NLRP3 inflammasome inhibitors

Abstract

The present invention relates to NLRP3 inflammasome inhibitors, in particular pyridazin-3-yl phenol compounds having the formula (I) wherein R1, R2, R3, R4, R5 and Z are defined herein, which inhibit NOD-like receptor protein 3 (NLRP3) inflammasome activity. The invention further relates to processes for their preparation, pharmaceutical compositions and medicaments containing them, and their use in the treatment of diseases and disorders mediated by NLRP3. # imgabs0 #

Description

[0001] This application is a divisional application of the international application with application number PCT / IB2020 / 054613 filed on May 15, 2020 and invention name “NLRP3 inflammasome inhibitor”. The international application entered the Chinese national phase on November 2, 2021 with application number 202080033109.9. Technical Field

[0002] The present invention relates to novel pyridazin-3-ylphenol compounds that can be used as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The present invention also relates to methods for preparing the compounds, pharmaceutical compositions containing the compounds, methods for using the compounds in the treatment of various diseases and disorders, and medicaments containing the compounds, and their uses in diseases and disorders mediated by NLRP3. Background Art

[0003] NOD-like receptor protein 3 (NLRP3) is a gene encoding a protein that belongs to the nucleotide binding and oligomerization domain-like receptor (NLR) family and is also known as "pyrin domain-containing protein 3" (Inoue et al., Immunology, 2013, 139, 11-18). This gene encodes a protein containing a pyrin domain, a nucleotide binding site domain (NBD), and a leucine-rich repeat (LRR) motif. In response to sterile inflammatory danger signals, NLRP3 interacts with adaptor proteins, apoptosis-associated speck-like protein (ASC), and procaspase-1 to form the NLRP3 inflammasome. NLRP3 inflammasome activation then leads to the release of inflammatory cytokines IL-1β (interleukin-1β) and IL-18 (interleukin-18), and when dysregulated, can drive pathology in many disease settings.

[0004] NLRP3 inflammasome activation usually requires two steps. The first step involves triggering signals, in which Toll-like receptors recognize pathogen-activated molecular patterns (PAMPs) or dangerous activated molecular patterns (DAMPs), leading to activation of nuclear factor κB (NF-κB)-mediated signal transduction, which in turn upregulates the transcription of inflammasome-related components, including inactive NLRP3 and IL-1β precursor (interleukin-1β precursor) (Bauernfeind et al., J. Immunol. [Journal of Immunology] 2009, 183, 787-791; Franchi et al., Nat. Immunol. [Natural Immunology] 2012, 13, 325-332, Franchi et al. J. Immunol. [Journal of Immunology] 2014, 193, 4214-4222). The second step is NLRP3 oligomerization and subsequent assembly of NLRP3, ASC, and procaspase-1 into inflammasome complexes. This triggers the conversion of procaspase-1 to caspase-1, and the production and secretion of mature IL-1β and IL-18 (Kim et al., J. Inflamm. 2015, 12, 41; Ozaki et al., J. Inflamm. Res. 2015, 8, 15–27; Rabeony et al., Eur. J. Immunol. 2015, 45, 2847-2857).

[0005] NLRP3 inflammasome activation has been linked to various inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases, such as autoinflammatory febrile syndromes (such as cryopyrin-associated periodic syndrome (CAPS)) (Mortimer et al., Nature Immunol. 2016, 17(10), 1176-1188); sickle cell disease; systemic lupus erythematosus (SLE); liver-related diseases / disorders, such as chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease (Petrasek et al., J. Clin. Invest. 2012, 122, 3476-89; Petrasek et al., Nat. Rev. Gastroenterol. Hepatol. [Nature Reviews Gastroenterology and Hepatology] 2015, 12, 387-400; Mridha et al., J. Hepatol. [Journal of Hepatology] 2017, 66, 1037-46; inflammatory arthritis-related disorders such as gout, pseudogout (chondrocalcinosis), osteoarthritis (Ridker et al., N. Engl. J. Med. [New England Journal of Medicine] 2017, 377, 1119-31), and rheumatoid arthritis (Mathews et al., Ann. Rheum. Dis. [Annals of Rheumatic Diseases] 2014, 73, 1202-10), acute or chronic arthropathy; kidney-related diseases such as hyperoxaluria (Knauf et al., Kidney Int. [Kidney International] 2013, 84, 895-901), lupus nephritis, hypertensive nephropathy (Krishnan et al., Br. J. Pharmacol. [British Journal of Pharmacology] 2016, 173, 752-65), hemodialysis-related inflammation and diabetic nephropathy, which is a kidney-related complication of diabetes (type 1, type 2 diabetes), also known as diabetic kidney disease (Shahzad et al., Kidney Int. [Kidney International] 2015, 87, 74-84).Emerging studies reveal that the increased production of IL-1β and IL-18 involved in NLRP3 inflammasomes can contribute to the onset and progression of various diseases, such as neuroinflammation-related disorders, such as brain infection, acute injury, multiple sclerosis, Alzheimer's disease, and neurodegenerative diseases (Shao et al., Front. Pharmacol. [Pharmacology Frontier] 2015, 6, 262); cardