to embodiment 1 or a pharma- ceutical thereof. With respect to acceptable salts, the compound is 2-(6-((3-hydroxy-3-methylcyclobutene (amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound is 2-(6-((( trans)-3-Hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl )-3-Methyl-5-(trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof In one preferred embodiment, the compound is 2-(6-((cis)-3-hydroxy- 3-Methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl) The compound is preferably (fluoromethyl)phenol or a pharma- ceutically acceptable salt thereof.

[0065] In embodiment 11f, the present invention relates to a compound of formula (I) according to embodiment 1 or a pharma- ceutical thereof. With respect to acceptable salts, the compound is 2-(6-((3-hydroxycyclohexyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or In one embodiment, the compound is a pharma- ceutically acceptable salt of 2-(6-(((1S,3R )-3-Hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5 In one embodiment, the compound is 1-(trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof. The compound is 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or In one embodiment, the compound is a pharma- ceutically acceptable salt of 2-(6-(((1S,3S )-3-Hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5 A preferred embodiment of the compound is 1-(trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof. In the examples, the compound is 2-(6-(((1R,3S)-3-hydroxycyclohexyl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof.

[0066] In embodiment 11g, the present invention relates to a compound of formula (I) according to embodiment 1 or a pharma- ceutical thereof. With respect to acceptable salts, the compound is 5-((6-(2-hydroxy-6-methyl-4-(thiazolidinyl) (trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidine In one embodiment, the compound is (3R, -3-ol or a pharma- ceutically acceptable salt thereof. 5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl 1-methyl-3-pyridazinyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol or its drug In one embodiment, the compound is a physiologically acceptable salt. 2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazine-3- 1-methyl-3-(phenyl)amino)-1-methylpiperidin-3-ol or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound is (3S,5S)-5-((6-(2-hydroxy-6-methyl) (4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methyl In one preferred embodiment, the compound is ethyl piperidin-3-ol or a pharma- ceutically acceptable salt thereof. The compound is (3S,5R)-5-((6-(2-hydroxy-6-methyl-4-(thiazide) (trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidine -3-ol or a pharma- ceutically acceptable salt thereof.

[0067] In embodiment 12, the present invention relates to a compound represented by formula (I), ( A therapeutically effective amount of any one of the compounds of (II), (III), and (III-A) or Pharmaceutical compositions comprising pharma- ceutically acceptable salts and one or more pharma- ceutically acceptable carriers. do.

[0068] In embodiment 13, the present invention relates to a compound represented by formula (I), ( A therapeutically effective amount of any one of the compounds of (II), (III), and (III-A) or It relates to pharma- ceutically acceptable salts as well as combinations comprising one or more therapeutic agents.

[0069] In embodiment 14, the present invention provides a therapeutically effective amount of a compound of formula (I), (II) according to embodiment 13. (III), (III-B), or a pharma- ceutically acceptable salt thereof. For combinations including salts, one or more of the therapeutic agents is a farnesoid X receptor (FXR) agonist. agonists; anti-lipid drugs; anti-fibrotic drugs; JAK inhibitors; anti-PD1 inhibitors, anti-LAG-3 inhibitors checkpoint inhibitors, including anti-TIM-3 inhibitors or anti-PDL1 inhibitors; therapy, radiation therapy and surgical procedures; uric acid lowering therapies; anabolic drugs and cartilage regeneration therapies IL-17 blockade; Complement inhibitors; Bruton's tyrosine kinase inhibitors (BTK inhibitors) );Toll-like receptor inhibitors (TLR7 / 8 inhibitors);CAR-T therapy;Antihypertensive drugs;Co Lactate dehydrogenase; Leukotriene A4 hydrolase (LTAH4) inhibitor; SGLT 2 inhibitors; beta2 agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs ("NSAIDs"); Acetylsalicylic acid (ASA) drugs, including aspirin; paracetamol; regenerative therapy treatment treatment of cystic fibrosis; or treatment of atherosclerosis.

[0070] In one embodiment, the present invention relates to any of the 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~ Formula (I), (II), (III) according to any one of 11g, 12, 13, and 14; or (III-A) or a pharma- ceutical acceptable salt thereof is administered to a subject. The present invention relates to a method for inhibiting NLRP3 activity in a subject, comprising administering to a subject a therapeutically effective amount of NLRP3.

[0071] In embodiment 15, the present invention relates to any of embodiments 1 to 11g for use as a medicament. Any one of formulas (I), (II), (III), and (III-A) according to any one of the following: or a pharma- ceutically acceptable salt thereof, or a compound according to any one of embodiments 13 to 14. In particular, the present invention relates to the combination of the compounds according to the embodiments 1 to 11 for use as a medicament. Any one of formulas (I), (II), (III), and (III-A) according to any ...B) according to any one of formulas (I), (II), (III), and (III-C) according to any one of formulas (I), (II), (III), and (III-D) according to any one of formulas (I), (II), (III), (III- In particular, the present invention relates to a compound or a pharma- ceutical acceptable salt thereof that inhibits NLRP3 expression. The method according to any one of embodiments 1 to 11g for use as a medicament for inhibiting the endothelial pathway. A compound of any one of formulas (I), (II), (III), and (III-A) or In another particular embodiment, the present invention relates to a pharma- ceutically acceptable salt of The present invention relates to a combination according to any one of embodiments 13 to 14 for the purpose of

[0072] In embodiment 16, the present invention relates to a disease or disorder, wherein NLRP3 signaling is In the treatment of a disease or disorder that contributes to the pathology and / or symptoms and / or progression of the disease or disorder. The compound of formula (I), (II), (II) according to any one of embodiments 1 to 11g for use in II), and (III-A) or a pharma- ceutically acceptable salt thereof. Regarding.

[0073] In embodiment 17, the present invention relates to a disease or disorder in which NLRP3 signaling is To treat a disease or disorder that contributes to the pathology and / or symptoms and / or progression of the disease or disorder. The method comprises the steps of: A therapeutically effective amount of a compound according to any one of (I) and (III-A) or a pharma- ceutical acceptable salt thereof. The present invention relates to a method comprising administering an acceptable salt thereof.

[0074] In embodiment 18, the present invention relates to a method for the preparation of a composition according to embodiment 1 to 1 for use according to embodiment 16. Any one of formulas (I), (II), (III), and (III-A) according to any one of 1g. or a pharma- ceutically acceptable salt thereof, or The method relates to a method for treating a disease or disorder, the disease or disorder being an inflammasome-associated disease / disorder, an immune disorder, , inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as autoinflammatory fever syndrome (e.g., Chlamydia trachomatis), leiopyrin-associated periodic syndrome), liver-related diseases / disorders (e.g., chronic liver disease, viral Hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic Alcoholic liver disease), diseases related to inflammatory arthritis (e.g., gout, pseudogout (chondrocalcinosis) osteoarthritis, rheumatoid arthritis, arthropathy (e.g. acute and chronic), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, diabetes mellitus type I / II and related complications (e.g., For example, nephropathy, retinopathy), hypertensive nephropathy, inflammation associated with hemodialysis, and inflammation associated with neuroinflammation. Diseases (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease) ), cardiovascular / metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension , Atherosclerosis, Type I and II Diabetes and Related Complications, Peripheral Arterial Disease (PAD, acute heart failure), inflammatory skin diseases (e.g., hidradenitis suppurativa, acne), wound healing and Diseases / disorders related to scarring, asthma, sarcoidosis, age-related macular degeneration, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), bone marrow In a specific aspect of embodiment 16, the present invention provides a compound according to formula (I), (II) Any one of the compounds represented by the following formula (III), (III-A) or a pharma- ceutically acceptable salt thereof. For the salt, the disease or disorder is preferably autoinflammatory fever syndrome (e.g., CAPS), sickle cell syndrome, or the like. Diabetes mellitus type I / II and related complications (e.g., nephropathy, retinopathy), hyperstimulation Associated with aciduria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, and neuroinflammation Disorders (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease) ), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvR R), hypertension), sweat gland abscesses, wound healing and scarring, and cancer (e.g., colon cancer, lung cancer) , myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), and myelofibrosis). .

[0075] In one embodiment, the present invention relates to a method for treating inflammasome-associated diseases / disorders, immune diseases, inflammation, and the like. autoimmune or autoinflammatory diseases, such as autoinflammatory fever syndrome (e.g., cryotherapy) pyridine-associated periodic syndrome), liver-related diseases / disorders (e.g., chronic liver disease, viruses Hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcohol liver disease), inflammatory arthritis-related diseases (e.g., gout, pseudogout (cartilage calcification) , osteoarthritis, rheumatoid arthritis, arthropathy, e.g. acute and chronic), kidney-related diseases (e.g. For example, hyperoxaluria, lupus nephritis, type I / II diabetes and related complications (e.g. , nephropathy, retinopathy), 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., cardiovascular risk reduction (CvRR), hypertension, Atherosclerosis, type I and type II diabetes mellitus and related complications, peripheral arterial disease (P AD), acute heart failure), inflammatory skin diseases (e.g., hidradenitis suppurativa, acne), wound healing and scarring Diseases / disorders related to retinal plaque, asthma, sarcoidosis, age-related macular degeneration, and cancer (e.g. For example, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), myelofibrosis, The method according to any one of embodiments 1 to 11g for use in the treatment of a disease or disorder selected from the group consisting of Any one of the formulae (I), (II), (III), and (III-A) according to In a particular aspect of embodiment 18, the present invention relates to a compound or a pharma- ceutically acceptable salt thereof. The invention relates to a compound of any one of formulas (I), (II), (III), and (III-A): or a pharma- ceutically acceptable salt thereof, the disease or disorder is preferably autoinflammatory fever syndrome. (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., , nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NA SH, disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegeneration) diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g. Vascular Risk Reduction (CvRR), Hypertension), Sweat Gland Abscess, Wound Healing and Scarring, and Cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), bone myelofibrosis).

[0076] In embodiment 19, the present invention provides a method for inhibiting NLRP3 inflammasome activity in a subject in need thereof. A method for carrying out the method in a subject according to any one of embodiments 1 to 11g, A therapeutically effective amount of any one of formulas (I), (II), (III), and (III-A) according to the invention or a pharma- ceutically acceptable salt thereof to a subject in need thereof. The present invention relates to a method comprising the steps of:

[0077] In one embodiment, the present invention is a method for inhibiting NLRP3 activity in a subject. and embodiments 1, 2, 3, 3a, 4, 5, 5a to 5e, 6, 6a to 6c, 7, 7a to 7d. , 8, 8a, 9, 9a-9b, 10, 10a, 11, 11a-11g, 12, 13, and 14. Treatment of the compounds of formula (I), (II), (III), and (III-A) according to any one of The method comprises administering to a subject an effective amount of a compound or a pharma- ceutically acceptable salt thereof. .

[0078] In one embodiment, the present invention relates to a method for treating inflammasome-associated diseases / disorders, immune diseases, inflammation, and the like. autoimmune or autoinflammatory diseases, such as autoinflammatory fever syndrome (e.g., cryotherapy) Pyrine-associated periodic syndrome, sickle cell disease, systemic lupus erythematosus (SLE), liver disease Associated diseases / disorders (e.g., chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis) (NASH, alcoholic steatohepatitis, and alcoholic liver disease), and inflammatory arthritis Related diseases (e.g. gout, pseudogout (cartilage calcification), osteoarthritis, rheumatoid arthritis, acute chronic arthropathy, kidney-related diseases (e.g. hyperoxaluria, lupus nephritis, diabetes mellitus) pathologic nephropathy, hypertensive nephropathy, hemodialysis-related inflammation), diseases related to neuroinflammation (e.g. , multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular system / Metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis) atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (e.g., sweat gland abscess, acne), wound healing and scar formation, asthma Diseases / disorders related to glaucoma, sarcoidosis, age-related macular degeneration, and cancer (e.g., intestinal cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis) A method for treating a selected disease or disorder, comprising the steps of: , 5, 5a~5e, 6, 6a~6c, 7, 7a~7d, 8, 8a, 9, 9a~9b, 10 , 10a, 11, 11a to 11g, 12, 13, and 14 according to any one of the formulas (I) a therapeutically effective amount of a compound of (II), (III), or (III-A) or a pharma- ceutical acceptable salt thereof; In particular, the disease or disorder is preferably Autoinflammatory syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related conditions Associated complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis) ), chronic liver disease, NASH, disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections) acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular Systemic risk (e.g., cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, as well as cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplasia, syndrome (MDS, myelofibrosis).

[0079] Depending on the choice of starting materials and procedures, the compound may be in the form of one of the possible stereoisomers. or as mixtures thereof, e.g. as pure optical isomers or as chiral isomers depending on the number of asymmetric carbon atoms. It exists as a mixture of stereoisomers, such as racemic and diastereoisomeric mixtures. The present invention relates to racemic mixtures, diastereomeric mixtures and optically pure mixtures. It is intended to include all such possible stereoisomers, including the forms The (R)- and (S)-stereoisomers are prepared using chiral synthons or chiral reagents. The compound may be separated or resolved using conventional techniques. When present, the cycloalkyl substituents may have a cis or trans configuration. The invention is intended to include all tautomeric forms thereof as used herein. (s)-, which does not change when reflected in a mirror, but by exchanging any two entities, It is also intended to include any pseudo-asymmetric carbon atom in which the chirality is reversed (PAC 1996, 68, 2 193,Basic terminology of stereochemistry IUPAC recommendations 1996).

[0080] As used herein, the term "salt" or "salts" refers to " refers to an acid addition salt or a base addition salt of the compound of the present invention. "Salt" is used in particular as a "medicinal The term "pharmaceutically acceptable salt" includes a salt that is biologically acceptable for the compounds of the present invention. retain their effectiveness and properties, and are not usually biologically or otherwise undesirable In many cases, the compounds of the invention contain amino and / or carboxyl groups or salts thereof. The presence of similar groups makes it possible to form acid and / or base salts.

[0081] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0082] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. and other similar.

[0083] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, cyano acid, ethyl ester ... Oxic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, Andric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicyl Includes acids and the like.

[0084] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0085] Inorganic bases from which salts can be derived include, for example, ammonium salts and salts of the compounds of the I-XI periodic table. In some embodiments, the salts include sodium, potassium, ammonium, calcium, Particularly suitable salts are derived from ammonia, calcium, magnesium, iron, silver, zinc and copper. Includes ammonium, potassium, sodium, calcium and magnesium salts.

[0086] Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, aryl ... Substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and other Specific organic amines include isopropylamine, benzathine, coryne amine, diethanolamine, diethylamine, lysine, meglumine, piperazine and thoronine. Contains methamine.

[0087] In another aspect, the present invention provides an acetate, an ascorbyl salt, an adipate, an aspartate. , benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate Acid salt, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllon Salts, citrates, ethanedisulfonates, fumarates, gluceptates, gluconates , glucuronate, glutamate, glutarate, glycolate, hippurate, iodide Hydrogen salt / iodide, isethionate, lactate, lactobionate, lauryl sulfate, Malate, maleate, malonate, mandelate, mesylate, methyl sulfate, mu Tinates, naphthoates, napsylates, nicotinates, nitrates, octadecanoates, Oleate, Oxalate, Palmitate, Pamoate, Phosphate / Hydrogen Phosphate / Dihydrate Polyphosphate, polygalacturonate, propionate, sebacate, stearate, cobalt salt Succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, Compounds of formula (I), (II), (III) and (IV) in the form of their trifluoroacetate or xinafoate salts and (III-A).

[0088] In another aspect, the present invention provides a method for the preparation of a compound comprising the steps of: Sodium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine in the form of amido, diethylamine, lysine, meglumine, piperazine or tromethamine salts Any one of compounds represented by formula (I), (II), (III) and (III-A) provide.

[0089] Any formula given herein represents unlabeled and isotopically labeled forms of the compound. It is also intended that isotopically labeled compounds have one or more atoms with a selected atomic mass or Represented by the formulas shown herein except for the replacement of atoms having mass numbers Isotopes that can be incorporated into the compounds of the present invention include, for example, Contains isotopes.

[0090] In addition, certain isotopes, particularly deuterium (i.e. 2 H or D) is better. Metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements or a shorter therapeutic index This may provide certain therapeutic advantages due to improvements in efficacy or tolerability. It is understood that deuterium is considered a substituent of the compounds of formula (I). can be defined by the isotopic enrichment factor. The term "reduction factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the invention is indicated to be deuterium, such a compound may have at least at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), At least 4000 (60% deuterium atom incorporation), at least 4500 (67.5 % deuterium incorporation), at least 5000 (75% deuterium incorporation), at least At least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation) incorporation), at least 6333.3 (95% deuterium incorporation), at least 646 6.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) ) or at least 6633.3 (99.5% deuterium incorporation) The term "isotopic enrichment factor" refers to the isotopic enrichment factor for deuterium. It should be understood that the same applies to any isotope as described above. do.

[0091] In another aspect, the present invention provides a compound of formula (I) as defined herein [ka] or a pharma- ceutically acceptable salt thereof, wherein R 5 is selected from: [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 in the (Deuterium R 5a or R 5b For example, but not limited to, deuterium can be incorporated as follows: [ka]

[0092] In another aspect, the present invention provides a compound of formula (I) as defined herein [ka] or a pharma- ceutically acceptable salt thereof, 2 , R 3 , R 4 But the next H, C1 to C4 alkane When the alkyl group is selected from the group consisting of alkyl, haloC1-C4 alkyl, or haloC1-C4 alkyl, one or more hydrogen atoms present in said group may An atom can be replaced with deuterium. For example, and without limitation, deuterium can be substituted for It can be incorporated as follows. [ka]

[0093] Other examples of isotopes that can be incorporated into the compounds of the present invention include, respectively: 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 I, etc. of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine The present invention therefore includes, for example, 3 H and 14 Radioisotopes such as C Compounds incorporating one or more of the aforementioned isotopes, including 2 H and 13 C, etc. It should be understood that this includes compounds in which non-radioactive isotopes such as Isotopically labeled compounds are useful for metabolic studies ( 14 C), reaction rate studies (e.g. 2 H Kuha 3 H), positron emission tomography (P Detection techniques such as single photon emission computed tomography (SPECT) or or in imaging techniques or in radiation treatment of patients. 18 F or label The compounds may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of pharma- ceutically acceptable salts can generally be prepared by conventional techniques known to those skilled in the art. or by substituting an appropriate isotopically labeled reagent for the previously used unlabeled reagent. Prepared by processes similar to those described in the accompanying examples and preparations using It is possible.

[0094] Pharmaceutical Compositions As used herein, the term "pharmaceutical composition" refers to a pharmaceutical composition suitable for oral or parenteral administration. or a compound of the present invention, in a form similar to that described above, together with at least one pharma- ceutically acceptable carrier. It refers to a pharma- ceutically acceptable salt thereof.

[0095] As used herein, the term "pharmaceutical acceptable carrier" refers to a pharmaceutical composition. " refers to materials useful in the preparation or use of, for example, suitable diluents that would be known to one of skill in the art. , solvent, dispersion medium, surfactant, antioxidant, preservative, isotonic agent, buffer, emulsifier, absorption delay agent agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, Dyes and combinations thereof (see, for example, Remington The Science and Practice of Pharmacy, 22 nd Ed.Pharma (See Ceutical Press, 2013, pp. 1049-1070.) .

[0096] The term "therapeutically effective amount" of a compound of the invention refers to a therapeutically effective amount of a compound that is effective to induce a biological or medical response in a subject, For example, it may cause a decrease or inhibition of the activity of an enzyme or protein or cause a symptom. ameliorating, alleviating, slowing or delaying the progression of a disease or preventing a disease In one non-limiting embodiment, the term A "therapeutically effective amount" is an amount that, when administered to a subject, (1)(i) inhibits an inhibitor of ... or (ii) associated with NLRP3 activity; or (iii) inhibited NLRP3 activity ( A condition, disorder or disease characterized by at least one of the following: (2) partially reduce, inhibit, prevent, and / or ameliorate the activity of NLRP3; (3) reducing or inhibiting the expression of NLRP3; In another non-limiting embodiment, the amount of a compound of the present invention that is effective to inhibit or inhibit The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound that is effective to treat a cell, tissue, or non-cellular organism. When administered to the body or culture medium, it at least partially reduces the activity of NLRP3. or inhibiting; or at least partially reducing the expression of NLRP3; or It refers to an amount that is effective to inhibit.

[0097] As used herein, the term "subject" refers to a primate (e.g., a human, male or female), dog, rabbit, guinea pig, pig, rat and mouse. In some embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0098] As used herein, the terms "inhibit," "inhibit," or "inhibiting" " means the reduction or inhibition of a given condition, symptom, disorder, or disease, or the enhancement of biological activity or This refers to a significant decrease in baseline activity for the NLRP3 process. Inhibition of the NLRP3 inflammasome pathway results in increased expression of IL-1beta and / or IL- 18 production by suppressing the function of NLRP3 or the NLRP3 inflammasome pathway This includes inactivating, destabilizing, and / or altering the distribution of NLRP3. This can be achieved by mechanisms including, but not limited to, .

[0099] As used herein, the term "NLRP3" refers, without limitation, to a nuclear factor-binding protein (NLRP3). Acids, polynucleotides, oligonucleotides, sense and antisense polynucleotides strand, complementary sequence, peptide, polypeptide, protein, homologous and / or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants It is intended to include variants, alleles, various species, and active fragments thereof.

[0100] As used herein, the term "treat" refers to any disease or disorder. "Treating" or "treatment" refers to reducing or ameliorating a disease or disorder. (i.e., delaying or delaying the onset of the disease or at least one of its clinical symptoms) or suppressing disease or other symptoms, including those that may not be discernible to the patient. The method reduces at least one physical parameter or biomarker associated with the disorder. It refers to bringing a disease into remission or into remission.

[0101] As used herein, the term "prevent" refers to any disease or disorder. "Preventing" or "prevention" means the prophylactic treatment of a disease or disorder; or the prevention of a disease or disorder. It refers to delaying the onset or progression of a disorder.

[0102] As used herein, a subject is someone who has a medical condition that causes symptoms such as a disease or a condition that is not treatable by the patient. Are you "in need of" a treatment if you would benefit physically, medically, or in quality of life? , or "I need it."

[0103] All of the methods described herein are or in any suitable order unless the context clearly indicates otherwise. Any and all examples or exemplary phrases provided herein (e.g., "etc." The use of "such as" is intended merely to make the invention more clear and is not intended to be construed as limiting the scope of the invention. It is not intended to limit the scope of the invention as claimed.

[0104] Any asymmetric atom (e.g., carbon or other similar) of the compounds of the present invention may be present in a racemic form. or being enantiomerically enriched, e.g., existing in the (R)-, (S)- or (R,S)-configuration In certain embodiments, each asymmetric atom may be at least in the (R)- or (S)-configuration. At least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 7 0% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess Enantiomeric excess, at least 95% enantiomeric excess or at least 99% enantiomeric excess Has excess body weight.

[0105] Thus, as used herein, the compounds of the present invention include all possible stereoisomers. The compound may take the form of one of the isomers, rotamers, atropisomers, tautomers, or mixtures thereof. For example, substantially pure geometric (cis or trans) stereoisomers, di Can exist as an asterisk, optical isomer, racemate, or mixture of these can.

[0106] Any resulting mixture of stereoisomers may be classified according to the physical and chemical differences of the constituent elements. , pure or substantially pure geometric or optical isomers, diastereomers, racemates For example, the separation can be effected by chromatography and / or fractional crystallization.

[0107] Any resulting racemates of the compounds of the invention or of the intermediates can be prepared by known methods. Separation and optical activity of the diastereomeric salts thereof obtained, for example, by using optically active acids or bases. The compounds can be separated into their optical antipodes by liberation of the acidic or basic compounds. The base moiety may thus be, for example, an optically active acid, such as tartaric acid, dibenzoyltartaric acid, di Acetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid or sucrose The compounds of the invention can be obtained by fractional crystallization of the salts formed with uno-10-sulfonic acid. The racemic product can be resolved into its optical antipodes by chiral chromatography. by high performance liquid chromatography (HPLC) using chiral adsorbents can also be divided.

[0108] Methods of Synthesizing the Compounds of the Invention The compounds of the present invention can be prepared by the following schemes or the routes described in the Examples: or a pharma- ceutically acceptable salt thereof. All methods described herein are intended to be illustrative unless otherwise indicated herein or the context clearly indicates. Unless expressly stated otherwise, the steps may be performed in any suitable order. Use of any and all examples or exemplary language (e.g., "such as") provided herein The use is intended merely to better illustrate the invention and is not intended to be limiting of the invention as claimed separately. The following general method is not intended to be limiting in scope. 1 , R 2 , R 3 , R 4 , R 5 , halo and Z are as defined above in the above embodiments or in the scheme Unless otherwise specified, starting materials are either commercially available or is prepared by known methods.

[0109] Reaction Scheme 1 The compounds of the present invention can be prepared as shown in Scheme 1 (below), as described herein. may be prepared by the reaction sequence shown, whereby appropriately substituted 3,6-dihalo Pyridazines (M1) can be typically 1 between 50°C and 180°C (optionally under microwave irradiation) with the appropriate amine (M2a) or a base, such as NaH At low temperature, typically 0° C., reaction with an appropriate alcohol (M2b) in the presence of 3,4-dihalo-6-alkoxypyridazine (M3b) is obtained. (M3b) is then reacted with a suitable solvent such as DME or dioxane. A palladium catalyst, such as Pd(PPh3)4, and an aqueous base, typically Na2CO3 or The reaction is carried out using NaHCO3, and the appropriate boronator in the form of a boronic acid or boronic ester is reacted with NaHCO3. (M4), for example, with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane is subjected to Suzuki cross-coupling reaction to give a compound of formula (I) or a pharma- ceutically acceptable derivative thereof. This produces salt. [ka]

[0110] Reaction Scheme 2 Instead, the compounds of the present invention can be prepared according to Scheme 2 ( may be prepared by the reaction sequence shown in (below), whereby 3,6-Dihalopyridazine (M1) is a miscible amine such as DME or dioxane. In a solvent, a suitable palladium catalyst, such as Pd(PPh3)4 or XantPh Using os-Pd-G2 and an aqueous base, typically Na2CO3 or NaHCO3 a suitable boronate (M4) in the form of a boronic acid or boronic ester, e.g. Suzuki's reaction with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (path A) This is then subjected to a Ross coupling reaction to give 3-halo-pyridazine (M5) or methyl or boronates (M6) with a phenol protecting group P, such as benzyl, (Path B), which gives the compound of formula 3-halo-pyridazine (M7). The intermediate (M5) is then reacted in the presence of a base, such as DIPEA, at elevated temperature, typically by Between 150°C and 180°C (optionally under microwave irradiation), the appropriate amine (M2a) to give a compound of formula (I) or a pharma- ceutically acceptable salt thereof. The intermediate (M7) is treated in the same manner to give the protected form (M8), which is further , BBr3, etc., or catalytic hydrogenation to give the compound of formula (I) or a pharma- ceutically acceptable salt thereof. [ka]

[0111] Reaction Scheme 3 Alternatively, the compounds of the present invention may be prepared as shown in Scheme 3 (below) as described herein. The reaction sequence may be such that the appropriately substituted intermediate (M5) can be prepared by In an aprotic solvent such as toluene, a suitable palladium catalyst, such as PdCl 2(dppf) and a base, typically LiOtBu, in the presence of an appropriate amine (M2a) to obtain a compound of formula (I) or a pharma- ceutically acceptable salt thereof. This produces salt. [ka]

[0112] The process comprises reacting a compound represented by any one of formulas (I), (II), (III), and (III-A): To prepare the compound or a pharma- ceutically acceptable salt thereof, The above-described schemes 1, 2, and 3 can be expanded as follows. Thus, depending on the starting materials and the route chosen, one skilled in the art can easily obtain a compound of formula (I) or Methods for preparing pharma- ceutically acceptable salts are known. The process is described herein below in the experimental section.

[0113] The present invention further includes any of the different inventive processes, obtained at any stage thereof. Either the intermediate product is used as the starting material and the remaining steps are carried out, or the starting material is reacted. Either formed in situ under conditions, or the reaction components are either their salts or optically pure The compounds and intermediates of the present invention are used in the form of a substance generally known to those skilled in the art. They can also be legally converted into each other.

[0114] In another aspect, the present invention provides a compound of the present invention or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable salt thereof. A pharmaceutical composition comprising an acceptable carrier is provided. In a further embodiment, the composition is a pharmaceutical composition as described herein. and at least two pharma- ceutically acceptable carriers, such as those described in The pharmaceutical compositions can be administered orally, parenterally (e.g., by injection, infusion, transdermally, or topically). ), and rectal administration. The pharmaceutical composition of the present invention may also be for inhalation or intranasal application. (including capsules, tablets, pills, granules, powders or suppositories without limitation) or liquid The composition may be formulated in any form (including, without limitation, a solution, suspension, or emulsion). Tablets can be film coated or coated according to methods known in the art. Typically, the pharmaceutical composition is a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol ethanol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium salts or calcium salts; and / or polyethylene glycol; for tablets, further c) Binders, such as magnesium aluminum silicate, starch paste, gelatin, Laganth, methylcellulose, sodium carboxymethylcellulose and / or polyvinyl chloride dimethylpyrrolidone; if necessary, d) disintegrants, such as starch, agar, alginic acid or its sodium salt or effervescent Mixtures; e) Absorbents, colouring agents, flavouring and sweetening agents The active ingredient is preferably a tablet or gelatin capsule containing one or more of the following:

[0115] Methods of using the present invention NLRP3 induction is involved in inflammatory responses associated with or resulting from many different disorders. There is evidence for a role for IL-1 and IL-18 in the pathogenesis of Clinical and Experimental Immunology,2011 ,166,1-15;Strowig et al.Nature,2012,481, NLRP3 mutations are associated with a rare autoinflammatory disorder known as CAPS. It was found that this is the cause of a group 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 disease characterized by relapsing fever and inflammation. It comprises three autoinflammatory disorders that are linked on a clinical continuum. These diseases are: In order of increasing severity, these are familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, Neonatal-onset multisystem inflammatory syndrome (MWS) and chronic infantile neurological cutaneous and articular syndrome (CINCA) All of the NLRP3 gene-related pathologies are caused by gain-of-function mutations in the NLRP3 gene. It has been shown to be caused by a mutation that results in increased secretion of IL-1 beta. LRP3 is involved in the pathogenesis of septic arthritis, pyoderma gangrenosum, and acne (PAPA), Sweet's syndrome, and chronic It is also associated with many autoinflammatory diseases, including chronic nonbacterial osteomyelitis (CNO) and acne vulgaris. (Cook et al.Eur.J.Immunol.,2010,40,595-6 53).

[0116] Many autoimmune diseases, especially multiple sclerosis, type 1 diabetes (T1D), psoriasis, and rheumatoid arthritis, Rheumatoid arthritis (RA), Behcet'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), and its complications such as systemic lupus erythematosus and lupus nephritis (L u et al.J.Immunol.,2017,198(3),1119-29) and systemic sclerosis (Artlett et al. Arthritis Rheum. 2013). 011,63(11),3563-74), which have been shown to be associated with NLRP3. NLRP3 is a regulator of chronic obstructive pulmonary disorder (COPD), asthma (including steroid-resistant asthma), and ), and 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 a marker of multiple sclerosis (MS), Parkinson's disease, and Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, lung Brain damage from Streptococcus pneumoniae meningitis (Walsh et al. Nature Reviews, 2014,15,84-97; and Dempsey et al.Brain.Beha v.Immun.2017,61,306-16), intracranial aneurysms (Zhang et al.J.Stroke and Cerebrovascular Dis.,201 5,24,5,972-9) and traumatic brain injury (Ismael et al. J. Neu rotrauma.,2018,35(11),1294-1303) and many others. It has also been suggested to have a role in conditions of the central nervous system. NRLP3 activity is associated with type 2 diabetes. (T2D) and its organ-specific complications, atherosclerosis, obesity, gout, and pseudogout , metabolic syndrome (Wen et al. Nature Immunolog y,2012,13,352-357;Duewell et al.Nature,2 010,464,1357-1361;Strowig et al.Nature,2 014,481,278-286) and nonalcoholic fatty liver disease (Mridha e t al. J. Hepatol. 2017, 66(5), 1037-46) It has also been shown to be involved in metabolic diseases. The role is in atherosclerosis, 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 Dissection (Wu et al. Arterioscler. Thromb .Vase.Biol.,2017,37(4),694-706) and other cardiovascular Vent (Ridker et al. N. Engl. J. Med., 2017, 377( 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.Acta Opht halmol.,2017,95(8),803-8), non-infectious uveitis and optic nerve Translesion (Puyang et al. Sci. Rep. 2016, 6, 20998) eye diseases such as glaucoma; nonalcoholic steatohepatitis (NASH) and acute alcoholic hepatitis 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) and inflammatory responses in the lungs and skin (Primiano et al. J. Imm. unol.2016,197(6),2421-33); Inflammatory response in 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 disease, 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). The NLRP3 inflammasome is involved in the regulation of oxidative stress. NLRP3 has also been shown to be involved in inflammatory hypersensitivity. (Dolunay et al. Inflammation, 2017, 40, 36 6-86).

[0118] NLRP3 inflammasome activation is involved in the pathogenesis of infectious diseases such as influenza and leishmaniasis. It has been shown to enhance several pathogenic infections such as Rep.,2016,10(6),27912-20;Novias et al.P LOS Pathogens 2017,13(2),e1006196).

[0119] NLRP3 has also been implicated in the pathogenesis of many cancers (Menu et al. Clinical l and Experimental Immunology,2011,166,1 For example, several previous studies have demonstrated that IL-1-mediated signaling pathways play a key role in cancer invasion, growth, and metastasis. This suggests a role for IL-1 beta in randomized controlled trials. Reduce the incidence of lung cancer and total cancer mortality in double-blind, placebo-controlled clinical trials was shown (Ridker et al. Lancet., 2017, 390(1010 5), 1833-42). Inhibition of the NLRP3 inflammasome or IL-1 beta also reduces inflammation. 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). A role for the flammasome in myelodysplastic syndromes, myelofibrosis, and other myeloproliferative neoplasms and acute myeloid leukemia (AML) (Basiorka et al. Blood, 2014). 16,128(25),2960-75.) and in gliomas (Li et al. l.Am.J.Cancer Res.2015,5(1),442-9), Inflammatory tumors (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. .Clin.Cancer Res.,2017,36(1),116) and various others. NLRP3 inflammasome activation is associated with the oncogenesis of cancer. It has also been shown to mediate chemotherapy resistance of 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 contributes to chemotherapy-induced neuropathic Contributes to pain (Jia et al. Mol. Pain., 2017, 13, 1-1 1) NLRP3 has been shown to be required for efficient control of viruses, bacteria, and fungi. It was also shown.

[0120] Activation of NLRP3 leads to cell pyroptosis, a hallmark of the disease that may contribute to the emergence of clinical disease. plays an important role in cell death (Yan-gang et al. 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, inhibitors of NLRP3 may be able to inhibit pyroptosis and the release of pro-inflammatory sites from cells. It is expected that these antibodies will block the release of IL-1 beta and other cytokines, such as IL-1β.

[0121] Formula (I), (II), (III) in free form or in the form of a pharma- ceutically acceptable salt or any one of the compounds according to any one of the preceding embodiments. or the illustrated embodiments (e.g., Ex001 to Ex104 disclosed herein). Compounds according to any one of the above methods may have beneficial pharmacological properties, such as those provided in the following section. NRLP3 inhibitory properties on the NLRP3 pathway, as shown, for example, by in vitro tests and therefore are desirable for use as therapeutic or research chemicals, e.g., tool compounds. can be.

[0122] The compounds of the present invention are useful for treating inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, The present invention may be useful in the treatment of an indication selected from an autoimmune disease or an autoinflammatory disease, e.g. For example, NLRP3 signaling contributes to pathology and / or symptoms and / or progression and NLR Responsive to P3 inhibition and according to any one of embodiments 1 to 19 or the exemplified embodiments of the present invention. According to any one of the examples (e.g., Ex001 to Ex104 disclosed herein), Diseases, disorders or conditions that may be treated or prevented in accordance with the compounds include: I. Inflammatory disorders, e.g., inflammation resulting from autoinflammatory diseases, and non-inflammatory disorders inflammation occurring as a result of infection, or inflammation occurring as a result of trauma, injury or autoimmunity Examples of inflammation that may be treated or prevented include inflammation associated with or associated with The resulting inflammatory response includes: (a) Contact sensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, Allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, rash Skin conditions such as rashes, patches or alopecia; (b) Osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing multiple cartilage degeneration 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) ) joint conditions such as; (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 not closely related to the intestine Food-related allergies that may have adverse effects (e.g., migraines, rhinitis, or eczema) Condition of the gastrointestinal tract; (e) Chronic obstructive pulmonary disease (COPD), asthma (bronchial, allergic, intrinsic, extrinsic, and pulmonary Chronic or persistent asthma, such as dust asthma, and especially late-onset asthma and airway hyperresponsiveness. Asthma included), 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 rhinitis, sinusitis, idiopathic pulmonary fibrosis (IPF) , sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome, hypersensitivity pneumonitis or Respiratory conditions such as chronic interstitial pneumonia; (f) Atherosclerosis, Behcet's disease, vasculitis, or Wegener's granulomatosis What is the condition of the blood vessels; (g) immune conditions, e.g., systemic lupus erythematosus (SLE), Sjögren's syndrome, Systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura or Graves' autoimmune conditions such as rheumatoid arthritis; (h) eye conditions such as uveitis, allergic conjunctivitis or vernal conjunctivitis; (i) neurological conditions such as multiple sclerosis or encephalomyelitis; (j) Acquired immune deficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic Chronic parasitic infections, acute or chronic viral infections, acute or chronic fungal infections Infection, meningitis, hepatitis (A, B or C or other viral hepatitis), peritonitis, pneumonia, throat Skull infection, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, tuberculosis (myco bacterium tuberculosis), Mycobacterium avium Mycobacterium avium intracellulare are), Pneumocystis carinii pneumonia, orchitis / epididymitis, Legionella, leprosy Malignant encephalitis, influenza A, Epstein-Barr virus, viral encephalitis / aseptic meningitis or infection or infection-related conditions, such as pelvic inflammatory disease; (k) Mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure Renal conditions such as kidney disease, uremic or nephritic syndrome; (l) Lymphatic conditions such as Castleman's disease; (m) Hyper-IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis or graft-reactive syndrome Conditions of or related to the immune system, such as host disease; (n) Chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcohol-induced hepatitis , Nonalcoholic fatty liver disease (NAFLD), Alcoholic fatty liver disease (AFLD) , liver conditions such as alcoholic steatohepatitis (ASH) or primary biliary cirrhosis status; (o) cancer, including those listed herein below; (p) burns, wounds, trauma, hemorrhage or stroke; (q) exposure to radiation; and / or (r) obesity; and / or (s) Pain, such as inflammatory hyperalgesia; II. Inflammatory disorders, such as cryopyrin-associated periodic syndrome (CAPS), Muckle-Wall Ells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever ( FMF), neonatal onset multisystem inflammatory disease (NOMID), Majeed syndrome, suppurative inflammation Arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), Adult-onset Still's disease (AOSD), A2 Haploinsufficiency 0 (HA20), childhood granulomatous arthritis (PGA), PLCG2-associated antibody deficiency Autoinflammatory and Antibody Deficiency Immune Dysregulation (PLAID), PLCG2-Associated Autoinflammatory and Antibody Deficiency Immune Dysregulation (APL AID) or B-cell immunodeficiency, sideroblastic anemia with periodic fever and growth retardation (SIFD), etc. Inflammatory diseases, including inflammation resulting from autoinflammatory diseases such as; III. Immunologic diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibodies syndrome (APS), anti-synthetic enzyme antibody syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune Infectious hepatitis, autoimmune oophoritis, autoimmune polyendocrine deficiency, autoimmune thyroiditis, parsley Achilles' disease, Crohn's disease, Type 1 diabetes (T1D), Goodpasture's syndrome, Graves' disease , Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, systemic lupus erythematosus, including systemic lupus erythematosus (SLE), primary progressive multiple sclerosis (P PMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRM Multiple sclerosis (MS), including myasthenia gravis, opsoclonus-myoclonus syndrome (OMS), optic neuritis, ordinothyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary Liver cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, intractable Gouty arthritis, Reiter's syndrome, Sjogren's syndrome, systemic sclerosis, systemic connective tissue Tissue disorder, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, Alopecia areata, Beliefs' disease, Chagas' disease, autonomic neuropathy, endometriosis, sweat gland abscess (HS) , interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Hunitzler syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis, white Autoimmune diseases such as plaques or vulvodynia; IV. Lung cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), Langerhans cell histiocytosis ( LCH), myeloproliferative neoplasms (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndromes (MDS), acute Lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), promyelocytic leukemia (APML) or APL), adrenal cancer, anal cancer, basal and squamous cell skin cancer, bile duct cancer , 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 Membrane cancer, esophageal cancer, Ewing family tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, Gastric stromal tumor (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's lymphoma cancer, renal cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumor, and cutaneous T-cell lymphoma. lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal cancer, and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, 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, gastric cancer, testicular cancer, thymic cancer, Thyroid cancer, including acellular thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's disease Chromoglobulinemia and cancer, including Wilms tumor; V. Viral infections (e.g., influenza virus, human immunodeficiency virus (HIV) ), alphaviruses (such as Chikungunya virus and Ross River virus), flaviviruses viruses (such as dengue and zika viruses), herpes viruses (Epstein-Barr virus, -virus, cytomegalovirus, varicella zoster virus and KSHV, etc.), poc Vaccinia virus (modified vaccinia virus Ankara) and myxoma virus viruses, adenoviruses (such as adenovirus 5), or papillomaviruses ), bacterial infections (e.g., Staphylococcus aureus s), Helicobacter pylori, Bacillus anthracis s anthracis), Bordetella pertussis, Burkholderia pseudomallei, Corynebacterium diphtheriae (C orynebacterium diphtheriae), Clostridium tetani (Clostri tetani, Clostridium botulinum m), Streptococcus pneumoniae, pyogenes Streptococcus pyogenes, Listeria ia monocytogenes, Haemophilus influenzae fluenzae, Pasteurella multocida ida), Shigella dysenteriae, Mycobacterium tuberculosis (Myc obacterium tuberculosis, Mycobacterium leprae um leprae, Mycoplasma pneumoniae ae), Mycoplasma hominis, meningitis Neisseria meningitidis, Neisseria gonorrhoeae onorrhoeae, Rickettsia rickettsii ttsii), Legionella pneumophila ila), Klebsiella pneumoniae, Pseudomonas aeruginosa udomonas aeruginosa, Propionibacter ium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae (V cholerae, Salmonella typhi murium, Salmonella typhi, Borrelia burgdorferi Borrelia burgdorferi or Yersinia pestis nia pestis), fungal infections (e.g., Candida species or Aspergillus species), protozoal infections (e.g., Plasmodium, Babesia, Giardia, Ento Amoeba, Leishmania or Trypanosoma), helminth infections (e.g. Schistosoma, infectious diseases, including blood flukes, roundworms, tapeworms or flukes) and prion infections; VI. Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease brain injury from pneumococcal meningitis; intracranial aneurysms; traumatic brain injury; multiple sclerosis Central nervous system diseases such as glaucoma 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 stroke, including stroke, transient ischemic attack, myocardial infarction, including recurrent myocardial infarction, congestive heart failure and Heart failure, including heart failure with preserved ejection fraction; embolism; aneurysms, including abdominal aortic aneurysms; cardiovascular risk Cardiovascular disease such as chronic kidney disease (CvRR) and pericarditis, including Dressler syndrome; IX. Chronic Obstructive Pulmonary Disorder (COPD), Allergic Asthma and Steroid-Resistant Asthma Such as asthma, asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis and idiopathic respiratory diseases, including pulmonary fibrosis; X. Nonalcoholic fatty liver disease (NAFL), including advanced fibrosis stages F3 and F4 D) and nonalcoholic steatohepatitis (NASH), alcoholic fatty liver disease (AFLD) ) as well as liver disease, including alcoholic steatohepatitis (ASH); XI. Acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis and kidney disease, including diabetic nephropathy; XII. Diseases of the Ocular Epithelium, Age-Related Macular Degeneration (AMD) (Dry and Wet), Uveitis, Keratinitis 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, including hidradenitis suppurativa (HS), other cystic skin diseases and acne congenita skin diseases; XIV. Lymphatic conditions such as lymphangitis and Castleman's 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. An individual has a germline or somatic non-silent mutation in NLRP3 Any disease determined to be

[0123] More particularly, the compounds of the present invention are useful in the treatment of indications selected from the following: Obtained: Inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, 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, nonalcoholic steatohepatitis (NASH), and alcoholism. fatty liver disease and alcoholic liver disease), inflammatory arthritis-related diseases (e.g., gout, Pseudogout (cartilage calcification), osteoarthritis, rheumatoid arthritis, arthropathy (e.g. acute, chronic), Kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes and associated complications (e.g., nephropathy, retinopathy, 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., cardiovascular risk reduction (C vRR), hypertension, atherosclerosis, type I and type II diabetes and related conditions comorbidities, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (e.g., sweat gland abscess, psoriasis, In the treatment of various conditions, including acne, wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration and cancer Associated diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes) (MDS), myelofibrosis). In particular, autoinflammatory fever syndromes (e.g., CAPS), sickle cell diabetes mellitus type I / II and related complications (e.g., nephropathy, retinopathy), gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders related to neuroinflammation (e.g. multiple sclerosis) brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), hidradenitis pyosum Tumors, wound healing and scar formation and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, Myelodysplastic syndrome (MDS), myelofibrosis.

[0124] In particular, the compounds of the present invention or pharma- ceutically acceptable salts thereof are preferably used to treat autoinflammatory fever syndromes. Group A (e.g., CAPS), Sickle Cell Disease, Type I / II Diabetes and related complications (e.g., (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (cartilage calcification), chronic liver disease, ASH, disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurological disorders) degenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g. Cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scarring, and Cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), bone The subject invention may be useful in the treatment of a disease or disorder selected from the group consisting of myelofibrosis.

[0125] Thus, in a further aspect, the present invention relates to a compound of formula (I), (II), (III) or (IV) in therapy. III), and (III-A), or any of the preceding embodiments. A compound according to any one of the embodiments 1 to 11g (i.e. according to any one of the embodiments 1 to 11g), or Any one of the examples (e.g., Ex001 to Ex104 disclosed herein) In a further embodiment, the use of a compound according to the present invention or a pharma- ceutically acceptable salt thereof is provided. The present invention relates to a method for treating a disease that can be treated by inhibition of the NLRP3 inflammasome pathway. In another embodiment, the disease is selected from the list above, suitably inflammasome-related. Diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, e.g. Fever syndromes (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythema tos (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis , nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease diseases), diseases related to inflammatory arthritis (e.g., gout, pseudogout (cartilage calcification), degenerative joint disease, Arthritis, rheumatoid arthritis, arthropathy, e.g. acute and chronic), kidney-related diseases (e.g. hypertension, Oxaluria, lupus nephritis, diabetes mellitus type I / II and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), diseases related to neuroinflammation (e.g. , multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular system / Metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis) atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (e.g., sweat gland abscess, acne), wound healing and scar formation, asthma Diseases / disorders related to lung disease, sarcoidosis, age-related macular degeneration, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis) In particular, autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, and type I / II Diabetes mellitus and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders related to neuroinflammation (e.g. multiple sclerosis) brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), hidradenitis pyosum Tumors, wound healing and scar formation and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, Myelodysplastic syndrome (MDS), myelofibrosis.

[0126] Thus, in a further aspect, the present invention provides a compound of formula (I) for use in therapy , (II), (III), and (III-A), or any one of the compounds of the above According to any one of the embodiments (i.e. according to any one of the embodiments 1 to 11g) The compound or the exemplified embodiment (e.g., Ex001 to E disclosed herein) x104) or a pharma- ceutically acceptable salt thereof. In certain embodiments, the therapy may be treated by inhibition of the NLRP3 inflammasome pathway. In another embodiment, the disease is selected from the above list, suitably inflammatories. Some-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases , e.g. autoinflammatory fever syndromes (e.g. cryopyrin-associated periodic syndrome), sickle cell disease, Systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, Viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and Alcoholic liver disease), inflammatory arthritis-related diseases (e.g., gout, pseudogout (chondrolithiasis) ashing), osteoarthritis, rheumatoid arthritis, arthropathy (e.g. acute and chronic), kidney-related diseases Diseases (e.g., hyperoxaluria, lupus nephritis, diabetes mellitus type I / II and related complications) For example, nephropathy, retinopathy), hypertensive nephropathy, inflammation associated with hemodialysis, and inflammation associated with neuroinflammation. Diseases that cause glaucoma (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's Diseases), cardiovascular / metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension Disease, atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease Percutaneous pulmonary artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g., sweat gland abscess, acne), wound healing and Diseases / disorders related to retinal scarring, asthma, sarcoidosis, age-related macular degeneration and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), bone marrow In particular, autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease , Type I / II diabetes mellitus and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, Gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, and disorders related to neuroinflammation (e.g. (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis, Atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension, pressure, sweat gland abscess, wound healing and scarring, and cancer (e.g., colon cancer, lung cancer, myeloproliferative tumors, leukemia, myelodysplastic syndromes (MDS), and myelofibrosis).

[0127] In another aspect, the present invention provides a method for treating a disease that is treated by inhibiting NLRP3. The method comprises administering to a patient a therapeutically effective amount of a compound represented by formula (I), (II), (III), or (III-A). Any one of the compounds or according to any one of the preceding embodiments (i.e., According to any one of the embodiments 1 to 11g), or the exemplified examples (e.g., A compound according to any one of Ex001 to Ex104) disclosed in the specification or In a further embodiment, the method comprises administering a pharma- ceutically acceptable salt thereof. The disease may be any of the diseases / disorders listed above, as appropriate, inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune or autoinflammatory diseases, such as autoinflammatory fever syndrome (e.g., cryoprevention) Phosphate-associated periodic syndrome, sickle cell disease, systemic lupus erythematosus (SLE), liver-related Related diseases / disorders (e.g., chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis ( NASH), alcoholic steatohepatitis and alcoholic liver disease), and inflammatory arthritis-related Diseases that cause osteoarthritis (e.g. gout, pseudogout (cartilage calcification), osteoarthritis, rheumatoid arthritis, osteoarthritis , e.g. acute, chronic), kidney-related diseases (e.g. hyperoxaluria, lupus nephritis, Type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hematology dialysis-related inflammation), diseases associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g. Cardiovascular Risk Reduction (CvRR), Hypertension, Atherosclerosis, Type I and II Diabetes and related complications, peripheral arterial disease (PAD), acute heart failure, inflammatory skin diseases (e.g., hidradenitis suppurativa, acne), wound healing and scarring, asthma, sarcoidosis, age-related Macular degeneration and cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, white Hematologic malignancies, myelodysplastic syndromes (MDS), and myelofibrosis. In particular, autoinflammatory fever Syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., For example, nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (cartilage calcification), chronic liver disease, NASH, disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, degenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g. , Cardiovascular Risk Reduction (CvRR), Hypertension), Sweat Gland Abscess, Wound Healing and Scarring, and Cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), Myelofibrosis).

[0128] In a further aspect, the present invention relates to an NLRP3 inflammasome as disclosed herein. Llamasome activity and / or NLRP3-induced IL-1beta and / or NLRP3 induction In the treatment of a disease, disorder, or condition that is substantially or completely mediated by human IL-18, Compounds of any one of formulas (I), (II), (III), and (III-A) are useful in or according to any one of the preceding embodiments (i.e., any of embodiments 1 to 11g). or one of the compounds according to the exemplary embodiments disclosed herein. The present invention provides a compound according to any one of Ex101 to Ex104) or a pharma- ceutically acceptable salt thereof. Some of the diseases, disorders, or conditions described herein are associated with NLRP3. This occurs due to a mutation in NLRP3, which specifically results in increased NLRP3 activity.

[0129] Thus, in a further aspect, the present invention relates to a compound of formula (I), (I Compounds of any one of I), (III), and (III-A), or the preceding embodiments. a compound according to any one of the embodiments (i.e. according to any one of the embodiments 1 to 11g); or the exemplified embodiments (e.g., Ex001 to Ex10 disclosed in this specification) 4) or a pharma- ceutically acceptable salt thereof. In one embodiment, the medicament is for the treatment of a disease, the disease being an NLRP3 inflammasome. In another embodiment, the disease is treated by inhibition of the lamasome pathway. Suitably, inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as autoinflammatory fever syndrome (e.g., cryopyrin-associated periodic syndrome) ), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g. For example, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), and alcoholism. and alcoholic fatty liver disease), inflammatory arthritis-related diseases (e.g., gout, , pseudogout (cartilage calcification), osteoarthritis, rheumatoid arthritis, arthropathy (e.g. acute, chronic) , kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes, and and associated complications (e.g., nephropathy, retinopathy, 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., cardiovascular risk reduction ( CvRR), hypertension, atherosclerosis, type I and type II diabetes and related Complications include peripheral arterial disease (PAD), acute heart failure, inflammatory skin diseases (e.g., sweat gland abscess, acne, wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration and cancer Associated diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes) In particular, autoinflammatory fever syndrome (e.g., CAP) is selected from the group consisting of myelofibrosis, myelofibrosis, and myelofibrosis. S), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy) , hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, and neuroinflammation Related disorders (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's Immers disease), atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), sweat gland abscess, wound healing and scarring, and cancer (e.g., colon cancer) , lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), and myelofibrosis.

[0130] In another embodiment of the present invention, a disease or disorder treated by inhibition of the NLRP3 pathway is 3-Methyl-2-(5-methyl-6-((1-methylpiperidinyl)) (pyridazin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)pheno In another embodiment of the present invention, NL or a pharma- ceutically acceptable salt thereof is provided. (S) for use in the treatment of a disease or disorder treated by inhibition of the RP3 pathway -3-Methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-5-(trifluoromethyl)phenol or its pharma- ceutically acceptable salt In a preferred embodiment of the present invention, the inhibition of the NLRP3 pathway is (R)-3-methyl-2-( 5-Methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl )-5-(trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof is provided. For example, the disease or disorder may be any of those listed above, suitably an inflammasome-associated disease or disorder. disease / disorder, immune disease, inflammatory disease, autoimmune disease, or autoinflammatory disease, e.g., autoinflammatory Fever syndromes (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus Systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, Nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease diseases), diseases related to inflammatory arthritis (e.g., gout, pseudogout (cartilage calcification), degenerative joint disease, Arthritis, rheumatoid arthritis, arthropathy, e.g. acute and chronic), kidney-related diseases (e.g. hypertension, Oxaluria, lupus nephritis, diabetes mellitus type I / II and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), diseases related to neuroinflammation (e.g. , multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular system / Metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis) atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (e.g., sweat gland abscess, acne), wound healing and scar formation, asthma Diseases / disorders related to glaucoma, sarcoidosis, age-related macular degeneration, and cancer (e.g., intestinal cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis) In particular, the compounds of the present invention are useful in treating autoinflammatory fever syndrome (e.g., CAPS), sickle cell syndrome (SCS), and other conditions. Hemocytosis, type I / II diabetes mellitus and related complications (e.g., nephropathy, retinopathy), hyperoxalic acid Disorders related to urinaria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, and neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), Atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR) , hypertension), sweat gland abscesses, wound healing and scarring, and cancer (e.g., colon cancer, lung cancer, bone Useful for treating myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), and myelofibrosis may be also possible.

[0131] In one embodiment of the present invention, the present invention relates to a method for treating a disease or disorder that is treated by inhibition of the NLRP3 pathway. 2-(4-methyl-6-((1-methylpiperidin-3-yl) )Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol or its drug In another embodiment of the present invention, a compound that inhibits the NLRP3 pathway is provided. (S)-2-(4-methyl-2-phenylindole (S)-2-methyl-2-propanediol (4-sulfonyl) 6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-methyl -(trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof is provided. In a preferred embodiment of the invention, a disease or disorder treated by inhibition of the NLRP3 pathway is (R)-2-(4-methyl-6-((1-methylpiperidinyl) (3-amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol For example, the disease or disorder may be one of the diseases described above. and, appropriately, inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, Infectious diseases or autoinflammatory diseases, such as autoinflammatory fever syndrome (e.g., cryopyrin-associated periodontal disease) Syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders Harm (e.g., chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), diseases related to inflammatory arthritis (e.g. , gout, pseudogout (cartilage calcification), osteoarthritis, rheumatoid arthritis, arthropathy, e.g. acute, chronic), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes) Diabetic diseases and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), diseases associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurological disorders, degenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., cardiovascular risk CvRR, hypertension, atherosclerosis, type I and type II diabetes and related associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (e.g., sweat gland abscesses, acne, wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration and Cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes) In particular, the compounds of the present invention are selected from the group consisting of autoinflammatory, myelofibrosis, myelofibrosis, and myelofibrosis. Fever syndromes (e.g. CAPS), sickle cell disease, diabetes mellitus type I / II and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (cartilage calcification), chronic liver disease Disease, NASH, disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injury) , neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g. For example, cardiovascular risk reduction (CvRR), hypertension, sweat gland abscesses, wound healing and scarring and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS) ), myelofibrosis).

[0132] In another embodiment of the present invention, a disease or disorder treated by inhibition of the NLRP3 pathway is 2-(6-((1-ethylpiperidin-3-yl)amino)- Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or its Pharmaceutically acceptable salts are provided. In another embodiment of the present invention, (S)-2-(6- ((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl- 5-(trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof is provided. In a preferred embodiment of the present invention, a disease or disorder that is treated by inhibition of the NLRP3 pathway is (R)-2-(6-((1-ethylpiperidine-3-yl)phenyl ether for use in the treatment of neuropathies (amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno For example, the disease or disorder may be any of the above-mentioned List of diseases / disorders, as appropriate, inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, Immunologic or autoinflammatory diseases, such as autoinflammatory fever syndrome (e.g., cryopyrin-associated cycle Syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / Disorders (e.g., chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), Alcoholic fatty liver disease and alcoholic liver disease), inflammatory arthritis-related diseases (e.g. For example, gout, pseudogout (cartilage calcification), osteoarthritis, rheumatoid arthritis, arthropathy, e.g. acute , chronic), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II Diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), diseases associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, degenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g., cardiovascular risk CvRR, hypertension, atherosclerosis, type I and type II diabetes, and associated complications, peripheral arterial 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 and cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelopathies) In particular, the compounds of the present invention are selected from the group consisting of autoinflammatory, myelofibrosis, myelofibrosis, and myelofibrosis. Sickle cell disease, diabetes mellitus type I / II and related complications Disease (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic hepatitis Disease, NASH, disorders associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute wounds) damage, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk ( For example, cardiovascular risk reduction (CvRR), hypertension, hidradenitis suppurativa, wound healing and scar formation and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS) S), myelofibrosis).

[0133] In another embodiment of the present invention, a disease or disorder treated by inhibition of the NLRP3 pathway is 2-(6-((3-hydroxy-3-methylcyclobutyl)) for use in therapy Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof. In another embodiment of the present invention, 2-(6-3) PHASE-3 PATHWAY FOR USE IN THE TREATMENT OF A DISEASE OR DISORDER TREATED BY INHIBITION OF THE PATHWAY (((trans)-3-hydroxy-3-methylcyclobutyl)amino)pyridazine-3 3-methyl-5-(trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof In a preferred embodiment of the present invention, inhibition of the NLRP3 pathway results in 2-(6-(((cis)-3- Hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl- 5-(trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof is provided. For example, the disease or disorder may be any of those listed above, suitably an inflammasome-associated disease / disorder. Disorders, immune disorders, inflammatory disorders, autoimmune disorders or autoinflammatory disorders, such as autoinflammatory fever syndrome. group (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic fatty liver disease, Nonalcoholic fatty liver disease (NASH), alcoholic fatty liver disease and alcoholic liver disease), Diseases associated with inflammatory arthritis (e.g., gout, pseudogout (cartilage calcification), osteoarthritis, Rheumatoid arthritis, arthropathy (e.g. acute and chronic), kidney-related diseases (e.g. hyperoxalic acid Diabetes mellitus, lupus nephritis, diabetes mellitus type I / II and related complications (e.g. nephropathy, retinopathy) , hypertensive nephropathy, hemodialysis-related inflammation), diseases related to neuroinflammation (e.g., multifocal Sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic Disease / Disorder (e.g., Cardiovascular Risk Reduction (CvRR), Hypertension, Atherosclerosis) diabetes mellitus and related complications; peripheral arterial disease (PAD); acute heart failure allergies), inflammatory skin diseases (e.g., sweat gland abscess, acne), wound healing and scar formation, asthma, monkeys coidosis, age-related macular degeneration, and cancer-related diseases / disorders (e.g., colon cancer, lung cancer) , myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), and myelofibrosis). In particular, the compounds of the present invention are useful in treating autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, I Type 1 / 2 diabetes mellitus and associated complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout , pseudogout (chondrocalcinosis), chronic liver disease, NASH, and disorders related to neuroinflammation (e.g. Multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atheroma Atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension ), sweat gland abscesses, wound healing and scarring, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms) , leukemia, myelodysplastic syndromes (MDS), myelofibrosis).

[0134] In another embodiment of the present invention, a disease or disorder treated by inhibition of the NLRP3 pathway is 2-(6-((3-hydroxycyclohexyl)amino)pyridin for use in therapy ridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or its drug In another embodiment of the present invention, a compound that inhibits the NLRP3 pathway is provided. 2-(6-(((1S) for use in the treatment of a disease or disorder treated by ,3R)-3-Hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl The present invention provides a method for the preparation of a compound comprising administering to a subject a compound having the above-mentioned structure a phenyl-5-(trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof. In another embodiment of the present invention, a disease or disorder that is treated by inhibition of the NLRP3 pathway is 2-(6-(((1R,3R)-3-hydroxycyclohexyl 1-methyl-2-propanediol for use in the treatment of pulmonary circulation disorders - Patents.com Hexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl) In another embodiment of the present invention, there is provided a compound comprising phenol or a pharma- ceutically acceptable salt thereof. for use in the treatment of a disease or disorder treated by inhibition of the NLRP3 pathway 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol or its pharma- ceutically acceptable salt In a preferred embodiment of the present invention, the inhibition of the NLRP3 pathway is 2-(6-(((1R,3S )-3-Hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5 -(trifluoromethyl)phenol or a pharma- ceutically acceptable salt thereof is provided. For example, the disease or disorder may be any of those listed above, suitably an inflammasome-associated disease / disorder. Injuries, immune disorders, inflammatory disorders, autoimmune diseases or autoinflammatory disorders, such as autoinflammatory fever syndrome. (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus ( SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic fatty liver disease, Nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), inflammation Diseases related to osteoarthritis (e.g., gout, pseudogout (cartilage calcification), osteoarthritis, Rheumatoid arthritis, arthropathy (e.g. acute and chronic), kidney-related diseases (e.g. hyperoxaluria) nephritis, lupus nephritis, diabetes mellitus type I / II and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), diseases associated with neuroinflammation (e.g., multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases Diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis) type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure ), inflammatory skin diseases (e.g., sweat gland abscess, acne), wound healing and scar formation, asthma, sarcoidosis, idiopathies, age-related macular degeneration, and cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes (MDS), and myelofibrosis. In particular, the compounds of the present invention are useful in treating autoinflammatory fever syndromes (e.g., CAPS), sickle cell disease, type I / Type II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, Pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders related to neuroinflammation (e.g., sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), atherosclerosis Atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension) , sweat gland abscesses, wound healing and scarring, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, It may be useful in treating cancers including leukemia, myelodysplastic syndromes (MDS), and myelofibrosis.

[0135] In another embodiment of the present invention, a disease or disorder treated by inhibition of the NLRP3 pathway is 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-2-phenylpropanediol for use in therapy (fluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidine-3 In another embodiment of the present invention, there is provided a compound comprising: For use in the treatment of a disease or disorder treated by inhibition of the NLRP3 pathway 3R,5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) )phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol or In another embodiment of the present invention, a NLRP3 mediated agonist is provided. (3R,5R) for use in the treatment of a disease or disorder treated by inhibition of the -5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Pyridazin-3-yl)amino)-1-methylpiperidin-3-ol or its pharma- In another embodiment of the present invention, inhibition of the NLRP3 pathway results in (3S,5S)-5-((6 -(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazine- 3-yl)amino)-1-methylpiperidin-3-ol or a pharma- ceutically acceptable salt thereof In a preferred embodiment of the present invention, a therapeutic method is provided comprising the steps of: inhibiting the NLRP3 pathway; (3S,5R)-5-((6-(2- Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl )amino)-1-methylpiperidin-3-ol or a pharma- ceutically acceptable salt thereof is provided. For example, the disease or disorder may be any of those listed above, suitably associated with inflammasomes. Diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, e.g. Fever syndromes (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythema tos (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis , nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease diseases), diseases related to inflammatory arthritis (e.g., gout, pseudogout (cartilage calcification), degenerative joint disease, Arthritis, rheumatoid arthritis, arthropathy, e.g. acute and chronic), kidney-related diseases (e.g. hypertension, Oxaluria, lupus nephritis, diabetes mellitus type I / II and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), diseases related to neuroinflammation (e.g. , multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular system / Metabolic diseases / disorders (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis) atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (e.g., sweat gland abscess, acne), wound healing and scar formation, asthma Diseases / disorders related to lung disease, sarcoidosis, age-related macular degeneration, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis) In particular, the compounds of the present invention are useful in treating autoinflammatory fever syndrome (e.g., CAPS), sickle cell anemia, and the like. Diabetes mellitus type I / II and related complications (e.g., nephropathy, retinopathy), hyperoxaluria , gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders related to neuroinflammation ( For example, multiple sclerosis, brain infections, acute injuries, neurodegenerative diseases, Alzheimer's disease, Atherosclerosis and cardiovascular risk (e.g., cardiovascular risk reduction (CvRR), hypertension), sweat gland abscesses, wound healing and scarring, and cancer (e.g., colon cancer, lung cancer, bone marrow apoptosis, It is useful in treating various types of cancers, including myelodysplastic syndromes (MDS), myelofibrosis, and myeloproliferative disorders. It is possible.

[0136] The pharmaceutical composition or combination of the present invention is administered in an amount of about 1 to 100 mg / kg per subject weighing about 50 to 70 kg. 0 mg of active ingredient or about 1-500 mg, or about 1-250 mg, or about 1-1 A unit dosage of 50 mg, or about 1 to 100 mg, or about 1 to 50 mg of active ingredient. The therapeutically effective dosage of the compound, pharmaceutical composition, or combination thereof may be Depending on the species, weight, age and individual condition, disorder or disease or its severity being treated A physician, clinician, or veterinarian of ordinary skill may use any of the following methods to prevent, treat, or inhibit the progression of a disorder or disease: The effective amount of each of the active ingredients required to inhibit the action of the agonist can be readily determined.

[0137] The dosage characteristics listed above are for use in mammals, e.g. mice, rats, dogs, monkeys or The isolated organs, tissues and preparations are advantageously used for in vitro and in vivo testing. The compounds of the present invention can be demonstrated in vitro in the form of liquid formulations, e.g. and in vivo enterally, parenterally, conveniently intravenously, e.g., as a suspension. The in vitro dosage is about 10 -3 Mol concentration Degrees ~ 10 -9 The therapeutically effective amount in vivo will vary depending on the route of administration. Depending on the dose, the range may range from about 0.1 to 500 mg / kg or from about 1 to 100 mg / kg. .

[0138] Combination Products and Therapeutic Combinations of the Invention "Combination" means a fixed combination or administration combination in one dosage unit form. The term "combination agent" refers to a compound of the present invention and a combination partner (e.g., another drug described below). The therapeutic agents (also called "therapeutic agents" or "co-agents") may be administered simultaneously, separately, or within a time frame. These time frames, among other things, allow the combination partners to be cooperative. The single components may be packaged in one kit or separately. One or both of the components (e.g., powder or liquid) may be dispensed to the desired dose prior to administration. As used herein, the terms "co-administration" and "combination administration" refer to "Combination" or other similar terms refer to the combination partner that is selected. It is intended to encompass administration to a single subject (e.g., patient) in which the agents are administered simultaneously. It is intended to include therapeutic regimens that are not necessarily administered by the same route of administration or at the same time. As used herein, the term "pharmaceutical combination" refers to the mixing of two or more therapeutic agents. or resulting from combinations of fixed and non-fixed combinations of therapeutic agents. As used herein, the term "pharmaceutical combination" refers to a product that contains both: Fixed or non-fixed combinations in one dosage unit form or Refers to a kit of parts for administration combinations, where two or more therapeutic agents are administered separately at the same time. The combination of the two drugs may be administered separately or over a time frame, and in particular such a time frame may allow for the administration of the two drugs in combination. The term "fixed combination" refers to a combination of therapeutic partners that exhibit a cooperative, e.g., synergistic, effect. The therapeutic agents, e.g., the compounds of the invention and the combination partners, may both be administered as a single entity or dosage. The term "non-fixed combination" refers to the combination of the two drugs administered simultaneously to a patient. " refers to the therapeutic agent, e.g., a compound of the invention, and the combination partner, both being treated as separate entities. are administered to a patient simultaneously, in parallel or sequentially, without any specific time limit, and such administration By "administration," we mean providing therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more therapeutic agents.

[0139] The term "combination therapy" refers to a combination of therapies that treat a therapeutic condition or disorder described in this disclosure. Such administration refers to the administration of two or more therapeutic agents for the treatment of a disease with a fixed ratio of active ingredients. This includes the simultaneous administration of these therapeutic agents substantially simultaneously, such as in one capsule. Alternatively, such administration may be accomplished by administering the active ingredient in multiple or separate containers (e.g., For example, co-administration in tablets, capsules, powders and liquids. The liquid formulation may be reconstituted or diluted to the desired dose prior to administration. The use of each type of therapeutic agent simultaneously or sequentially at different times is also encompassed. In some cases, the therapeutic regimen may include a combination of drugs in treating the conditions or disorders described herein. combination will have beneficial effects.

[0140] The compounds of the present invention may be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention may be administered separately or together with other agents by the same or different routes of administration. The therapeutic agent may be, for example, a chemical compound, a peptide, or the like. The compound of the present invention is a compound, an antibody, an antibody fragment or a nucleic acid, which is therapeutically active or enhances therapeutic activity when administered to a patient in combination with

[0141] In one embodiment, the present invention provides a preparation for simultaneous, separate or sequential use in therapy. As a combination of compounds, any one of the compounds represented by formula (I), (II), (III), and (III-A) A composition comprising one or more compounds or a pharma- ceutical acceptable salt thereof and at least one other therapeutic agent. In one embodiment, the therapy is for treating a disease or condition mediated by NLRP3. Products provided as combination preparations are those that are administered together in the same pharmaceutical composition. and a compound of any one of formulas (I), (II), (III), and (III-A) or pharma- ceutically acceptable salts thereof, as well as other therapeutic agents, or in separate form, e.g., in the form of a kit. In the compound represented by formula (I), (II), (III), or (III-A), or pharma- ceutically acceptable salts thereof, as well as compositions containing other therapeutic agents.

[0142] In one embodiment, the present invention provides a compound represented by formula (I), (II), (III), and (III-A): Any one of the compounds or a pharma- ceutically acceptable salt thereof or any of the preceding embodiments. a compound according to any one of the embodiments 1 to 11g (i.e. according to any one of the embodiments 1 to 11g) or Pharmaceutical combinations comprising a pharma- ceutical acceptable salt and another therapeutic agent are provided. The pharmaceutical combination may include a pharma- ceutically acceptable carrier, as described above. Good too.

[0143] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, At least one of the compositions comprises a compound represented by formula (I), (II), (III), or (III-A). Any one of the compounds or pharma- ceutically acceptable salts thereof or any one of the preceding embodiments. A compound according to any one of the embodiments (i.e. according to any one of embodiments 1 to 11g) or a pharmaceutical composition thereof. In one embodiment, the kit comprises a container, separate bottle, or Such a kit may include a means for keeping the compositions separate, such as separate foil packets. An example of a blister pack is the blister pack commonly used in the packaging of tablets, capsules, and the like. It is Turpack.

[0144] The kits of the present invention may be configured to contain different dosage forms for administration, e.g., oral and parenteral. To administer the separate compositions at intervals of 10 minutes or to titrate the separate compositions to each other. To facilitate compliance, the kits of the invention typically include instructions for administration. Includes instructions for use.

[0145] In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent may be the same or different. Moreover, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by manufacturers. Therapeutic agents may be administered in combination with other therapeutic agents (e.g., a combination product of the present invention and another therapeutic agent) prior to (i) the release of the combination product to physicians (e.g., a combination product of the present invention and another therapeutic agent). (ii) by the physician (or under the guidance of the physician) immediately prior to administration; (iii) for example, during sequential administration of a compound of the invention and another therapeutic agent, the patient may It may be combined into one therapy.

[0146] Thus, the present invention provides a method for treating a disease or condition mediated by NLRP3. A compound represented by any one of formulas (I), (II), (III), and (III-A) or and the medicament is prepared for administration with another therapeutic agent. The present invention also provides another therapeutic agent for treating a disease or condition mediated by NLRP3. The present invention also provides a method for treating a medicament comprising administering to a patient of the present invention ... compound of the formula (I), (II), (III), and (III-A) Any one of the compounds or a pharma- ceutically acceptable salt thereof or any of the preceding embodiments. A compound according to any one of the embodiments 1 to 11g or a drug thereof. It is administered together with a physiologically acceptable salt.

[0147] The present invention also relates to a method for treating a disease or condition mediated by NLRP3. A compound represented by any one of formulas (I), (II), (III), and (III-A) for use in A compound or a pharma- ceutically acceptable salt thereof according to any one of the preceding embodiments. (i.e. according to any one of embodiments 1 to 11g) or a pharmaceutical Acceptable salts are also provided, and the compounds of any of formulas (I), (II), (III), and (III-A) are or one of the compounds or a pharma- ceutically acceptable salt thereof or any one of the preceding embodiments. A compound according to any one of the embodiments 1 to 11g or a pharmaceutical composition thereof. The present invention also provides a method for the preparation of NLRP3 inhibitors and / or NLRP3 inhibitors. Another therapeutic for use in a method for treating a disease or condition mediated by The present invention also provides a method for treating a pulmonary circulation comprising administering to a subject a therapeutic agent having the formula (I), (II), (III), or (III-A). Any one of the compounds or pharma- ceutically acceptable salts thereof or any one of the preceding embodiments. A compound according to any one of the embodiments 1 to 11g or a pharmaceutical composition thereof. The present invention also provides a method for the preparation of a medicament for administration of a medicament for the treatment of a pulmonary artery disease (pulmonary artery disease) mediated by NLRP3. A compound represented by the formula (I), (II) for use in a method for treating a disease or condition mediated by ), (III), and (III-A) or a pharma- ceutically acceptable salt thereof. or according to any one of the preceding embodiments (i.e., any of embodiments 1 to 11g). Also provided is a compound according to any one of the formulas (I), (I Any one of compounds represented by I), (III) and (III-A) or a pharma- ceutical approved derivative thereof or according to any one of the preceding embodiments (i.e., embodiments 1 to 11g). The compound or a pharma- ceutical acceptable salt thereof may be administered in combination with another therapeutic agent. The present invention also provides a method for treating a disease or condition mediated by NLRP3. Also provided is an additional therapeutic agent for use in the method, the other therapeutic agent being a compound represented by formula (I), (II), Any one of the compounds of (III) and (III-A) or a pharma- ceutically acceptable salt thereof or according to any one of the preceding embodiments (i.e., any of embodiments 1 to 11g). The compound according to any one of the preceding claims or a pharma- ceutical acceptable salt thereof is administered.

[0148] The present invention also relates to a compound of formula (I) for treating a disease or condition mediated by NLRP3. ), (II), (III), and (III-A) or according to any one of the preceding embodiments (i.e., embodiments 1 to 11g) or a pharma- ceutical acceptable salt thereof. The patient may have previously been treated (e.g., within 24 hours) with another therapeutic agent. and another method for treating a disease or condition mediated by the NLRP3 inflammasome pathway. The present invention also provides the use of a therapeutic agent of formula (I), (II), (III), and (III- A) any one of the compounds or a pharma- ceutically acceptable salt thereof or any one of the preceding embodiments. A compound according to any one of the embodiments (i.e. according to any one of the embodiments 1 to 11g) or has been previously treated (eg, within 24 hours) with a pharma- ceutical acceptable salt thereof.

[0149] In one embodiment, the other therapeutic agent is an inflammasome, as disclosed herein. Treatment of cancer-related diseases / disorders, immune disorders, inflammatory disorders, autoimmune diseases or autoinflammatory diseases These are useful therapeutic agents in the treatment of

[0150] In one embodiment, the other therapeutic agent useful in the combination therapy is a farnesoid X receptor antagonist. Receptor (FXR) agonists; anti-lipid drugs; anti-fibrotic drugs; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiation therapy and surgery; uric acid lowering therapy; anabolic agents and 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; Cholesterol lowering; Leukotriene A4 hydrolase (LTAH4) inhibitor SGLT2 inhibitors; β2 agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs (NSA Acetylsalicylic acid drugs (ASA) including aspirin; paracetamol; regenerative medicines treatment with a steroid; treatment with cystic fibrosis; and treatment of atherosclerosis. do.

[0151] Suitable leukotriene A4 hydrolase (LTA4) inhibitors for use in combination H) inhibitors are disclosed in WO 2015 / 092740 (Attorney Docket No. PA T056044-WO-PCT do not have.

[0152] Suitable sodium-dependent glucose transporter 2 (SGTT2) antibodies for use in combination LT2) inhibitors are disclosed in U.S. Patent No. 8,163,704 (Attorney Docket No. PAT05 3854-WO-PCT), International Publication No. 2011 / 048112, International Publication International Publication No. 2011 / 048148 or International Publication No. 2010 / 128152 The compounds include, but are not limited to, those disclosed in the publication.

[0153] Suitable beta 2 agonists for use in combination include arformoterol, Bambuterol, Bitolterol, Broxaterol, Carbuterol, Clenbuterol , dopexamine, fenoterol, formoterol, hexoprenaline, ebuterol le, isoetharine, isoprenaline, levosalbutamol, mabuterol, merudrin , metaprotenol, noromilol, orciprenaline, pirbuterol, procaterol ol, reproterol, ritodrine, rimoterol, salbutamol, salmefamol , Salmeterol, Cibenadeto, Sotenerot, Sulfonterol, Terbutaline, Thia Lamido, 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 5-[2-(5,6-Diethylaminoethyl)imide hydrochloride monohydrate, carmoterol, QAB-149 and 5-[2-(5,6-diethylaminoethyl)imide hydrochloride monohydrate ruindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline Lin-2-one, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy )propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)-benzothiazolone, 1-(1-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl )-2-Methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl 4-(1-benzoimidazolyl)-2-methylamino)-4-hydroxyphenyl -2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1 ,4-Benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl 1-[2H-5-hydroxy-3-methyl-2-propylamino]ethanol -Oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl) phenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy -3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n- 1-[2H-5-ethyloxyphenyl]-2-methyl-2-propylamino]ethanol -Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4- [3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl -2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropyl 1-(4-(4H)-propylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one -amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino ) Ethanol, 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl (2-(tert-butylamino)ethanol and combinations thereof, Each of these may be optionally present in the form of a racemate, enantiomeric, diastereomeric, In the form of a stereoisomer or a mixture thereof, optionally with a pharmacologically compatible acid. It is in salt form.

[0154] Suitable cartilage regeneration therapies for use in combination are described in WO 2014 / 13 In Pamphlet No. 8687 (Attorney Case No. PAT055625-WO-PCT) The disclosed ANGPTL3 peptide mimetics or WO 2015 / 175487 Cartilage disclosed in FRET (Attorney Case No. PAT055940-WO-PCT) These include, but are not limited to, formation activators.

[0155] Suitable checkpoint inhibitors for use in combination include anti-PD1 inhibitors , anti-LAG-3 inhibitors, anti-TIM-3 inhibitors, anti-PDL1 inhibitors, but are not limited to these Suitable anti-PD1 inhibitors are described in WO 2015 / 112900. Suitable anti-LAG-3 inhibitors include, but are not limited to, the antibody molecules disclosed in The agent comprises an antibody molecule as disclosed in WO 2015 / 138920. Suitable anti-TIM-3 inhibitors include, but are not limited to, those described in WO 2015 / 11 Antibody molecules disclosed in US Pat. No. 7002, but are not limited to these. The anti-TIM-3 inhibitor is disclosed in the pamphlet of International Publication WO 2015 / 117002. Suitable anti-PDL1 inhibitors include, but are not limited to, the disclosed antibody molecules. The antibody molecule disclosed in Japanese Patent Application Publication No. 2016 / 061142 is also included. Not limited to.

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

[0157] A suitable FXR agonist for use in combination is obeticholic acid (also known as Yuru OCA, Intercept), GS9674, Elafibranor (GFT505 ), GW4064, UPF987, FXR-450, Fexaramine, Methylcholate, Methyl deoxycholate, 5β-cholanic acid, 5β-cholanic acid 7α,12α-diol, NI HS700, Marchantin A, Marchantin E, MFA-1 INT767 (International Publication No. Also known as 6α-ethyl-CDCA, which is disclosed in the brochure No. 2014 / 085474. (also called), MET409 (Metacrine), EDP-305 (Enanta), 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoro Methoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo 2,3-Di(3.2.1)octan-8-yl)-4-fluoro-1,3-benzothiazole-6 - carboxylic acid (also known as tropifexor) or its pharmaceutical equivalents Acceptable salts or those disclosed in WO 2012 / 087519. The compound or compounds disclosed in WO 2015 / 069666 Compounds include, but are not limited to:

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

[0159] Suitable NSAIDs for use in combination include aceclofenac, acemetidine, Syn, acetylsalicylic acid, alclofenac, aluminoprofen, amfenac, Ampiroxicam, Anthormetin Guacil, Anilorac, Antrafenine, Azapro Pazone, Benorilate, Belmoprofen, Bindarito, Bromfenac, Bucloxic Acid , Bucolome, Bufexamac, Bumadizone, Butibufen, Butixylat, Carbasara calcium salt, carprofen, choline magnesium trisalicylate, celecoxib, Methacin, cinnoxicam, clidanac, clobuzarit, devoxamethasone, dexibupro Fen, dexketoprofen, diclofenac, diflunisal, droxicam, erutero Naphthalene, Enfenamic Acid, Etersalate, Etodolaq, Etofenamate, Etoricoxy bu, feclobuzone, felbinac, fenbufen, fenclofenac, fenop Lofen, Fentiazac, Feprazinol, Feprazone, Flobufen, Floccta Fenine, flufenamic acid, flufenisal, flunoxaprofen, flurbiprofen fluprofen, flurbiprofen axetil, furophenac, fluprofen, glucamethasone ibuphenac, ibuprofen, indobufen, indomethacin, indomethacin amfarnesyl, indoprofen, isoxepac, isoxicam, ketoprofen, ketoprofen Trolac, Lobenzarit, Lonazolac, Lornoxicam, Loxoprofen, Lumira Coxib, meclofenamime, meclofen, mefenamic acid, meloxicam, mesalazine , miloprofen, mofezolac, nabumetone, naproxen, niflumic acid, olsalazid oxaprozin, oxypinac, oxyphenbutazone, parecoxib, phenyl Butazone, Perbiprofen, Pimeprofen, Pirazolac, Piriloxicam, Pirpro Fen, Pranoprofen, Priferon, Prinomod, Proglumetacin, Proquazone , Protidinic acid, Rofecoxib, Romazarit, Salicylamide, Salicylic acid, Sal Mysteine, salnacedin, salsalate, sulindac, sudoxicam, suprofen, Talniflumate, Tenidap, Tenosal, Tenoxicam, Tepoxalin, Tiaprofen phenoxyethanol, talamide, tirnoprofen albamel, timegadine, tinoridine, tiopinac , tolfenamic acid, tolmetin, ufenamate, valdecoxib, xymoprofen, Including, but not limited to, zaltoprofen, zoliprofen and combinations thereof .

[0160] Suitable BTK inhibitors include, for example, ibrutinib, acalabrutinib (ACP-196). , evobrutinib; fenebrutinib; tirabrutinib (ONO-4059, GS-40 59); zanubrutinib (BGB-3111), spabrutinib (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 Lett., International Publication No. 2015 / 083008, International Publication No. 2015 / 11 No. 0923 Brochure, International Publication No. 2014 / 173289 Brochure, International Publication Brochure No. 2012 / 021444, Brochure No. WO 2013 / 081016 Lett, WO 2013 / 067274, WO 2012 / 17 No. 0976, International Publication No. 2011 / 162515, U.S. Pat. Application Publication No. 2017 / 119766, International Publication No. 2016 / 065226 Frett, U.S. Pat. No. 9,688,676, International Publication No. WO 2016 / 201280 No. 2017 / 059702, U.S. Pat. No. 9,6 No. 30,968, U.S. Patent Application Publication No. 2014 / 0256734, International Patent Application Publication No. International Publication No. 2017 / 118277, International Publication No. 2014 / 039899 FRET, International Publication No. WO / 16 / 105531, International Publication No. WO 2018 / 00 No. 5849, International Publication No. 2013 / 185082 or J .Med.Chem., 2016, 59(19), 9173-9200 Of particular interest are compounds that inhibit BTK, such as those described in WO 2014 / 0398. The compound of Example 31 described in the brochure of Journal of Medicine No. 99 edicinal chemistry,2016,59(19),9173-9200 The compound has the following structure, which is depicted as compound 14f in [ka] The compounds of the present invention are disclosed in U.S. Patent Application Publication No. 2017 / 119766. The compound of Example 2 is described in WO 2016 / 065226. [ka] The compound of Example 223, which is Compound 1 described in WO 2017 / 059702 Compound 1 described in International Publication No. 2017 / 118277 or a pharma- ceutically acceptable salt thereof.

[0161] Of particular interest is another BTK inhibitor, which is disclosed in WO 2015 / 079417. Compounds described in FRET, such as N-(3-(5-((1-acryloylazepam) 6-aminopyrimidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2- Methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6- Amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidine-4- 5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorophenyl N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)amide )pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl -2-Fluorobenzamide;N-(3-(6-amino-5-(2-(N-methylpropionamide olamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-4-Cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-( 2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro N-(4-cyclopropyl-2-fluorobenzamide; 3-(6-amino-5-(2-(N-ethylacrylamide)ethoxy)pyrimidine-4 -yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzyl N-(3-(6-amino-5-(2-(N-(2-fluoroethyl)acrylamide) ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)- 4-Cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5 -(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro -2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;(S)-N -(3-(6-amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide, and N-(3-(6-amino-5-(3-(N-methylacrylamide amido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl -4-cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof . EXAMPLES

[0162] Exemplification of the Invention The present disclosure is further illustrated by the following examples and synthetic schemes, which are included to It is not intended to limit in scope or spirit to the specific procedures described herein. The examples are provided to illustrate certain embodiments and should not be construed as limiting the scope of the present disclosure. It should be understood that no limitation to the scope is thereby intended. Various other embodiments, modifications and equivalents thereof that may occur to one skilled in the art are within the spirit and / or scope of the present disclosure. It is further understood that the present invention may be practiced in accordance with the principles of the present invention without departing from the scope of the appended claims. It should be.

[0163] The compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods, protecting groups for sensitive or reactive groups are selected in accordance with general principles of chemistry. It will be understood that protecting groups may be utilized as needed according to standard methods of organic synthesis. (TWGreen and PGMWuts (2014) P rotective Groups in Organic Synthesis,5t (H edition, John Wiley & Sons). These groups are readily apparent to those skilled in the art. The amines may be removed at a convenient stage in the compound synthesis using methods that will become apparent below.

[0164] Unless otherwise noted, reagents and solvents were used as obtained from commercial suppliers.

[0165] Chemical names are shown in CambridgeSoft's ChemBioDraw Ultra v1 Generated using 4.

[0166] Temperatures are given in degrees Celsius. All evaporations were performed under reduced pressure unless otherwise stated. This is usually performed at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of final products, intermediates, and starting materials may be determined by standard analytical methods, e.g., microanalysis and spectroscopy. The abbreviations used are those of the art. It is common in.

[0167] Abbreviation AcOH Acetic acid ASC Apoptosis-associated speck-like protein BINAP (2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl) BippyPhos 5-(di-tert-butylphosphino)-1',3',5'-t Triphenyl-1'H-1,4-bipyrazole Boc tert-Butyloxycarbonyl CAPS Cryopyrin-Associated Periodic Syndrome DAMP Danger Activating Molecular Pattern DIAD Diisopropyl azodicarboxylate DIPEA N-Diisopropylethylamine DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene EtOAc Ethyl acetate EtOH Ethanol h time HCl Hydrogen chloride HTRF homogeneous time-resolved fluorescence Hz / MHz Hertz / Megahertz I C 50 Half the maximum inhibitory concentration IL-1β Interleukin 1 beta IR Infrared LC-MS Liquid Chromatography-Mass Spectrometry LPS: Lipopolysaccharide from Escherichia coli O111:B4 LRR Leucine-rich repeat M mole mCPBA 3-Chloroperbenzoic Acid MEK Methyl ethyl ketone; butan-2-one MeOH Methanol min mL / L Milliliters per liter mmol NASH Nonalcoholic Steatohepatitis NBD Nucleotide-binding site domain NLR NOD-like receptor NMP 1-Methylpyrrolidin-2-one NMR nuclear magnetic resonance PAD Peripheral Arterial Disease PAMP Pathogen Activation Molecular Patterns Pd / C Palladium Carbon PMA 13-Acetate 12-Myristate Phorbol ppm parts per million RP Reverse Phase RPMI Roswell Park Memorial Institute RT Room temperature in degrees 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-Performance Liquid Chromatography XantPhos-Pd-G2 Chloro[(4,5-bis(diphenylphosphino)-9 ,9-Dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium Mu (II)

[0168] Analysis details NMR: Measurements were performed with or without tetramethylsilane (TMS) as an internal standard. Bruker Ultrashield™ 400 (400MHz) or Br Bruker Ascend (400MHz) or Bruker cryo system The measurements were performed on a TEM (600 MHz) spectrometer. Chemical shifts (δ) were measured downfield from TMS. pm, and the spectral splitting patterns are singlet (s), doublet (d), triplet (t ), quartet (q), quintet (quint), septet (sept), multiplet, unresolved or multiplet The signals are shown as double (m) and broad (br) signals. Deuterated solvents are shown in brackets. Dimethyl sulfoxide (δ2.50 ppm), methanol (δ3.31 ppm), The chemical shift of chloroform (δ 7.26 ppm) or other solvents 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°C. Gradient: 5-98% B in 1.4 min, 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 mass to charge ratio.

[0169] Preparative separation method Flash column chromatography system: System: Teledyne ISCO, CombiFlash® Rf. Column: Prepacked RediSep Rf cartridge. 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, building blocks, reagents, acids, etc. utilized to synthesize the compounds of the present invention. The bases, dehydrating agents, solvents and catalysts are either commercially available or organic solvents 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) ethyl)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 (10 g) in 150 mL of toluene A mixture of sodium hydride (2.44 g, 102 mmol) and 1,2-dichlorobenzene (1.0 g, 50.9 mmol) was added. The mixture was stirred for 30 minutes at 0° C. Iodine (12.9 g, 50.9 mmol) was then added, The solution was stirred for 3 h at 0° C. The reaction mixture was then acidified with concentrated HCl to give 4- A final pH of 5 was obtained. It was extracted with EtOAc and the organic layer was washed with water and brine and diluted with N The crude mixture of regioisomers was then dried over a2SO4, filtered and evaporated. 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-(trifluoro (trimethyl)benzene, IntB003 [ka] (Chloromethoxy)ethane (7.25 mL, 62.5 mmol) in 70 mL of DMF IntB002 (16 g, 49.6 mmol) and CS2CO3 (16.2 g, 49.6 The reaction mixture was stirred for 18 h at RT. C) Ethane (2.88 mL, 24.8 mmol) was added and stirring was continued for 24 h. The suspension was filtered through Celite and the filtrate was evaporated to give the title compounds as a mixture of regioisomers. which was 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)phenyl 2-(4-nyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and Chloro-2-(ethoxymethoxy)-6-(trifluoromethyl)phenyl)-4,4, 5,5-Tetramethyl-1,3,2-dioxaborolane, IntB004 [ka] IntB003 (11.9 g, 31.3 mmol) in 60 mL of 1,4-dioxane, 4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane (9.08 mL, 62 A solution of NEt3 (1.5 mmol) and NEt3 (13.08 mL, 94 mmol) was perfused with nitrogen. Pd(OAc)2 (0.35 g, 1.56 mmol) and biphenyl-2-yl -Dicyclohexylphosphane (1.1 g, 3.13 mmol) was added, resulting in The resulting mixture was stirred at 80 °C for 3 h. Pd(OAc)2 (0.35 g, 1.56 mmol) was added. An additional portion of l) was added and heating was continued for 13 h. The reaction was cooled to RT and saturated NH The crude product was purified by washing with cyclohexane and water to give an orange oil. and EtOAc (0% to 100%) for column chromatography on silica gel. Purification gave the title compounds as a mixture of regioisomers. LC-MS: Rt=1.4 3 min.

[0178] (4) 3-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola 5-chloro-2-(4,4-phenyl-2-yl)-5-(trifluoromethyl)phenol and ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl) (Oromethyl)phenol, IntB001 IntB004 (8.5 g, 22.34 mmol) and TF in 25 mL of CH2Cl2 A solution of A (25.8 mL, 670.2 mmol) was purged with nitrogen and stirred for 1 h at 0 °C. The mixture was washed with saturated NH4Cl solution, water, and brine. The organic layer was diluted with Na2SO4 The crude product was extracted with cyclohexane and and EtOAc (0%-5%) by column chromatography on silica gel. The product was purified to give the title compound as a mixture of regioisomers. LC-MS: Rt=1.23mM 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) were added to 5 1-Bromo-3-methyl-5-(2-bromo-2-methyl-1,3-dioxane) in 0.00 mL of 1,4-dioxane and 50 mL of H2O The reaction mixture was added to a solution of 1,2-difluoromethyl-1,2-trifluoromethylbenzene (50 g, 210.11 mmol). The reaction mixture was purged with nitrogen and heated at 100° C. for 16 h. The reaction mixture was cooled to RT. The filtrate was filtered through a pad of Celite® and washed with EtOAc. , washed with 1.5M HCl, dried over Na2SO4, filtered and evaporated. The mixture was purified by column chromatography on silica gel using petroleum ether and EtOAc (0% to 15%). Purification by chromatography gave the title compound as a yellow oil. 1 H 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] To an ice-cold solution of IntB006 (13.03 g, 74 mmol) in 370 mL of toluene Then, NaH (60% dispersion in mineral oil, 5.92 g, 148 mmol) was added. The suspension was stirred for 3 h. Stir for 0 min at 0° C., then add iodine (18.77 g, 74 mmol) slowly in portions. The mixture was diluted with water and acidified with 2M HCl to pH=5. The organic layer was washed with brine, dried over Na2SO4, filtered, and The crude material was purified by cyclohexane and EtOAc (5% to 100%). Purified by column chromatography on silica gel (220 g) and appeared as a yellow oil. The title 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 (24 g, 172.22 mmol), methyl iodide in 300 mL of anhydrous acetone Chill (8.1 mL, 129.13 mmol), and IntB007 (26 g, 86.09 The mixture of (a) (mmol) was stirred for 5 h at RT. It was then filtered and the filtrate was evaporated. The residue was dissolved in CH2Cl2, washed with water, dried over Na2SO4, filtered, and Evaporation gave the title compound as an off-white solid. 1 H 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- Dicyclohexylphosphane (2.44 g, 6.96 mmol), Pd(OAc)2(1 .55g, 6.96mmol), and NEt3 (48.5mL, 348.03mmol). IntB008 (22 g, 6 The reaction mixture was purged with nitrogen and heated at 100 °C for 16 h. After cooling to RT, it was passed through a pad of Celite® The filtrate was evaporated and the residue was washed with petroleum ether and EtO Purification by column chromatography on silica gel using Ac (0%-10%) This afforded the title compound as an off-white solid. 1 H 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 added to 150 ml of Add to a solution of IntB009 (12 g, 37.95 mmol) in L of anhydrous CH2Cl2. The reaction mixture was stirred for 30 min at 0° C. After this, it was diluted with water to keep the pH at about 9. The resulting mixture was carefully poured into approximately 250 mL of 10% NaOH solution. The aqueous layer was separated and adjusted to pH 5 with 1.5 M HCl. A solid precipitated. This was filtered, washed with petroleum ether and dried under vacuum to give an off-white solid. This gave the title compound. 1 H 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) was dissolved in 30 mL of dry DMSO. IntB007 (8.50 g, 28.10 mmol) and CS2CO3 (9.17 g The reaction mixture was cooled to room temperature and then cooled to room temperature. The crude material was purified by cyclohexane and EtOAc (0% to 5%). The mixture was purified by column chromatography on silica gel to give the title compound. MS: Rt=1.39 min.

[0185] (2) 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl) Nyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, IntB01 2 [ka] IntB011 (10 g, 27.80 mmol) in 60 mL of 1,4-dioxane, 4 ,4,5,5-Tetramethyl-[1,3,2]dioxaborolane (20.15 mL, 13 A solution of NEt3 (28.6 mL, 205 mmol) and NEt3 (28.6 mL, 205 mmol) was purged with nitrogen. Pd(OAc)2 (0.81 g, 3.61 mmol) and biphenyl-2-yl- Dicyclohexylphosphane (2.33 g, 6.66 mmol) was added and the mixture was cooled to 18°C. The mixture was stirred at 80° C. for 1 h. It was then cooled to RT, diluted with EtOAc and saturated NH The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography using cyclohexane and CH2Cl2 (0% to 20%). The mixture was purified by column chromatography at 80° C. to give the title compound. LC-MS: Rt= 1.40min.

[0186] (3) 3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola (2-yl)-5-(trifluoromethyl)phenol, IntB010 TFA (44.9 mL, 583 mmol) was dissolved in 250 mL of CH2Cl2 at 0 °C. The solution of ntB012 (7.00 g, 19.43 mmol) was slowly added to the reaction mixture. The mixture was stirred for 20 min at 0° C. and then evaporated. The resulting oil was diluted with cyclohexane and and CH2Cl2 (0% to 100%), column chromatography on silica gel Purification by HPLC gave the title compound. 1 H 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-dioxaborola (2-yl)phenol, IntB013 [ka] (1) 2-Iodo-3,5-dimethylphenol, IntB014 [ka] 3,5-Dimethylphenol (1 g, 8.2 mmol) was dissolved in 40 mL of toluene. and cooled to 0°C. NaH (60% dispersion in mineral oil, 655 mg, 16.4 mmol) is added in portions and the mixture is stirred for 20 min at 0°C, then for 10 min at RT, and finally The mixture was then cooled to 0° C. Iodine (2.08 g, 8.2 mmol) was then added in portions and stirred. Stirring was continued for 30 min. The reaction mixture was quenched by the addition of 0.5 M HCl and The combined organic extracts were washed with water and brine, and dehydrated with Na2SO4. The crude was washed with water, filtered and evaporated. and purified by column chromatography on silica gel (100 g), followed by A second run (isocratic) was performed using n-heptane and EtOAc (5%). The title compound was obtained as a white solid. 1 H 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] To a solution of IntB014 (660 mg, 2.66 mmol) in 6 mL of DMF, CS2 CO3 (867 mg, 2.66 mmol) was added, followed by (chloromethoxy)ethane ( The reaction mixture was stirred overnight at RT and diluted with water. The mixture was quenched with ethyl acetate and extracted with EtOAc. The combined organic extracts were dried over Na2SO4. It was dried, filtered and evaporated. The crude was diluted with n-heptane and EtOAc (0% to 10%). The yellow solid was purified by column chromatography on silica gel (50 g). The title compound was obtained as an oil. 1 H 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] IntB015 (393 mg, 1.28 mmol) in 2.5 mL of 1,4-dioxane To the solution, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (373 μL Add NEt3 (537 μL, 3.85 mmol) and NEt3 (537 μL, 3.85 mmol) to the vial. The flask was purged with nitrogen. Pd(OAc)2 (14.4 mg, 64 μmol) and biphenyl Add 2-yl-dicyclohexylphosphane (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. The mixture was quenched with ethyl acetate and extracted with EtOAc. The combined organic extracts were dried over Na2SO4. It was dried, filtered and evaporated. The crude was diluted with n-heptane and EtOAc (0% to 20%). and purified by column chromatography on silica gel (50 g) to obtain a colorless The title compound was obtained as an oil. 1 H 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 (Borolan-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 slowly added. After a period of time, the reaction was quenched by the addition of water at -30 °C. The mixture was diluted with 1M NaHCO3 The mixture was neutralized by adding additional 10 mL of ethyl acetate and extracted twice with CH2Cl2. The combined organic extracts were Dry over Na2SO4, filter and evaporate to give the title compound as a yellow oil which is and used without further purification. 1 H 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 = 1.37 min; 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) was dissolved in 16 mL of EtO and The mixture was cooled to 0-5°C under vacuum. n-BuLi (1.6 M in hexane, 10.1 mL, 16 0.15 mmol) was added dropwise to the colorless solution while keeping the temperature below 10°C. The resulting yellow suspension was stirred for 1 h at RT, then it was cooled to -78 °C. Add B(OMe)3 (1.15 mL, 10.28 mmol) and keep the temperature below -70 °C. Stirring was continued for 20 minutes at -78°C, and then the reaction mixture was cooled to -78°C for 20 minutes. The mixture was allowed to warm to RT overnight. It was quenched by addition of water and washed with 4M HCl until pH 1. The mixture was extracted three times with CH2Cl2 and the combined organic extracts were 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=0.74 min; 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 (60% dispersion in mineral oil, 1.472 g, 36.8 mmol) was added under nitrogen at 0°C. 3,5-Dichlorophenol (2.00 g, 12.27 mmol) in 30 mL of dry toluene l) in portions. The resulting mixture was warmed to RT and stirred for 30 min. The suspension was then cooled to 0° C. and iodine (2.49 g, 9.82 mmol) was added. The reaction mixture was stirred at 0° C. for 1.5 hours and then diluted with 1M HCl. The mixture was quenched by the addition of 1,2-dichloromethane and extracted with CH2Cl2. The organic extract was washed with brine and The crude was dried over 2SO4, filtered and evaporated. ~50%) and purified by column chromatography on silica gel (50 g). This afforded the title compound as a yellow solid. 1 H 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 (2.8 g, 8.43 mmol), and CS2CO3 (2.75 g, 8 The suspension of 1.43 mmol) was stirred for 22 h at RT. The reaction mixture was quenched by the addition of water. The aqueous layer was extracted with CH2Cl2 and the combined organic extracts were washed with Na2 It was dried over SO4, filtered and evaporated. The crude was dissolved in n-heptane and EtOAc (0% ~25%) and purified by column chromatography on silica gel (100 g). Purification gave the title compound as a brown solid. 1 H 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] IntB020 (2.7 g, 7.78 mmol) in 15 mL of 1,4-dioxane, 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 min. Then, Pd(OAc)2 (87 mg, 0.38 9mmol) and biphenyl-2-yl-dicyclohexylphosphane (273mg, 0 0.778 mmol) was added and the mixture was stirred for 20 h at 80° C. The reaction mixture was diluted with saturated The mixture was quenched by the addition of NH4Cl and the layers were separated. The organic layer was washed with water and brine, then The crude was diluted with n-heptane and EtOAc (0% to 10%) and evaporated to give an orange oil. 20%) and continued by column chromatography on silica gel (100 g). The mixture was dissolved in n-heptane and EtOAc (0%-5%) on silica gel (50 g). Purification by a second chromatography gave the title compound as a pale yellow solid. 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)phenyl Knoll, IntB018 A solution of IntB021 (880 mg, 2.54 mmol) in 10 mL of CH2Cl2 It was cooled to 0° C. TFA (3.91 mL, 50.7 mmol) was added and the reaction mixture was The mixture was stirred for 1 h at 0° C. The mixture was quenched by the addition of saturated NH4Cl. The layers were separated. The organic extract was separated and washed with water and brine. The solvent was evaporated to give the title compounds as a mixture. This was used without purification. LC-MS: Rt=0.76 min and 1. 32min; MS m / z 205.0[MH]- and 289.0[M+H] +

[0196] 3-Chloro-5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxa 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] The mixture of positional isomers was prepared by the procedure described above, starting from 3-chloro-5-fluorophenol. The compound was synthesized similarly to IntB018 as described in the literature. LC-MS: Rt=1.25 min .

[0197] (2-hydroxy-4,6-bis(trifluoromethyl)phenyl)boronic acid, IntB 023 [ka] (2-Methoxy-4,6-bis(trifluoromethyl)phenyl)phenyl in 10 mL of CH2Cl2 A solution of BBr3( 1M in CH2Cl2, 8.68 mL, 8.68 mmol) was added dropwise. The pale orange solution was allowed to warm to RT and stirred for 17 h. The reaction mixture was washed with ice water (ca. 3 0 mL) and the pH was adjusted to 10 by addition of 2 M NaOH. The aqueous layer was separated. and acidified to pH 1 by addition of 2M HCl, followed by CH2Cl2, followed by EtOAc. The combined organic extracts were dried over Na2SO4, filtered and evaporated. The crude material was purified using CH2Cl2 and MeOH (0%-5%) on silica gel (25 g). The title compound was obtained as a beige solid by purification at 4° C. LC-MS: Rt=0.81min; MS m / z 273.1[MH]-

[0198] Synthesis of 6-Halo-pyridazin-3-amine Intermediates (R)-6-Chloro-N-(1-ethylpiperidin-3-yl)pyridazin-3-amine , IntP024 [ka] 3,6-Dichloropyridazine (3 g, 20.13 mmol) in 80 mL of NMP and To a solution of R)-1-ethylpiperidin-3-amine (5.24 g, 22.15 mmol) Then, DIPEA (17.59 mL, 101 mmol) was added and the reaction mixture was stirred for 48 h. Stirred at 0° C. It was then cooled to RT, poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The crude material was purified by silica gel column chromatography using CH2Cl2 and MeOH (0%-10%). Purification by column chromatography afforded the title compound. LC-MS: Rt= 0.42min; MS m / z 241.2[M+H] +

[0199] (R)-6-Chloro-N-(1-methylpiperidin-3-yl)pyridazin-3-amine , IntP025 [ka] 3,6-Dichloropyridazine (500 mg, 3.26 mmol) in 4 mL of NMP, ( R)-1-Methylpiperidin-3-amine (379 mg, 3.32 mmol), and DI The mixture was heated at 150° C. for 4 hours. The mixture was cooled to RT and evaporated to dryness. The residue was dissolved in EtOAc and The aqueous layer was extracted three more times with EtOAc. The combined organic extractions The material was dried over Na2SO4, filtered and evaporated to give a thick orange oil which was CH2Cl2 and MeOH (0%-10%) containing 5% NH4OH were used. Purification by column chromatography on silica gel (50 g) gave the title compound. 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) overlapping 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-methylpiperidin-3-yl)-4-(trifluoromethyl) (R)-6-chloro-N-(1-methyl)pyridazin-3-amine, IntP026 and (R)-6-chloro-N-(1-methyl)pyridazin-3-amine (Tyrpiperidin-3-yl)-5-(trifluoromethyl)pyridazin-3-amine, I ntP027 [ka] 3,6-Dichloro-4-(trifluoromethyl)pyridazine in 5 mL of 1-butanol (3.4 g, 15.67 mmol), (R)-1-methylpiperidin-3-amine (2. 468 mL, 18.80 mmol), and DIPEA (8.21 mL, 47.0 mmol) A solution of 1,2-dichlorophenyl ether was heated at 110° C. for 20 h. The reaction mixture was evaporated and the crude product was extracted with CH Column chromatography was performed on silica gel (220 g) using l2 and MeOH (0% to 10%). The mixture was purified and separated by HPLC. IntP026 (first elution) or IntP0 The fractions containing 27 (eluting second) were combined and evaporated separately. The extracts were then partitioned between CH2Cl2 and 1M NaOH individually. The organic extracts were washed with N Drying over a2SO4, filtering and evaporating gave the title compound Int as a brown oil, respectively. P026 and IntP027 were obtained as pale yellow solids. IntP026 (first elution): 1 H-NMR (400MHz, 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 (eluting second): 1 H 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 ,3H,m,overlaps with 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)pyridazin-3-yl)amino)- 1-Methylcyclobutan-1-ol, IntP028 and cis-((6-chloro-5- (Trifluoromethyl)pyridazin-3-yl)amino)-1-methylcyclobutane-1 -Oar, IntP029 [ka] 3,6-Dichloro-4-(trifluoromethyl)pyridazine in 5 mL of 1-butanol (1g, 4.61mmol), cis-3-amino-1-methylcyclobutan-1-ol Hydrochloride (0.698 g, 5.07 mmol), and DIPEA (2.415 mL, 13. A solution of 83 mmol) was heated in a microwave for 1 h at 180° C. The reaction mixture The material was partitioned between EtOAc and 10% NaHCO3 solution. The organic extract was washed with brine. The crude was dissolved in CH2Cl2 and MeOH and then extracted with 100% CO. The crude was ... (0% to 10%) and column chromatography on silica gel (40 g). The product-containing fractions were separately combined and evaporated to give brown toluene. The title compound IntP028 (eluted first) as a yellowish oil and IntP028 (eluted first) as a pale yellow solid. tP029 (second elution) was obtained. IntP028 (first elution): 1 H-NMR (400MHz, 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 elution): 1 H 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-methylpiperidin-3-yl)pyridazine -3-amine, IntP030 and (R)-6-chloro-5-methyl-N-(1-methyl Piperidin-3-yl)pyridazin-3-amine, IntP031 [ka] 3,6-Dichloro-4-methylpyridazine (1.02 g, 6.26 m) in 5 mL of NMP mol), (R)-1-methylpiperidin-3-amine (0.986 mL, 7.51 mm A solution of 1.28 mL of 18.77 mmol) and DIPEA (3.28 mL, 18.77 mmol) was subjected to microwave irradiation. The reaction mixture was then heated at 180°C under a radiant ray for 2 hours. The reaction mixture was then nearly evaporated and the residue was dissolved in CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, and filtered. The crude material was purified by silica gel chromatography using CH2Cl2 and MeOH (0% to 20%). The product was purified by column chromatography on gel (40 g) to give a ratio of approximately 1:3 of the regioisomers. This mixture was further purified by chiral SFC to give the title compound as a mixture of Separation (column: ChiralPak AY, 250×30 mm, 5 μm; 38° C., elution Agent B: 35% EtOH + 0.1% NH4OH, flow rate: 50 mL / min, pressure: 100 bar , cycle time: 8 min), respectively, to give the title compound IntP030 as an orange oil. (eluted first) and IntP031 (eluted second) as a brown solid. IntP030 (first elution): 1 H-NMR (400MHz, 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 (eluting second): 1 H NMR (400MHz, 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), overlapping with 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 can be catalyzed by the regioselective synthesis described below. Route was used to prepare the compound.

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

[0205] (2) (R)-2-(4-methoxybenzyl)-5-methyl-6-((1-methylpiperidinyl) (3-yl)amino)pyridazin-3(2H)-one, IntP033 [ka] IntP032 (30.5 g, 115.3 mmol) in 300 mL of dry toluene, ( R)-1-Methylpiperidin-3-amine (15 g, 131 mmol), and CSCO A mixture of 3 (75 g, 231 mmol) was purged with nitrogen for 5 min. Then, Pd(O Ac)2 (1.3 g, 5.79 mmol) and BINAP (8 g, 12.85 mmol). was added in sequence and the reaction mixture was stirred at reflux for 3 h. It was then cooled to RT and The mixture was filtered through a pad of elite®. The filter cake was washed with toluene. The filtrate was Evaporation to dryness under reduced pressure gave the title compound as a brown oil which could be further purified. Used without any modification. LC-MS: Rt = 0.51 min; MS m / z 343.5 [M+H ] +

[0206] (3) (R)-5-Methyl-6-((1-methylpiperidin-3-yl)amino)pyridin Gin-3(2H)-one, IntP034 [ka] IntP033 (39.4 g, 115 mmol) was dissolved in 250 mL of TFA. The dark brown mixture was stirred at reflux for 2 days. The reaction mixture was evaporated to dryness. The residue was The mixture was dissolved in 0.00 mL of acetonitrile and 5 mL of water and evaporated to dryness again. The resulting black oil was triturated with Et2O. The supernatant was removed and the remaining brown oil was concentrated under high vacuum. Drying at rt gave 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-methylpiperidin-3-yl)pyridine Dazin-3-amine, IntP030 [ka] POCl3 (250 mL) was dissolved in 250 mL of dry acetonitrile and IntP034 (3 A solution of 1,2-dichlorophenyl ether (8.7 g, 115 mmol) was added and the mixture was heated under reflux for 2.5 days. The reaction mixture was cooled to RT and evaporated to dryness. The black oily residue was dissolved in 200 mL of acetone. This solution was added dropwise to an ice-cold saturated solution of Na2CO3 (significant decomposition occurred). The pH was adjusted to >12 by addition of 30% NaOH. It was evaporated to dryness and then treated with a 1:1 mixture of CH2Cl2 and MeOH. The black suspension was stirred at RT for 30 min. It was then washed with Celite® The mixture was filtered through a pad of CH2Cl2 and MeOH (approximately 500 mL). The filtrate was evaporated to dryness to give a black solid. The product was used without further purification. LC-MS: Rt=0.43m in; MS m / z 241.1 [M+H] +

[0208] Cis-((6-chloro-4-methylpyridazin-3-yl)amino)-1-methylcyclo Butan-1-ol, IntP035 and cis-((6-chloro-5-methylpyridazine -3-yl)amino)-1-methylcyclobutan-1-ol, IntP036 [ka] cis-3-amino-1-methylcyclobutan-1-ol in 1.9 mL of 1-butanol (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 for 90 min at 180° C. The reaction mixture was evaporated and The crude orange oil was partitioned between EtOAc and 2M Na2CO3 solution. The extract was washed with brine, dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (40 g) using l2 and MeOH (0% to 5%) The product-containing fractions were separately combined and evaporated, and purified by filtration. The title compound IntP035 (eluted first) as a beige solid and the white IntP036 (second elution) was obtained as a solid. IntP035 (first elution): 1 H-NMR (400MHz, 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 (eluting second): 1 H NMR (400MHz, 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 = 0.58 min; MS m / z 228.1 [M + H] +

[0209] Cis-((6-chloropyridazin-3-yl)amino)-1-methylcyclobutane-1- Oar, IntP037 [ka] 3,6-Dichloropyridazine (1 g, 6.71 mmol) in 8 mL of 1-butanol, cis-3-amino-1-methylcyclobutan-1-ol (0.970 g, 7.05 mm A solution of 1.5 mL of 1.5 ethanol and DIPEA (4.1 mL, 23.49 mmol) was subjected to microwave irradiation. The mixture was heated under reduced pressure for 1 h at 180° C. The reaction mixture was poured onto water and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was triturated with acetonitrile for 20 minutes, filtered, and washed once more 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 = 0.53 min; MS m / z 214.1 [M+H] +

[0210] (1S,3R)-3-((6-chloropyridazin-3-yl)amino)cyclohexane- 1-All, IntP038 [ka] 3,6-Dichloropyridazine (100 mg, 0.671 mmol), (1S,3R)- 3-Aminocyclohexan-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 h. The mixture was heated at 180° C. The residue was dissolved in EtOAc and washed with saturated NaHCO3 and brine. The mixture was washed, dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (12 g) using ~10% The title compound was obtained as a photosensitive solid. LC-MS: Rt=0.55 min; MS m / z 228.1[M+H] +

[0211] (R)-3-chloro-6-((1-methylpiperidin-3-yl)oxy)pyridazine, IntP039 [ka] 3,6-Dichloropyridazine (150 mg, 1.0 mm) in 1 mL of 1,4-dioxane ol) and (R)-3-hydroxy-1-methylpiperidine (128 mg, 1.1 mmol) To the ice-cold mixture of (a) and (b), slowly add NaH (60% in mineral oil, 161 mg, 4.0 mmol). and the suspension was stirred for 1 h at 0° C. It was then quenched by careful addition of water. Acidified with 1M HCl. The aqueous layer was separated and washed with EtOAc and then saturated NaCl. The mixture was made basic by the addition of O3 solution and extracted with EtOAc. The organic extract was evaporated to give the crude product. The product was purified by silica gel (25 g) using CH2Cl2 and MeOH (0%-20%). The residue was purified by column chromatography to give the title compound as a colorless oil. 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) were reacted with the corresponding 3,6-dihalopyridazines and the appropriate The amine was prepared similarly to the procedure above, optionally followed by a 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 the piperazine intermediate: 1-((R)-3-((6-chloropyridazin-3-yl)amino)piperidin-1-yl (l)propan-2-ol, IntP105 [ka] IntP100 (200 mg, 0.621 mmol) was dissolved in K2CO3 (429 mg, 3 0.11 mmol) and 1-chloropropan-2-ol (0.23 mL, 1.86 mmol) The yellow suspension was heated at 100 °C for 4.5 h before adding 2 mL of DMF. The mixture was then stirred at 120° C. for 1.5 h. The mixture was cooled to RT and diluted with a small amount of water. The mixture was purified by achiral reverse phase HPLC to give the title compound as a pale yellow solid. MS:Rt=0.40min;MS m / z 271.2[M+H] +

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

[0223] Synthesis of selected amines for the above intermediates (R)-2-(3-aminopiperidin-1-yl)ethane-1-ol dihydrochloride , IntA107 [ka] (1) tert-Butyl (R)-(1-(2-hydroxyethyl)piperidin-3-yl ) Carbamate, IntA108 [ka] tert-Butyl (R)-piperidin-3-ylcarba in 100 mL of acetonitrile Mate (10 g, 49.9 mmol), 2-bromoethan-1-ol (6.24 g, 4 A suspension of Na2CO3 (10.58 g, 100 mmol) was The mixture was stirred at RT for 1 day. The suspension was filtered and the solid was washed several times with acetonitrile. The filtrate was evaporated. The residue was purified using CH2Cl2 and MeOH (0%-10%). The mixture was purified by column chromatography on silica gel to give the title compound. MS:Rt=0.40min;MS m / z 245.1[M+H] +

[0224] (2) (R)-2-(3-aminopiperidin-1-yl)ethane-1-ol dihydrochloride 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 for 3 h at RT. The precipitate was filtered and washed several times with 1,4-dioxane. Washing and drying under high vacuum at 60° C. overnight afforded the title compound. LC-MS: t=0.15min; MS m / z 145.2[M+H] +

[0225] 1-(tert-butyl) 2-methyl 5-aminopiperidine-1,2-dicarboxylate T, IntA109 [ka] (1) 1-(tert-butyl) 2-methyl 5-hydroxypiperidine-1,2-dicarboxamide Boxylate, IntA110 [ka] 1-tert-Butyl-2-methyl-5-oxopiperidine-1,2-dicarboxylate Dissolve 500 mg (1.943 mmol) in 15 mL of MeOH and cool to 0 °C. NaBH4 (73.5 mg, 19.43 mmol) was added in portions. After stirring, half of the MeOH was removed under reduced pressure. The residue was diluted with EtOAc and The organic extract was washed successively with 0.5 M HCl, 0.5 M NaOH, and brine. 4, filtered and evaporated to give the title compound as a colorless oil. The mixture was used without further purification. 1 H-NMR (400MHz, 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(di astereomer), 9H), 1.04-0.94(m,1H).

[0226] (2) 1-(tert-butyl) 2-methyl 5-azidopiperidine-1,2-dicarboxil Silane, IntA111 [ka] IntA110 (526 mg, 1.927 mmol) was dissolved in 10 mL of toluene. PPh3 (1.064 g, 4.06 mmol) and Zn(N3)2 (468 mg, 1 This mixture was treated with DIAD (0.789 mL, After stirring for 4 h at RT, the reaction mixture was diluted with Hyf The mixture was filtered through lo and washed with EtOAc. The filtrate was evaporated and the crude product was diluted with n-heptane and EtOAc (10% to 80%) on silica gel (50 g). Purification by chromatography gave the title compounds as a mixture of diastereomers. 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-methyl-5-aminopiperidine-1,2-dicarboxil Silane, IntA109 Pd / C (159 mg, 0.15 mmol, 10% Pd content) in 10 mL MeOH To a suspension of IntA111 (426 mg, 1.498 mmol) in 30 mL of MeOH The mixture was hydrogenated at atmospheric pressure for 1 h at RT. The mixture was Filter through a pad of ® and wash with EtOAc. Mixture of diastereomers The filtrate was evaporated to give the title compound as a crude product which was 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 Overlapped with 1(m,1H), 1.49-1.40(m,2H) and 1.38(s,9H).

[0228] Synthesis of Examples Example Ex001 (R)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)phenol [ka] IntP024 (770 mg, 1.663 mmol) and IntB010 (754 mg , 2.495 mmol) was dissolved in 8 mL of 1,4-dioxane and 2 M NaCO 3 (0.25 mL, 0.499 mmol) was added. Then, Pd(Ph3P)4(9 6 mg, 0.083 mmol) was added and the reaction mixture was purged with nitrogen for 5 minutes, then The mixture was stirred under microwave irradiation for 1 h at 120° C. The reaction mixture was poured into water and EtOAc was added. The combined organic extracts were evaporated and the residue was extracted twice with CH2Cl2 and Me Purification by column chromatography on silica gel with OH (0%-10%) This resulted in the title compound. 1 H 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. 42min; MS m / z 241.3[M+H] +

[0229] Example Ex002 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin 5-(trifluoromethyl)-3-phenyl-3-ylphenol [ka] IntP037 (50 mg, 0.145 mmol) in 1 mL of DME and 1 mL of water, IntB005 (35.1 mg, 0.160 mmol), and 2M Na2CO3 (0. The mixture (218 mL, 0.435 mmol) was purged with argon for 3 min. Add d(PPh3)4 (8.38 mg, 7.25 μmol) and microwave the mixture. The reaction mixture was heated at 140° C. under irradiation for 30 min. The reaction mixture was evaporated and diluted with CH2Cl2 and MeO H (0% to 4%) and column chromatography on silica gel (4 g). Purification afforded the title compound as a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6)δ(ppm)10.13(s,1H),7.22(d,1H),7.1 3(d,1H),7.10(s,1H),7.04(s,1H),6.81(d,1H) ,4.99(s,1H),4.03-3.90(m,1H),2.45-2.38(m, 2H),2.12(s,3H),2.00-1.92(m,2H),1.29(s,3H ).LC-MS:Rt=0.80min;MS m / z 354.1[M+H] +

[0230] Example Ex003 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol [ka] IntP038 (50 mg, 0.220 mmol) in 5 mL of 1,4-dioxane, I ntB010 (73.0 mg, 0.242 mmol) and 2M Na2CO3 (0.3 The mixture (29 mL, 0.659 mmol) was purged with argon for 3 min. Then, Pd (PPh3)4 (7.61 mg, 6.59 μmol) was added and the mixture was heated at 120 °C for 6 h. The mixture was stirred at rt. Together with additional Pd(PPh3)4 (5 mg, 4.33 μmol), In Another portion of tB010 (50.0 mg, 0.166 mmol) was added and heating was continued for 24 hours. The reaction mixture was cooled to RT. It was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and evaporated. C (column: Waters TORUS 2-PIC 130A, 250 × 30 mm, 5 μm; 35 °C, eluent B: 17-25% MeOH 10 min, flow rate: 100 mL / min, pressure: 120 bar) to give the title compound as a white solid. 1 H-NMR( 400MHz,DMSO-d6)δ(ppm)10.14(s,1H),7.21(d, 1H),7.10(s,1H),7.04(s,1H),6.84-6.76(m,2H ),4.65(d,1H),3.93-3.80(m,1H),3.54-3.45(m ,1H),2.27-2.18(m,1H),2.13(s,3H),2.02-1.9 2(m,1H),1.87-1.79(m,1H),1.76-1.65(m,1H), 1.37-1.22(m,1H),1.18-1.00(m,3H).LC-MS:Rt = 0.78 min; MS m / z 368.2 [M+H] +

[0231] Example Ex004 (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin Din-3-yl)-5-(trifluoromethyl)phenol [ka] IntP031 (438 mg, 1.819 mmol) in 9 mL of 1,4-dioxane, Commercially available (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid ( CA 1072951-50-8, 412mg, 2.001mmol), Pd(PPh3 )4 (63.1 mg, 0.055 mmol), and 1.2 M NaHCO3 (4.55 m L, 5.46 mmol) was heated at 105 °C overnight. , (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (187 mg, 0 0.909 mmol) was added once more and the mixture was heated under microwave irradiation for 30 min at 180 °C. The reaction mixture was diluted with water and extracted twice with CH2Cl2. The combined organic extracts were The extract was dried over Na2SO4, filtered and evaporated. The crude product was purified by distillation with CH2Cl2 and M Column chromatography on silica gel (40 g) using eOH (0% to 20%) The product-containing fractions were evaporated and triturated with CH2Cl2 to give a white solid. The title compound was obtained as a solid. 1 H-NMR (400MHz, DMSO-d6) δ(ppm )10.45(s,1H),7.39(d,1H),7.26-7.16(m,2H), 6.70(s,1H),6.63(d,1H),4.11-3.98(m,1H),2. 89-2.82(m,1H), 2.18(s,3H), 2.01(s,3H,m,1H overlap), 1.94-1.78(m,3H),1.75-1.66(m,1H),1.59 -1.48(m,1H),1.35-1.24(m,1H).LC-MS:Rt=0.6 7min; MS m / z 367.3[M+H] +

[0232] Example Ex005 (R)-3-Methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)a 5-(trifluoromethyl)-3-aminopyridazin-3-ylphenol [ka] Amine IntP030 (76 mg, 0.316 mmol) in 2 mL of 1,4-dioxane ), boronate IntB010 (124 mg, 0.410 mmol), and 2M Na A mixture of CO3 and water (0.474 mL, 0.947 mmol) was purged with argon for 3 min. Then, Pd(Ph3P)4 (10.9 mg, 9.4 μmol) was added and the mixture was The mixture was heated at 120° C. for 2 h. IntB010 (50 mg, 0.166 mmol) and P Another portion of d(Ph3P)4 (10.9 mg, 9.4 μmol) was added and heating was continued overnight. The reaction mixture was cooled to RT, diluted with water and extracted with ethyl acetate. The crude product was purified by SFC using 1,2-dichloromethane, ... The column was purified (Waters Viridis 2-EP 130A, 250 x 30 m m, 5 μm; 35°C, eluent B: 16-24% MeOH 10 min, flow rate: 100 mL / min , pressure: 120 bar), yielding the title compound as a white solid. 1 H NMR( 400MHz,DMSO-d6)δ(ppm)10.12(s,1H),7.13-7. 11(m,1H),7.09(br s,1H),7.05(br s,1H),5.8 0(d,1H),4.33-4.22(m,1H),3.00-2.89(m,1H), 2.69-2.59(m,1H),2.21(s,3H),2.12(br s,3+3 H),2.04-1.92(m,2H),1.92-1.84(m,1H),1.77- 1.66(m,1H),1.63-1.51(m,1H),1.49-1.36(m,1 H).LC-MS:Rt=0.74min;MS m / z 381.3[M+H] +

[0233] The following examples each show the appropriate halo-pyridazine intermediate (IntP) and the corresponding Boronic acid or boronate intermediate (IntB) or commercially available boronic acid (BCA) was used to synthesize similarly to the procedure above, optionally followed by a deprotection step.

[0234] [Table 10]

[0235] [Table 11]

[0236] [Table 12]

[0237] [Table 13]

[0238] [Table 14]

[0239] [Table 15]

[0240] [Table 16]

[0241] [Table 17]

[0242] [Table 18]

[0243]

Table 19

[0244]

Table 20

[0245]

Table 21

[0246]

Table 22

[0247]

Table 23

[0248]

Table 24

[0249]

Table 25

[0250]

Table 26

[0251]

Table 27

[0252]

Table 28

[0253] [Table 29]

[0254] [Table 30]

[0255] The following Examples Ex083(A / B) to Ex096(A / B) are as defined herein. As shown, a similar procedure to Example Ex001 was carried out using the corresponding amines and boronates. It is prepared as a racemate according to the procedure, followed by a chiral chromatographic separation step. I did.

[0256] Examples Ex083A and Ex083B 3-Methyl-2-(6-(((8R,8aR)-octahydroindolizin-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol and 3-methyl Leu-2-(6-(((8S,8aS)-octahydroindolizin-8-yl)amino) Pyridazin-3-yl)-5-(trifluoromethyl)phenol Racemic (rac)-3-methyl-2-(6-(((8r,8ar)-octahydro- 2-( ... Starting from phenol (IntP041 and IntB010, for example Ex001 (prepared as described in) were separated by chiral normal phase chromatography (column: C hiralpak AD, 250×30 mm, 5 μm; RT, eluent: n-heptane:E tOH=90:10+0.05%DEA; flow rate: 20mL / min; cycle time: 15min ), two enantiomers, Ex083A (first eluting, Rt = 25 min) and Ex0 83B (eluting second, Rt=31 min) was obtained. Ex 083A 1 H NMR(400MHz,DMSO-d6)δ 10.14(s, 1H),7.21(d,1H),7.12-7.08(m,1H),7.07-7.02 (m,1H),6.88-6.75(m,2H),3.96-3.77(m,1H),3 .29-3.20(m,2H),3.13-2.93(m,2H),2.16-2.09 (m,4H),2.05-1.88(m,2H),1.72-1.45(m,5H),1 .17-1.04(m,1H).LC-MS:Rt=0.73min;MS m / z 3 93.2[M+H]+ Ex 083B 1 H NMR(600MHz,DMSO-d6)δ 10.19(s, 1H),7.23(d,1H),7.11(s,1H),7.06(s,1H),6.9 6-6.76(m,2H),3.99-3.82(m,1H),3.34-3.28(m ,2H),3.17-3.02(m,2H),2.19-2.11(m,4H),2.0 3-1.87(m,2H),1.77-1.49(m,5H),1.20-1.13(m ,1H).LC-MS:Rt=0.73min;MS m / z 393.2[M+H]+

[0257] Examples Ex084A and Ex084B (R)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (S)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl) methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan Enol Racemic 2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl (amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Starting from the steps IntP044 and IntB010, the example Ex001 is described. (prepared as described above) were separated by chiral normal phase chromatography (column: Chi ralpak AD, 250×30 mm, 5 μm; RT, eluent: n-heptane:EtO H=80:20+0.05%DEA; flow rate: 20mL / min; cycle time: 30min), The two enantiomers, Ex084A (eluting first, Rt = 15 min) and Ex084 B (eluting second, Rt = 23.5 min) was obtained. Ex 084A 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.1 5(s,1H),7.22(d,1H),7.10(s,1H),7.04(s,1H) ,6.93(d,1H),6.70(s,1H),4.51-4.38(m,1H),3 .68-3.57(m,2H),3.56-3.47(m,2H),3.44-3.34 (m,1H),2.97-2.77(m,2H),2.37-2.23(m,1H),2 .13(s,3H),1.70-1.62(m,2H),1.57-1.41(m,4H ).LC-MS:Rt=0.72min;MS m / z 411.3[M+H]+ Ex 084B 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.1 5(s,1H),7.22(d,1H),7.10(s,1H),7.04(s,1H) ,6.93(d,1H),6.70(s,1H),4.51-4.38(m,1H),3 .68-3.57(m,2H),3.56-3.47(m,2H),3.44-3.34 (m,1H),2.97-2.77(m,2H),2.37-2.23(m,1H),2 .13(s,3H),1.70-1.62(m,2H),1.57-1.41(m,4H ).LC-MS:Rt=0.72min;MS m / z 411.3[M+H]+

[0258] Examples Ex085A and Ex085B 3-Methyl-2-(6-(((1S,2S,5S)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro Methyl)phenol (Ex085A) and 3-Methyl-2-(6-(((1R,2R,5R)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro Methyl)phenol (Ex085B) [ka] Racemic product (starting from IntP048 and IntB010, Example Ex001 (prepared as described for Column: Chiralpak IG, 250 x 30 mm, 5 μm; 40°C, eluent: n-hexane butane:i-PrOH=70:30+0.1% ammonia; flow rate: 80mL / min, pressure: 120 bar, cycle time: 20 min), two enantiomers, Ex085A ( Ex085B (eluting first, Rt = 7 min) and Ex085B (eluting second, Rt = 11.9 min). The configuration was assigned by X-ray crystallography. Ex 085A 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.1 6(s,1H),7.21(d,1H),7.10(s,1H),7.04(s,1H) ,6.82(d,1H),6.75(br d,1H),4.13-4.04(m,1H ),3.28-3.21(m,1H),3.06-3.0(m,1H),2.20(s, 3H),2.13(s,3H),2.05-1.94(m,1H),1.86-1.61 (m,4H),1.55-1.29(m,3H).LC-MS:Rt=0.71min; MS m / z 393.2[M+H]+ Ex 085B 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.2 1(s,1H),7.21(d,1H),7.10(s,1H),7.04(s,1H) ,6.82(d,1H),6.75(br d,1H),4.12-4.04(m,1H ),3.26-3.22(m,1H),3.06-3.0(m,1H),2.20(s, 3H),2.13(s,3H),2.01-1.92(m,1H),1.80-1.61 (m,4H),1.48-1.28(m,3H).LC-MS:Rt=0.71min; MS m / z 393.2[M+H]+

[0259] Examples Ex086A and Ex086B 2-(6-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenyl)-2-hydroxyethyl 2-[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol (Ex086B) and 2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenyl)-1,2-dihydro-1,2-tri ... 2-[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol (Ex086A) [ka] Racemic 2-(6-((-8-(2-hydroxyethyl)-8-azabicyclo[3.2 .1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trimethylphenyl) Starting from fluoromethyl)phenol (IntP050 and IntB010, examples Ex001) were separated by chiral SFC (column: Chiralpak IG, 250 × 30 mm, 5 μm; 40 °C, eluent B: i-PrO H 35% + 0.1% ammonia; flow rate: 70 mL / min; pressure: 110 bar, cycle Time: 6 min), two enantiomers, Ex086A (first eluting, Rt = 5.2 1 min) and Ex086B (eluting second, Rt = 6.5 min). Assignment was made by ROESY NMR. Ex 086A 1 H NMR(600MHz,DMSO-d6)δ 10.17(s, 1H),7.21(d,1H),7.11(s,1H),7.05(s,1H),6.8 3(d,1H),6.75(d,1H),4.41-4.30(m,1H),4.16- 4.04(m,1H),3.52-3.43(m,2H),3.33-3.29(m,1 H),3.23-3.15(m,1H),2.47-2.36(m,2H),2.13( s,3H),1.94-1.85(m,1H),1.80-1.61(m,4H),1. 49-1.30(m,3H).LC-MS:Rt=0.71min;MS m / z 42 3.3[M+H]+ Ex 086B 1 H NMR(600MHz,DMSO-d6)δ 10.17(s, 1H),7.21(d,1H),7.11(s,1H),7.05(s,1H),6.8 3(d,1H),6.75(d,1H),4.41-4.30(m,1H),4.16- 4.04(m,1H),3.52-3.43(m,2H),3.33-3.29(m,1 H),3.23-3.15(m,1H),2.47-2.36(m,2H),2.13( s,3H),1.94-1.85(m,1H),1.80-1.61(m,4H),1. 49-1.30(m,3H).LC-MS:Rt=0.71min;MS m / z 42 3.3[M+H]+

[0260] Examples Ex087A and Ex087B 2-(6-(((3R,6R)-6-(hydroxymethyl)-1-methylpiperidine-3 -yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan Enol and 2-(6-(((3S,6S)-6-(hydroxymethyl)-1-methylphenyl (3-fluoro-5-(trifluoro-2-phenyl-2-pyridazinyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoro-2-phenyl-2-pyridazinyl) (trimethyl)phenol Racemic 2-(6-((-6-(hydroxymethyl)-1-methylpiperidine-3-yl) (amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Starting from the steps IntP052 and IntB010, the example Ex001 is described. (prepared as described above) were separated by chiral SFC (column: Chiralpak I G-LL, 250×30 mm, 5 μm, 40° C., eluent B: MeOH 22%+0.1% ammonia; flow rate: 80 mL / min; pressure: 120 bar; cycle time: 20 min), 2 Two diastereoisomers, Ex087A (first eluting, Rt = 8.2 min) and E This resulted in x087B (eluting second, Rt = 11.3 min). Ex 087A 1 H NMR(600MHz,DMSO-d6)δ 10.19(s, 1H),7.22(d,1H),7.10(s,1H),7.04(s,1H),7.0 2(d,1H),6.72(d,1H),4.44-4.34(m,1H),4.27- 4.17(m,1H),3.64-3.56(m,1H),3.48-3.40(m,1 H),2.80-2.73(m,1H),2.44-2.37(m,1H),2.27( s,3H),2.13(s,3H),2.07-1.98(m,1H),1.86-1. 78(m,1H),1.66-1.52(m,3H).LC-MS:Rt=0.71mi n; MS m / z 423.3[M+H]+ Ex 087B 1 H NMR(600MHz,DMSO-d6)δ 10.19(s, 1H),7.22(d,1H),7.10(s,1H),7.04(s,1H),7.0 2(d,1H),6.72(d,1H),4.45-4.33(m,1H),4.26- 4.15(m,1H),3.64-3.55(m,1H),3.50-3.40(m,1 H),2.81-2.72(m,1H),2.44-2.36(m,1H),2.27( s,3H),2.13(s,3H),2.07-1.99(m,1H),1.86-1. 78(m,1H),1.68-1.51(m,3H).LC-MS:Rt=0.71mi n; MS m / z 423.3[M+H]+

[0261] Examples Ex088A and Ex088B (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) (Nyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol and ( R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) pyridazin-3-yl)amino)-2-methylpropane-1,2-diol Racemic 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)fluor) (phenyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol (I Starting from ntP053 and IntB010, the sequence is as described for Example Ex001. The mixture was separated by chiral SFC (column: Chiralpak IG, 25 0×30 mm, 5 μm; 40° C., eluent B: MeOH 25% + 0.1% ammonia; flow speed: 80mL / min; pressure: 120 bar; cycle time: 20 min), two enantiomers , respectively, Ex088A (first eluting, Rt = 8.7 min) and Ex088B (second eluting). The results showed that the 10-fold increase in the β-blocking rate was due to the increase in the β-blocking rate (Rt = 13.8 min). Ex 088A 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.1 9(s,1H),7.24(d,1H),7.10(s,1H),7.04(s,1H) ,7.02(d,1H),6.88-6.83(m,1H),4.99-4.92(m, 1H),4.77(s,1H),3.44-3.37(m,2H),3.32-3.27 (m,1H),3.24-3.18(m,1H),2.12(s,3H),1.11(s ,3H).LC-MS:Rt=0.7min;MS m / z 358.1[M+H]+ Ex 088B 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.1 7(s,1H),7.24(d,1H),7.10(s,1H),7.04(s,1H) ,7.02(d,1H),6.90-6.82(m,1H),4.99-4.92(m, 1H),4.77(s,1H),3.43-3.37(m,2H),3.32-3.26 (m,1H),3.24-3.18(m,1H),2.12(s,3H),1.11(s ,3H).LC-MS:Rt=0.7min;MS m / z 358.1[M+H]+

[0262] Examples Ex089A and Ex089B (1S,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol (1R,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trimethylsilyl) Fluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2- Diol Racemic 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)fluor) (phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol (IntP Starting from 054 and IntB010, the compounds were prepared as described for Example Ex001. (manufactured by Sigma-Aldrich Co., Ltd.) were separated by chiral SFC (column: i-LuxCel (IC), 250 × 3 0 mm, 5 μm; Eluent B: MeOH 15% + 0.1% ammonia; Flow rate: 80 mL / cycle time: 30 min), two diastereoisomers, Ex089A (the Ex089B (eluting first, Rt = 14.3 min) and Ex089B (eluting second, Rt = 22.2 min). was brought about. Ex 089A 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.1 8(s,1H),7.24(d,1H),7.10(s,1H),7.04(s,1H) ,7.02(d,1H),6.89(d,1H),5.11(d,1H),4.43(d ,1H),4.19-4.05(m,1H),3.98-3.91(m,1H),3.7 4-3.66(m,1H),2.29-2.19(m,1H),2.13(s,3H), 1.95-1.83(m,1H),1.63-1.52(m,1H),1.42-1.3 2(m,1H).LC-MS:Rt=0.7min;MS m / z 370.3[M+H ]+ Ex 089B 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.1 9(s,1H),7.24(d,1H),7.10(s,1H),7.06-6.98( m,2H),6.89(d,1H),5.11(d,1H),4.43(d,1H),4 .16-4.05(m,1H),3.98-3.90(m,1H),3.76-3.68 (m,1H),2.28-2.18(m,1H),2.13(s,3H),1.95-1 .85(m,1H),1.63-1.52(m,1H),1.42-1.32(m,1H ).LC-MS:Rt=0.7min;MS m / z 370.3[M+H]+

[0263] Examples Ex090A and Ex090B (S)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazine-3- (R)-2-(6-(yl)-3-methyl-5-(trifluoromethyl)phenol and (R)-2-(6-( (2-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl- 5-(Trifluoromethyl)phenol Racemic 2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazine-3 -yl)-3-methyl-5-(trifluoromethyl)phenol (IntP056 and I Starting from ntB010, prepared as described for Example Ex001), Separation was performed by SFC (column: Chiralpak IB-N, 250 × 30 mm, 5 μm, 40 °C, eluent B: i-PrOH 23% + 0.1% ammonia; flow rate: 80 m L / min; pressure: 120 bar, cycle time: 20 min), two enantiomers, respectively Ex090A (eluting first, Rt = 9.6 min) and Ex090B (eluting second, Rt = 13 minutes) was provided. Ex 090A 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.1 8(s,1H),7.22(d,1H),7.10(s,1H),7.04(s,1H) ,6.94(d,1H),6.83(t,1H),4.82(d,1H),3.59-3 .52(m,1H),3.49-3.43(m,1H),3.27-3.21(m,1H ),2.12(s,3H),1.76-1.66(m,1H),0.96-0.89(m ,6H).LC-MS:Rt=0.85min;MS m / z 356.2[M+H]+ Ex 090B 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.1 7(s,1H),7.22(d,1H),7.10(s,1H),7.04(s,1H) ,6.94(d,1H),6.83(t,1H),4.82(d,1H),3.58-3 .50(m,1H),3.50-3.42(m,1H),3.28-3.21(m,1H ),2.12(s,3H),1.77-1.67(m,1H),0.96-0.89(m ,6H).LC-MS:Rt=0.85min;MS m / z 356.2[M+H]+

[0264] Examples Ex091A and Ex091B 3-Methyl-2-(6-(((2S,3S)-2-methylpiperidin-3-yl)amino ) Pyridazin-3-yl)-5-(trifluoromethyl)phenol and 3-methyl-2 -(6-(((2R,3R)-2-methylpiperidin-3-yl)amino)pyridazine- 3-yl)-5-(trifluoromethyl)phenol Racemic 3-methyl-2-(6-((2-methylpiperidin-3-yl)amino)pyridine Dazin-3-yl)-5-(trifluoromethyl)phenol (IntP099 and In tB010 (prepared as described for Example Ex001) was reacted with chiral Separation was performed by SFC (column: Lux i-Cellulose 5, 250 x 30 m) m, 5 μm, 40 °C, eluent B: MeOH 23% + 0.1% NH3, flow rate: 80 mL / min; pressure: 120 bar, cycle time: 20 min), the title compound, Ex091 A (first eluting, Rt = 9.17 min) and Ex091B (second eluting, Rt = 12.0 1 min) was provided. Ex 091A 1 H NMR(400MHz,CD3OD)δ(ppm)7.34(d ,1H),7.08(s,1H),7.01-7.03(m,2H),4.27-4.2 2(m,1H),3.18-3.12(m,1H),3.10-3.03(m,1H), 2.81-2.73(m,1H),2.21(s,3H),2.08-2.01(m,1 H),1.75-1.70(m,2H),1.59-1.53(m,1H),1.15( d,3H).LC-MS:Rt=0.73min;MS m / z 367.1[M+H] + Ex 091B 1 H NMR(400MHz,CD3OD)δ(ppm)7.35(d ,1H),7.07(s,1H),7.05-7.01(m,2H),4.27-4.2 1(m,1H),3.18-3.12(m,1H),3.11-3.02(m,1H), 2.81-2.72(m,1H),2.21(s,3H),2.10-1.99(m,1 H),1.78-1.68(m,2H),1.61-1.51(m,1H),1.16( d,3H)LC-MS:Rt=0.73min;MS m / z 367.1[M+H] +

[0265] Examples Ex092A and Ex092B 2-(6-(((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl )Amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol 2-(6-(((R)-1-((R)-2-hydroxypropyl)piperidine-3 -yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan Enol 2-(6-(((3R)-1-(2-hydroxypropyl)piperidin-3-yl)a (amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Starting from the diastereomeric mixture (IntP105 and IntB010, Example Ex 001) were separated by chiral SFC (column: Ch iralPak AD, 250 x 30 mm, 5 μm, 40°C, eluent B: EtOH 25 %+0.1%NH3, Flow rate: 80mL / min; Pressure: 120 bar, Cycle time: 20 min), the title compound, Ex092A (first eluting, Rt = 8.7 min) and Ex09 2B (second elution, Rt = 12.0 min) was obtained. Ex 092A 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.1 4(s,1H),7.22(d,1H),7.10(s,1H),7.05(s,1H) ,6.88(d,1H),6.79(d,1H),4.32-4.26(m,1H),4 .14-4.06(m,1H),3.80-3.72(m,1H),3.48-3.40 (m,1H),2.95-2.87(m,1H),2.28-2.16(m,3H),2 .12(s,3H),1.86-1.78(m,1H),1.76-1.67(m,1H ),1.58-1.47(m,1H),1.43-1.34(m,1H),1.03(d ,3H).LC-MS:Rt=0.73min;MS m / z 411.2[M+H] + Ex 092B 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.1 4(s,1H),7.22(d,1H),7.10(s,1H),7.05(s,1H) ,6.88(d,1H),6.79(d,1H),4.29-4.24(m,1H),4 .14-4.06(m,1H),3.80-3.72(m,1H),3.48-3.40 (m,1H),2.95-2.87(m,1H),2.29-2.16(m,3H),2 .13(s,3H),1.88-1.78(m,1H),1.76-1.67(m,1H ),1.61-1.48(m,1H),1.42-1.31(m,1H),1.04(d ,3H)LC-MS:Rt=0.73min;MS m / z 411.2[M+H] +

[0266] Examples Ex093A and Ex093B 2-(6-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyridazine 2-(6-(phenyl-3-yl)-3-methyl-5-(trifluoromethyl)phenol and ((3R,5R)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl )-3-Methyl-5-(trifluoromethyl)phenol 2-(6-((5-fluoropiperidin-3-yl)amino)pyridazin-3-yl) Diastereomeric mixture of 3-methyl-5-(trifluoromethyl)phenol (In Starting from tP102 and IntB005, as described for example Ex003 The mixture was separated by chiral SFC (column: Lux i-Cellulose- 5, 250×30 mm, 5 μm, 40°C, Eluent B: 33% [iPrOH + 0.1% NH 3], flow rate: 80 mL / min; pressure: 120 bar; cycle time: 20 min), title compound The compounds were Ex093A (eluted first, Rt = 6.9 min) and Ex093B (eluted second). Elution, Rt=11.5 min) was achieved. Ex 093A 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.1 7(s,1H),7.23(d,1H),7.10(s,1H),7.04(s,1H) ,6.85(d,1H),6.81(d,1H),4.89-4.72(m,1H),4 .25-4.15(m,1H),3.12-3.05(m,1H),2.94-2.84 (m,1H),2.82-2.68(m,1H),2.44-2.35(m,2H),2 .24-2.13(m,1H),2.13(s,3H),1.86-1.68(m,1H );LC-MS:Rt=0.85min;MS m / z 371.2[M+H] + Ex 093B 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.1 4(s,1H),7.24(d,1H),7.10(s,1H),7.05(s,1H) ,6.85(d,1H),6.82(d,1H),4.93-4.75(m,1H),4 .28-4.18(m,1H),3.16-3.10(m,1H),2.99-2.90 (m,1H),2.86-2.71(m,1H),2.49-2.40(m,2H),2 .26-2.15(m,1H),2.13(s,3H),1.88-1.70(m,1H );LC-MS:Rt=0.85min;MS m / z 371.2[M+H] +

[0267] Examples Ex094A and Ex094B 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol and 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazine Diastereomers of (3-yl)-3-methyl-5-(trifluoromethyl)phenol The mixture was prepared as follows: rac-Ex093A / B (40 mg, 0.10 mm ol) was dissolved in THF and formaldehyde (0.038 mL, 0.51 mmol, NaBH(OAc)3 (43 mg, 0.205 mmol) was added. and the resulting mixture was stirred for 1 h at RT. Further formaldehyde (0. 038mL, 0.51mmol, 37% in water), NaBH(OAc)3 (43mg, 0.038mL, 0.51mmol, 37% in water). After stirring for an additional 2 hours, the reaction was The mixture was quenched by the addition of NaHCO3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by achiral RP chromatography. The fractions containing the pure product were collected. Combine and adjust to pH 8-9 using saturated NaHCO3 solution, then wash twice with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The polymeric products were separated by chiral SFC (column: Lux i-Cellulo se-5, 250×30 mm, 5 μm, 40°C, eluent B: 33% [iPrOH+0.1 % NH3], flow rate: 80 mL / min; pressure: 120 bar, cycle time: 20 min), Table The title compounds, Ex094A (first eluting, Rt = 3.99 min) and Ex094B ( The second eluted, Rt=4.52 min. Ex 094A 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.1 8(s,1H),7.24(d,1H),7.10(s,1H),7.04(s,1H) ,6.88-6.84(m,1H),5.02-4.84(m,1H),4.42-4. 33(m,1H),2.93-2.86(m,1H),2.80-2.70(m,1H) ,2.37-2.24(m,1H),2.22(s,3H),2.12(s,3H),2 .12-2.03(m,1H),2.01-1.93(m,1H),1.77-1.58 (m,1H).LC-MS:Rt=0.86min;MS m / z 385.2[M+H ] + Ex 094B 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.1 9(s,1H),7.24(d,1H),7.10(s,1H),7.04(s,1H) ,6.88-6.84(m,1H),5.02-4.84(m,1H),4.42-4. 33(m,1H),2.93-2.86(m,1H),2.80-2.70(m,1H) ,2.37-2.24(m,1H),2.22(s,3H),2.12(s,3H),2 .12-2.03(m,1H),2.01-1.93(m,1H),1.77-1.58 (m,1H).LC-MS:Rt=0.86min;MS m / z 385.2[M+H ] +

[0268] Examples Ex095A and Ex095B 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol and 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amine Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazine Diastereomers of (3-yl)-3-methyl-5-(trifluoromethyl)phenol Starting from the mixture (IntP103 and IntB005), the following is described for Example Ex001: The chromatograms (prepared as described above) were separated by chiral SFC (column: Lux Amylos e-1, 250×30 mm, 5 μm, 40°C, eluent B: 17% [iPrOH+0.1% NH3], flow rate: 80 mL / min; pressure: 120 bar, cycle time: 20 min), title Compounds Ex095A (first eluting, Rt = 13.58 min) and Ex095B ( The second eluted, Rt=15.01 min. Ex 095A 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.1 6(br s,1H),7.24(d,1H),7.09(s,1H),7.04(s, 1H),6.88(d,1H),6.82(d,1H),4.84-4.63(m,1H ),4.20-4.09(m,1H),3.01-2.91(m,2H),2.39-2 .30(m,1H),2.26(s,3H),2.12(s,3H),2.10-2.0 4(m,1H),1.91-1.84(m,1H),1.56-1.44(m,1H). LC-MS:Rt=0.83min;MS m / z 385.3[M+H] + Ex 095B 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.1 7(br s,1H),7.24(d,1H),7.09(s,1H),7.04(s, 1H),6.89(d,1H),6.82(d,1H),4.84-4.63(m,1H ),4.20-4.10(m,1H),3.01-2.91(m,2H),2.39-2 .32(m,1H),2.26(s,3H),2.12(s,3H),2.10-2.0 4(m,1H),1.91-1.84(m,1H),1.56-1.44(m,1H). LC-MS:Rt=0.83min;MS m / z 385.2[M+H] +

[0269] Examples Ex096A and Ex096B 2-(6-(((3S,5R)-5-fluoropiperidin-3-yl)amino)pyridazine 2-(6-(phenyl-3-yl)-3-methyl-5-(trifluoromethyl)phenol and ((3R,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl )-3-Methyl-5-(trifluoromethyl)phenol 2-(6-((5-fluoropiperidin-3-yl)amino)pyridazin-3-yl) Diastereomeric mixture of 3-methyl-5-(trifluoromethyl)phenol (In Starting from tP104 and IntB005, as described for example Ex001 The mixture was separated by chiral SFC (column: Lux Amylose-1, 25 0×30mm, 5μm, 40℃, Eluent B: 40% [MeOH+0.1%NH3], flow rate : 80 mL / min; pressure: 120 bar, cycle time: 20 min), the title compound, Ex096A (first eluting, Rt = 4.79 min) and Ex096B (second eluting, R t=9.34 min). Ex 096A 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.1 6(br s,1H),7.24(d,1H),7.09(s,1H),7.04(s, 1H),6.87-6.82(m,2H),4.67-4.46(m,1H),4.04 -3.96(m,1H),3.17-3.08(m,2H),2.47-2.37(m, 2H), 2.25-2.18(m, 1H), 2.13(s, 3H), 1.60-1.49 (m,1H). LC-MS:Rt=0.82min;MS m / z 371.2[M+H] + Ex 096B 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.1 7(br s,1H),7.24(d,1H),7.10(s,1H),7.04(s, 1H),6.87-6.82(m,2H),4.67-4.46(m,1H),4.04 -3.96(m,1H),3.17-3.08(m,2H),2.47-2.37(m, 2H), 2.25-2.18(m, 1H), 2.13(s, 3H), 1.60-1.49 (m,1H). LC-MS:Rt=0.82min;MS m / z 371.2[M+H] +

[0270] Example Ex097 (3S,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol [ka] Using intermediate IntP043 and boronic acid IntB005 in 3 mL of CH2Cl2 Crude tert-butyl (3S,5R)-3-hydrogen ether prepared in the same manner as in Example Ex002 was 5-(6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) (3-yl)pyridazin-3-yl)amino)piperidine-1-carboxylate (660 mg, A solution of 1.409 mmol) was added to 4 M HCl ( The reaction mixture was evaporated. The resulting solid was dissolved in a mixture of 2 mL of DMSO and 2 mL of CH2Cl2, and the mixture was cooled to room temperature. The mixture was treated with formaldehyde (76 mg, 2.52 mmol). After 1 h, NaBH (OAc)3 (534 mg, 2.52 mmol) was added and stirring at RT was continued for 18 h. The reaction mixture was evaporated and the crude was purified by distillation with CH2Cl2 and 5% ammonia. By column chromatography on silica gel using MeOH (0%-30%) Purification afforded the title compound as an off-white solid. 1 H NMR (600M Hz,DMSO-d6)δ(ppm)10.17(s,2H),7.26(d,1H), 7.11(s,1H),7.06(s,1H),6.96-6.89(m,1H),6. 86(d,1H),4.20-4.09(m,1H),3.76-3.65(m,1H) ,3.41-3.29(m,1H),3.37(s,3H),3.26-3.15(m, 1H),3.07-2.94(m,1H),2.46-2.32(s,3H).LC-M S:Rt=0.61min;MS m / z 383.2[M+H] + .

[0271] Example Ex098 2-(6-(((1-hydroxycyclopentyl)methyl)amino)pyridazin-3-yl (trifluoromethyl)phenol [ka] (1) 2-(6-chloropyridazin-3-yl)-3-methyl-5-(trifluoromethyl) phenol, IntX109 [ka] IntB010 (150 mg, 0.497 mmol) in 3.9 mL of 1,4-dioxane ), 3,6-dichloropyridazine (89 mg, 0.596 mmol), Pd(Ph3P) 4 (28.7 mg, 0.025 mmol), and 2M Na2CO3 (0.75 mL, 1 A mixture of 1.5 mmol) was purged with nitrogen. The vial was sealed and irradiated in a microwave oven for 1 h. The mixture was heated at 120°C under irradiation. The reaction mixture was diluted with brine and extracted three times with AcOEt. The combined organic layers were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (25 g) was performed using hexane and EtOAc (0% to 50%). Purification by chromatography afforded the title compound. 1 H NMR (600M Hz,DMSO-d6)δ(ppm)10.43(s,1H),8.02(d,1H), 7.85(d,1H),7.19(s,1H),7.10(s,1H),2.11(s, 3H).LC-MS:Rt=0.95min;MS m / z 289.1[M+H] +

[0272] (2) 2-(6-(((1-hydroxycyclopentyl)methyl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol IntX109 (95 mg, 0.214 mmol), 1-(aminomethyl) (ethyl)cyclopentanol (73.9 mg, 0.642 mmol), and DIPEA (0 A mixture of 1.112 mL, 0.642 mmol) was heated at 150° C. for 18 hours. The mixture was evaporated and purified by SFC (column: Reprospher PEI 10 0A, 250×30mm, 5μm, 40℃, eluent B: 25-35% MeOH 10min, Flow rate: 100 mL / min; pressure: 120 bar) to afford the title compound. 1 H.N.M. R(400MHz,DMSO-d6)δ(ppm)8.37(s,1H),7.22(d ,1H),7.09(s,1H),7.05(s,1H),7.01(d,1H),6. 81-6.71(m,1H),4.66(s,1H),3.49(d,2H),2.13 (s,3H),1.79-1.54(m,8H).LC-MS:Rt=0.84min; MS m / z 368.2[M+H] +

[0273] Example Ex099 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-Methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one [ka] (1) 2-(6-chloro-5-methylpyridazin-3-yl)-3-methyl-5-(trimethylpyridazin-3-yl) Fluoromethyl)phenol, IntX110 [ka] 3,6-Dichloro-4-methylpyridazine (1.60 mL) in 95 mL of 1,4-dioxane g, 9.52 mmol), (2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl)boronic acid (2.09 g, 9.52 mmol), and 2M Na2CO3 (14 A mixture of 1.28 mL, 28.6 mmol) was purged with argon for 5 minutes. Add d(PPh3)4 (0.66 g, 0.57 mmol) and incubate the mixture at 120 The mixture was stirred at 0.degree. C. under an argon atmosphere. The reaction mixture was quenched with water and brine (50 mL each). The combined organic extracts were washed with NaSO The crude product was triturated with 5 mL of CH2Cl2 overnight. The resulting solid was collected by filtration, washed with a small amount of CH2Cl2, and dried. This afforded the title compound as a white solid. 1 H NMR (400MHz, DM SO-d6)δ 10.36(s,1H),7.80(d,1H),7.17(s,1H ),7.11(s,1H),2.45(s,3H),2.09(s,3H).LC-MS :Rt=1.07min,MS m / z 303.0[M+H]+

[0274] (2) 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) (4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one IntX110 (100 mg, 0.330 mmol) and 5-aminobutyric acid in 2 mL of toluene A suspension of no-1-methylpiperidin-2-one (63.5 mg, 0.496 mmol) , LiOtBu (167 mg, 1.982 mmol) and PdCl2(dppf) (12 An additional 0.09 mg, 0.017 mmol) was added to the vial. The vial was sealed and heated at 105 °C overnight. After cooling to RT, the reaction mixture was poured into water (30 mL) and The combined organic extracts were dried over Na2SO4, filtered, and The crude was first purified by distillation with n-heptane and EtOAc (0% to 100%), then by evaporation. CH2Cl2 and MeOH (0%-30%) were used for column chromatography on silica gel (25 g). Purification by column chromatography gave the title compound as a brown solid. 1 H.N.M. R(400MHz,DMSO-d6)δ 10.14(s,1H),7.18-7.15 (m,1H),7.10(s,1H),7.06(s,1H),6.16(d,1H), 4.68-4.51(m,1H),3.63(dd,1H),3.31-3.25(m, 1H),2.83(s,3H),2.42-2.35(m,2H),2.16(s,3H ),2.11(s,3H),2.09-1.94(m,2H).LC-MS:Rt=0. 93min; MS m / z 395.3[M+H]+

[0275] Example Ex100 (R)-3-Methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazin (3-yl)-5-(trifluoromethyl)phenol [ka] In step (2), the compound is reacted with tert-butyl (R)-3-aminopiperidine- The 1-carboxylate was used to synthesize the compound in a similar manner to the procedure described for Example Ex099. This was followed by TFA-mediated Boc cleavage and extraction with NaHCO3. , yielding the title compound as an off-white solid. 1 H NMR (400MHz, DMSO-d6)δ(ppm)7.10(s,1H),7.05(s,1H),7.02 (s,1H),5.75(d,1H),4.16-4.09(m,1H),3.12(d ,1H),2.81(d,1H),2.12(s,6H),1.99-1.91(m,1 H),1.70-1.43(m,3H),1.27-1.20(m,2H).LC-MS : Rt = 0.86 min; MS m / z 367.1 [M + H] + .

[0276] Example Ex101 (R)-2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridine Din-3-yl)-3-methyl-5-(trifluoromethyl)-phenol [ka] The compound was prepared by the reaction of the compound with (R)-1-ethylpiperidin-3-amine in step (2). and synthesized similarly to the procedure described for Example Ex099 to give an off-white solid. This afforded the title compound. 1 H NMR (400MHz, MeOH-d4) δ(p pm)7.26(s,1H),7.09(s,1H),7.02(s,1H),4.56 (s br,1H),3.67(s,1H),3.10-3.00(m,2H),2.8 8-2.66(m,2H),2.26(s,3H),2.17(s,3H),2.12- 2.05(m,2H),1.96-1.73(m,3H),1.31(t,3H).LC -MS:Rt=0.87min;MS m / z 395.2[M+H] +

[0277] Example Ex102 (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) Nyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one [ka] In step (2), the compound is reacted with (R)-3-amino-1-methylpiperidine-2- The compound was synthesized similarly to the procedure described for Example Ex099 using the hydrochloride salt of off. The title compound was obtained as a white solid. 1 H NMR (400MHz, DMS O-d6)δ(ppm)7.15(s,1H),6.92(s,1H),6.85(s, 1H),6.25(d,1H),4.73-4.66(m,1H),3.37-3.34 (m,2H),2.88(s,3H),2.37-2.30(m,1H),2.10(s ,3H),2.08(s,3H),1.96-1.90(m,2H),1.88-1.7 8(m,1H).LC-MS:Rt=0.87min;MS m / z 395.2[M+ H] +

[0278] Example Ex103 4-(2-((6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl) (N-amino)ethyl)benzenesulfonamide [ka] (1) 4-(2-((6-(2-methoxy-4,6-dimethylphenyl)pyridazine-3 -yl)amino)ethyl), IntX111 [ka] IntP101 (400mg, 1.279mmol), IntB017 (493mg, 1.918mmol), and Pd(Ph3P)4 (148mg, 0.128mmol). , dissolved in 10 mL of DME. 2M Na2CO3 (1.92 mL, 3.84 mmol) l) was added and the reaction mixture was stirred for 22 hours at 90° C. The reaction mixture was poured into water and E Extracted three times with tOAc. The combined organic extracts were washed with brine and evaporated to dryness. The crude material was purified using CH2Cl2 and MeOH (0%-10%) on silica gel (12 g). The product was purified by column chromatography at 4°C. The product-containing fractions were evaporated to dryness. Trituration with MeOH afforded the title compound as an off-white solid. LC-MS : Rt = 0.80 min; MS m / z 413.2 [M + H] +

[0279] (2) 4-(2-((6-(2-hydroxy-4,6-dimethylphenyl)pyridazine- 3-yl)amino)ethyl)benzenesulfonamide IntX111 (65 mg, 0.137 mmol) was suspended in 5 mL of CH2Cl2. Then, BBr3 (1M in CH2Cl2, 0.206 mL, 0.206 mmol) was added The resulting orange suspension was stirred for 3 h at RT. The reaction mixture The mixture was evaporated to dryness and the residue was purified by achiral RP chromatography. The fractions containing the product were combined and adjusted to pH 8-9 using saturated NaHCO3 solution. The combined organic extracts were evaporated to give a beige The title compound was obtained as a solid. 1 H NMR (400MHz, DMSO-d6) δ(pp m)9.46(s,1H),7.78(d,2H),7.49(d,2H),7.31( s,2H),7.20(d,1H),6.96-6.91(m,1H),6.84(d, 1H),6.60-6.55(m,2H),3.74-3.57(m,2H),3.07 -2.94(m,2H),2.22(s,3H),2.05(s,3H).LC-MS: Rt=0.71min; MS m / z 399.2[M+H] +

[0280] Example Ex104 (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)fluor) (phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxy Cid TFA salt [ka] A solution of Example Ex005 (27 mg, 0.071 mmol) in 1 mL of CH2Cl2 , treated with mCPBA (13.6 mg, 0.079 mmol) and stirred for 90 min at RT The reaction mixture was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. The product was purified by achiral RP chromatography to give the title compound as a white solid. was brought about. 1 H NMR(400MHz,DMSO-d6)δ(ppm)12.63 (s,1H),10.27(s,1H),7.36(s,1H),7.14(s,1H) ,7.08(s,1H),4.84-4.69(m,1H),4.08-3.92(m, 1H),3.88-3.80(m,1H),3.63-3.52(m,5H),2.20 (s,3H),2.26-2.10(m,1H),2.13(s,3H),2.08-1 .96(m,2H),1.85-1.70(m,1H).LC-MS:Rt=0.86m in; MS m / z 397.2[M+H]+

[0281] Biological Assays and Data The activity of the compounds according to the invention can be evaluated by the following in vitro methods: The compounds of formula (I) or pharma- ceutically acceptable salts thereof have beneficial pharmacological properties, such as Inhibiting NLRP3 activity, e.g., as shown in the assays provided in the next section. These results suggest that NLRP3 inflammasome activity may be a promising therapeutic option for cancer. It is shown as follows.

[0282] IL-1β secretion assay: Monocytic THP-1 cells (ATCC: TIB-202) were cultured in RPMI medium (RPMI / He PES + 10% fetal bovine serum + sodium pyruvate + 0.05 mM beta-mercapto Ethanol (1000x stock) + Pen-Strep) was maintained according to the supplier's instructions. The cells were incubated with 0.5 μM phorbol 12-myristate 13-acetate (PMA; S igma#P8139), and then the medium was replaced and the cells were cultured in 384-well flat-bottom cells. 50,000 cells per well in a culture plate (Greiner, #781986) 0 cells and allowed to differentiate overnight. Compounds serially diluted 1:3.16 in DMSO was added to the cells at 1:100 and incubated for 1 hour. 15 μM (final concentration) of nigericin (Enzo Life Sciences, # BML-CA421-0005) and incubated the cells for 3 h. 10 μL of the supernatant was removed and IL-1β levels were assayed using HTRF according to the manufacturer's instructions. Viability and proliferation were monitored using the IL1PEC assay (CisBio, #62IL1PEC). Rotation was measured using PrestoBlue cell viability reagent (Life Technologies, es, #A13261) directly to the cell culture plates.

[0283] TNF-α secretion assay: Monocytic THP-1 cells were cultured in RPMI medium according to the supplier's instructions as described above. Undifferentiated cells were maintained in culture in 384-well flat-bottom cell culture plates (Greiner, 781986) and rested overnight. Experimental compounds were prepared and added as described above. TNF-α secretion was measured depending on the experiment. Depending on the medium, 1 μg / mL LPS (Sigma, #L4391) or 100 ng / mL P Addition of am3CSK4 (Invivogen, #tlrl-pms) caused The cells were incubated for 3 hours. 10 μL of the supernatant was removed and TNF-α levels were determined by ELISA. Using the HTRF assay (CisBio, #62TNFPEC) according to the instructions of Carr. Survival was monitored as described above.

[0284] Interpretation of the data: I C 50 Values ​​are the percentage of inhibition by a logistic fit according to From the plot of vs. inhibitor concentration it was calculated: y=A2+(A1-A2) / (1+(x / IC 50 )^p) y is the inhibitor concentration, % inhibition at x; A1 is the lowest inhibition value, i.e. 0%; A2 is the highest inhibition value, i.e. 100%. The exponent, p, is the Hill coefficient. Curve Fitting was performed with an in-house developed software suite.

[0285] NLRP3-dependent IL-1β secretion was suppressed by the addition of nigericin in PMA-differentiated TH P-1 cells were stimulated and cytokines were measured in serum 3 hours later. As shown, activation of the NLRP3 inflammasome is mediated by an NF-kB-dependent priming pathway. The inhibitor requires both a priming step and the addition of an NLRP3 activator. To ensure that the steps involved in the Pam3CSK4 stimulation of NF-kB-dependent TNF-α secretion was monitored as a counter screen. The inhibitory effect of the compound (IC 50 ) data are shown in the table below.

[0286] [Table 31]

[0287] [Table 32]

[0288] [Table 33]

Claims

1. Compounds of formula (I) 【Chemistry 1】 (In the ceremony R １ is Cl, CH ３ , -OCF ３ , or C.F. ３ and R ２ H, halo, C １ ~C ４ Alkyl or haloC １ ~C ４ is alkyl; R ３ , R ４ H, CN, C １ ~C ４ Alkyl or haloC １ ~C ４ is alkyl; Z is -O- or -NH-(CH ２ ) ｎ -, where n is 0, 1, or 2; R ５ is C １ ~C ４ Alkyl, haloC １ ~C ４ Alkyl, Hydroxy C １ ~C ４ Alkyl , —OH, halo, oxo, and —CO ２ H, or R ５ Ha, Halo, Halo C １ ~C ４ Alkyl, C １ ~C ４ Alkyl, and -SO ２ N.H. ２ from Aryl or heterocyclic optionally substituted with 1 to 2 independently selected substituents is a aryl; or R ５ is C １ ~C ４ Alkyl, halo, haloC １ ~C ４ Independently of alkyl and -OH C optionally substituted with 1 to 3 selected substituents ３ ~C ６ 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 by one or more substituents independently selected from Substituted C ２ ~C ６ is alkyl) or a pharma- ceutically acceptable salt thereof.

2. Formula (II): 【Chemistry 2】 (In the formula, R １ , R ２ , R ３ , R ４ , and R ５ is as defined in claim 1 ( 2. The compound of claim 1, having the formula:

3. Formula (III): 【Chemistry 3】 wherein n is 0, 1, or 2; and R １ , R ２ , R ３ , R ４ , and R ５ Please As defined in claim 1.

2. The compound of claim 1, having the formula:

4. R ５ is C １ ~C ４ Alkyl, haloC １ ~C ４ Alkyl, Hydroxy C １ ~C ４ Alki -Ru, -OH, halo, oxo, and -CO ２ H, 1, 2 or 3, wherein the heterocyclyl is a monocyclic or bicyclic heterocyclyl optionally substituted with 1 or 2, 4. The compound according to claim 3, or a pharma- ceutically acceptable salt thereof.

5. R ５ is selected from the following: 【Chemistry 4】 R ５ａ is C １ ~C ４ Alkyl, Hydroxy C １ ~C ４ alkyl, and H; Selected; and R ５ｂ is -OH, hydroxy C １ ~C ４ Alkyl, H, halo, oxo, HaroC １ ~C ４ Alkyl, and -CO ２ H; X is independently selected from O or CH ２ in and m is 0 or 1. Salt.

6. R ５ Ha, Halo, Halo C １ ~C ４ Alkyl, C １ ~C ４ Alkyl, and -SO ２ N.H. ２ mosquito aryl or heteroaryl optionally substituted with 1 to 2 substituents independently selected from aryl; or a pharma- ceutically acceptable salt thereof. salt.

7. R ５ is C １ ~C ４ Alkyl, halo, haloC １ ~C ４ Independently of alkyl and -OH C optionally substituted with 1 to 3 substituents selected from ３ ~C ６ Cycloalkyl 4. The compound according to claim 1, 2, or 3, or a pharma- ceutically acceptable salt thereof.

8. R ５ is -OH, C １ ~C ４ Alkoxy, halo, -NH ２ , -NH(C １ ~C ４ Alki -N(C １ ~C ４ Alkyl) ２ and one or more substituents independently selected from C to be substituted ２ ~C ６ 4. The compound according to claim 1, 2 or 3, and pharma- ceutically acceptable salts thereof.

9. R ２ and R ３ At least one of the formula (1) is H. or a pharma- ceutically acceptable salt thereof.

10. R １ is -OCF ３ Or -CF ３ The compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof.

11. The compound is as follows: 2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3 -Methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)pyridine dazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin 5-(trifluoromethyl)phenyl; 2-(6-((3-hydroxycyclohexyl)amino)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-(((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-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pi ridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)a (amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)a (amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin 5-(trifluoromethyl)phenyl; (S)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((1-isopropylpiperidin-3-yl)amino)pyridazin-3-yl )-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazine-3- yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazin 5-(trifluoromethyl)phenyl; (S)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazine 5-(trifluoromethyl)phenyl; 2-(6-((5,5-difluoropiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-(trifluoro (fluoromethyl)propyl)amino)pyridazin-3-yl)-5-(trifluoromethyl ) phenol; 3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy-6-methyl 1-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile; (S)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy- 6-Methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile; (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy- 6-Methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile; 3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methyl Tylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino) -5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Rule; (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino) -5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Rule; 3-Methyl-2-(6-((pyrrolidin-2-ylmethyl)amino)pyridazin-3-yl (trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((pyrrolidin-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(6-((pyrrolidin-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-methylpyrrolidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(2-hydroxy-2-methylpropoxy)pyridazin-3-yl)-3-methyl ethyl-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazin-3-yl (trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; (S)-2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino)pyridazine 5-(trifluoromethyl)phenyl; (R)-2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((2-hydroxycyclopentyl)amino)pyridazin-3-yl)-3- Methyl-5-(trifluoromethyl)phenol; (cis)-2-(6-((2-hydroxycyclopentyl)amino)pyridazin-3-yl (trifluoromethyl)-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-yl l) phenol; 2-(6-((2-hydroxyethyl)amino)-5-(trifluoromethyl)pyridazinone 5-(trifluoromethyl)phenyl; 3,5-Dichloro-2-(6-((2,2,2-trifluoroethyl)amino)pyridazine (3-phenyl)phenol; 3-Methyl-2-(6-((pyridin-2-ylmethyl)amino)pyridazin-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)pyridazin-3-yl (trifluoromethyl)phenol, 3-Chloro-2-(6-((trans-3-hydroxycyclobutyl)amino)pyridazinone (3-phenyl-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)-5- (Trifluoromethyl)phenol; (R)-3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl )-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl )-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 5-Chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridin di-3-yl)-3-(trifluoromethyl)phenol; 3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-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-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol; (S)-5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl) Amino)pyridazin-3-yl)phenol; (R)-5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl) Amino)pyridazin-3-yl)phenol; 5-Chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol TFA salt; (S)-5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl) Amino)pyridazin-3-yl)phenol TFA salt; (R)-5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl) Amino)pyridazin-3-yl)phenol TFA salt; 2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3 , 5-bis(trifluoromethyl)phenol; (S)-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3,5-bis(trifluoromethyl)phenol; (R)-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl (trifluoromethyl)-3,5-bis(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazine 5-(trifluoromethyl)phenyl; 2-(4,5-dimethyl-6-(((S)-1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-(((R)-1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazine (trifluoromethyl)phenol TFA salt; 2-(4,5-dimethyl-6-(((S)-1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA salt ； 2-(4,5-dimethyl-6-(((R)-1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA salt ； 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridine ridazin-3-yl)amino)piperidine-2-carboxylic acid; 3-Methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(pyrimidin-5-ylamino)pyridazin-3-yl)-5- (Trifluoromethyl)phenol; 3,5-Dichloro-2-(6-(cyclopropylamino)pyridazin-3-yl)pheno Rule; 3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine (3-phenyl)phenol; (S)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol; (R)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol; 3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine (3-phenyl-3-yl)phenol TFA salt; (S)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol TFA salt; (R)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol TFA salt; 3-Methyl-2-(6-(pyridin-3-ylamino)pyridazin-3-yl)-5-( (trifluoromethyl)phenol; 3,5-Dimethyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine (3-phenyl)phenol; (S)-3,5-dimethyl-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol; (R)-3,5-dimethyl-2-(6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)phenol; 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazine (3-phenyl-5-(trifluoromethyl)phenol; (S)-2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-3-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-3-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 5-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl) (fluoromethyl)pyridazin-3-yl)phenol; (S)-5-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4- (Trifluoromethyl)pyridazin-3-yl)phenol; (R)-5-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4- (Trifluoromethyl)pyridazin-3-yl)phenol; 5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-3-(trifluoromethyl)phenol; (S)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-3-(trifluoromethyl)phenol; (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-3-(trifluoromethyl)phenol; 2-(6-((1,3-dimethylpiperidin-3-yl)amino)pyridazin-3-yl )-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((1,3-dimethylpiperidin-3-yl)amino)pyridazin-3-yl )-3-Methyl-5-(trifluoromethyl)phenol TFA salt; 2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl ) Pyridazin-3-yl)-5-(trifluoromethyl)phenol (S)-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoro (trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (R)-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoro (trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-5-methylpyridine di-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 Tylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridine di-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4 -methylpyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methyl Tylpyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-5-(trifluoro (trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Ru; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-5 -(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pyridazin-3-yl ethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-( (trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl ) phenol; 2-(6-((3-hydroxycyclohexyl)amino)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-(((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)pyridine ridazin-3-yl)amino)-1-methylpiperidin-2-one; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) 3-(1-methyl)pyridazin-3-yl)amino)-1-methylpiperidin-2-one; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) 3-(1-methyl)pyridazin-3-yl)amino)-1-methylpiperidin-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)pi ridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino)pi ridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridine ridazin-3-yl)amino)piperidin-2-one; (S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) 3-(4-amino)pyridazinyl)pyridazin-3-yl)amino)piperidin-2-one; (R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) 3-(4-amino)pyridazinyl)pyridazin-3-yl)amino)piperidin-2-one; 3-Methyl-5-(trifluoromethyl)-2-(6-((6-(trifluoromethyl) Piperidin-3-yl)amino)pyridazin-3-yl)phenol; 3-Methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidine-3- yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidinyl (amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol Ru; (R)-3-Methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidinyl (amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol Ru; 3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5-(trifluoromethyl) (fluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5- (Trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol Ru; (R)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5- (Trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol Ru; 2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; (S)-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoro (trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4 -(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)pheno Rule; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-( (trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol ； 2-(6-((3-hydroxy-3-(trifluoromethyl)cyclobutyl)amino)pyridine ridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-(trifluoromethyl)cyclobutene (amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)pheno Rule; 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- Methylpyridazin-3-yl)phenol; 5-Chloro-2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl) Amino)-4-methylpyridazin-3-yl)phenol; 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amine (n)-4-methylpyridazin-3-yl)phenol; 5-Chloro-2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4- (Trifluoromethyl)pyridazin-3-yl)phenol; 5-Chloro-2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl) Amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol; 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amine (no)-4-(trifluoromethyl)pyridazin-3-yl)phenol; 5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl) (fluoromethyl)pyridazin-3-yl)phenol; (S)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4- (Trifluoromethyl)pyridazin-3-yl)phenol; (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4- (Trifluoromethyl)pyridazin-3-yl)phenol; 5-Chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pi ridazin-3-yl)phenol; (S)-5-chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)a (amino)pyridazin-3-yl)phenol; (R)-5-chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)a (amino)pyridazin-3-yl)phenol; 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-(piperidin-3-ylamino)pyridazin-3-yl)-5- (Trifluoromethyl)phenol; (S)-3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl )-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl )-5-(trifluoromethyl)phenol; 2-(6-(((4-fluoropyrrolidin-2-yl)methyl)amino)pyridazine-3 -yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2S,4S)-4-fluoropyrrolidin-2-yl)methyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2R,4S)-4-fluoropyrrolidin-2-yl)methyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2R,4R)-4-fluoropyrrolidin-2-yl)methyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((((2S,4R)-4-fluoropyrrolidin-2-yl)methyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-(((4-methylmorpholin-3-yl)methyl)amine Pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-Methyl-2-(6-(((4-methylmorpholin-3-yl)methyl)amine Pyridazin-3-yl)-5-(trifluoromethyl)phenol; (rac)-3-methyl-2-(6-(((4-methylmorpholin-3-yl)methyl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropane propyl)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 Rule; (R)-3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2- (methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)pheno Rule; 3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropane 3-(propyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol HC 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)piperidin-3-yl)a (amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidine-3- 3-(3-(trifluoromethyl)phenyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenyl Nole; (R)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidine-3- 3-(3-(trifluoromethyl)phenyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenyl Nole; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridine di-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 Tylpyridazin-3-yl)-5-(trifluoromethoxy)phenol; 2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethoxy)phenol; (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethoxy)phenol; (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridin di-3-yl)-5-(trifluoromethoxy)phenol; 3-Methyl-2-(6-((octahydroindolizin-8-yl)amino)pyridazine -3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((8R,8aR)-octahydroindolizin-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((8R,8aS)-octahydroindolizin-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((8S,8aR)-octahydroindolizin-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((8S,8aS)-octahydroindolizin-8-yl) Amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Ru; 2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl)amino )pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Ru; 3-Methyl-2-(6-((8-methyl-8-azabicyclo[3.2.1]octane-2 -yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((1S,2S,5S)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro methyl)phenol; 3-Methyl-2-(6-(((1S,2R,5S)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro methyl)phenol; 3-Methyl-2-(6-(((1S,2R,5R)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro methyl)phenol; 3-Methyl-2-(6-(((1S,2S,5R)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro methyl)phenol; 3-Methyl-2-(6-(((1R,2R,5S)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro methyl)phenol; 3-Methyl-2-(6-(((1R,2S,5S)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro methyl)phenol; 3-Methyl-2-(6-(((1R,2S,5R)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro methyl)phenol; 3-Methyl-2-(6-(((1R,2R,5R)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoro methyl)phenol; 2-(6-((8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octa (2-amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl l) phenol; 2-(6-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[4.2.1.2]phenyl)-2-hydroxyethyl (ii) [3.2.1] octan-2-yl) amino) pyridazin-3-yl) -3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1R,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenylacetate (ii) [3.2.1] octan-2-yl) amino) pyridazin-3-yl) -3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1R,2S,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenylacetate (ii) [3.2.1] octan-2-yl) amino) pyridazin-3-yl) -3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1R,2R,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenylacetate (ii) [3.2.1] octan-2-yl) amino) pyridazin-3-yl) -3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1S,2S,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenyl)-1,2-dihydro-1,2-trimethylphenyl (ii) [3.2.1] octan-2-yl) amino) pyridazin-3-yl) -3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1S,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenylacetate (ii) [3.2.1] octan-2-yl) amino) pyridazin-3-yl) -3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1S,2R,5S)-8-(2-hydroxyethyl)-8-azabicyclo[4.2.1.2]phenylacetate (ii) [3.2.1] octan-2-yl) amino) pyridazin-3-yl) -3-methyl- 5-(trifluoromethyl)phenol; 2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1.2]phenylacetamide (ii) [3.2.1] octan-2-yl) amino) pyridazin-3-yl) -3-methyl- 5-(trifluoromethyl)phenol; 2-(6-((6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino) Pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,6R)-6-(hydroxymethyl)-1-methylpiperidine-3 3-(3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan Enol; 2-(6-(((3S,6R)-6-(hydroxymethyl)-1-methylpiperidine-3 3-(3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan Enol; 2-(6-(((3R,6S)-6-(hydroxymethyl)-1-methylpiperidine-3 3-(3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan Enol; 2-(6-(((3S,6S)-6-(hydroxymethyl)-1-methylpiperidine-3 3-(3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)furan Enol; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) (3-yl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridine ridazin-3-yl)amino)-2-methylpropane-1,2-diol; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) (3-yl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridine ridazin-3-yl)amino)cyclopentane-1,2-diol; (1S,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Ru; (1S,2R,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Ru; (1S,2S,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Ru; (1S,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Ru; (1R,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Ru; (1R,2S,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Ru; (1R,2R,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Ru; (1R,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoro (3-methyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol Ru; (S)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazine-3- yl)-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- yl)-3-methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((2-methylpiperidin-3-yl)amino)pyridazine-3 -yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((2S,3S)-2-methylpiperidin-3-yl)amino )pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((2R,3S)-2-methylpiperidin-3-yl)amino )pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((2S,3R)-2-methylpiperidin-3-yl)amino )pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((2R,3R)-2-methylpiperidin-3-yl)amino )pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((2-hydroxypropyl)piperidin-3-yl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Ru; 2-(6-(((S)-1-((R)-2-hydroxypropyl)piperidin-3-yl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Ru; 2-(6-(((S)-1-((S)-2-hydroxypropyl)piperidin-3-yl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Ru; 2-(6-(((R)-1-((R)-2-hydroxypropyl)piperidin-3-yl )amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol Ru; 2-(6-((5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)- 3-Methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyridazine 5-(trifluoromethyl)phenyl; 2-(6-(((3S,5R)-5-fluoropiperidin-3-yl)amino)pyridazine 5-(trifluoromethyl)phenyl; 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)pyridazine 5-(trifluoromethyl)phenyl; 2-(6-(((3R,5R)-5-fluoropiperidin-3-yl)amino)pyridazine 5-(trifluoromethyl)phenyl; 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidin-3-yl)amine (o) pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidin-3-yl)amine (o) pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amine (o) pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amido (o) pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazine- 3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidin-3-yl)amine (o) pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amido (o) pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidin-3-yl)amine (o) pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amine (o) pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)- 3-Methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoropiperidin-3-yl)amino)pyridazine 5-(trifluoromethyl)phenyl; 2-(6-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyridazine 5-(trifluoromethyl)phenyl; 2-(6-(((3R,5R)-5-fluoropiperidin-3-yl)amino)pyridazine 5-(trifluoromethyl)phenyl; 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)pyridazine 5-(trifluoromethyl)phenyl; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridine ridazin-3-yl)amino)-1-methylpiperidin-3-ol; (3S,5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol; (3R,5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol; (3R,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol; (3S,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol; 2-(6-(((1-hydroxycyclopentyl)methyl)amino)pyridazin-3-yl (trifluoromethyl)-3-methyl-5-(trifluoromethyl)phenol; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one; 3-Methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazine-3- yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazin (3-phenyl-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazin (3-phenyl-5-(trifluoromethyl)phenol; 2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridazine-3 -yl)-3-methyl-5-(trifluoromethyl)-phenol; (S)-2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridine di-3-yl)-3-methyl-5-(trifluoromethyl)-phenol; (R)-2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridine di-3-yl)-3-methyl-5-(trifluoromethyl)-phenol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) 4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one ； (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) 4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one ； 4-(2-((6-(2-hydroxy-4,6-dimethylphenyl)pyridazine-3-yl n-ethyl)amino)ethyl)benzenesulfonamide; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide; (3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)fluor (phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxy Sid: (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)fluor (phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxy Sid: 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 4-Methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide TFA salt; (3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)fluor (phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxy Cid TFA salt; (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)fluor (phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxy Cid TFA salt; or a pharma- ceutically acceptable salt thereof 2. The compound of claim 1, selected from:

12. A therapeutically effective amount of a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof. A pharmaceutical composition comprising a salt thereof and one or more pharma- ceutical acceptable carriers.

13. A therapeutically effective amount of a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof. and one or more therapeutic agents.

14. The one or more therapeutic agents may be a farnesoid X receptor (FXR) agonist; an anti-adipogenic agent; Fibrotics; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiation therapy and surgical treatment Placement; Uric acid lowering therapy; Anabolic and cartilage regeneration therapy; IL-17 blockade; Complement inhibition Bruton's tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors ( TLR7 / 8 inhibitors; CAR-T therapy; antihypertensive drugs; cholesterol lowering drugs; leukotrienes Lien A4 hydrolase (LTAH4) inhibitors; SGLT2 inhibitors; β2 agonists; anti Inflammatory Agents; Nonsteroidal Anti-inflammatory Drugs ("NSAIDs"); Acetylsalicylic Acid Agents (ASAs) from regenerative therapy treatment; from the treatment of cystic fibrosis; and from the treatment of atherosclerosis. The combination of claim 13 which is independently selected.

15. A compound according to any one of claims 1 to 11 or a compound thereof for use as a medicament. or a combination according to claim 13 or 14.

16. The contribution of NLRP3 signaling to abnormalities and / or symptoms and / or progression of a disease or disorder.

12. The method according to claim 1, for use in the treatment of a disease or disorder in which or a pharma- ceutically acceptable salt thereof.

17. The contribution of NLRP3 signaling to abnormalities and / or symptoms and / or progression of a disease or disorder. A method for treating said disease or disorder, comprising administering a therapeutically effective amount of any one of claims 1 to 11. A method comprising administering a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt thereof.

18. Inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoimmune disorders Autoinflammatory diseases, such as autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndromes), hepatitis, Liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, nonalcoholic fatty liver disease, Hepatitis (NASH, alcoholic fatty liver disease and alcoholic liver disease), inflammatory arthritis Associated diseases (e.g. gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, e.g. acute and chronic), kidney-related diseases (e.g. hyperoxaluria, lupus Nephritis, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy , inflammation associated with hemodialysis), and diseases associated with neuroinflammation (e.g., multiple sclerosis, brain sensitization, infectious diseases, acute injuries, neurodegenerative diseases, Alzheimer's disease), cardiovascular / metabolic diseases / disorders (e.g. For example, cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and Type II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure, inflammatory skin diseases Skin diseases (e.g., sweat gland abscess, acne), wound healing and scarring, asthma, sarcoidosis, Age-related macular degeneration and cancer-related diseases / disorders (e.g., colon cancer, lung cancer, myeloproliferative tumors) a disease or disorder selected from the group consisting of cancer, leukemia, myelodysplastic syndrome (MDS), and myelofibrosis A compound according to claim 16 or a compound according to claim 17 for use in therapy. The methods of treatment described herein.

19. Methods for inhibiting NLRP3 inflammasome activity in a subject in need thereof A method for treating a patient suffering from atopic dermatitis, comprising administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 11 or a pharmaceutical composition thereof. The method comprises administering a physiologically acceptable salt thereof to a subject in need thereof.

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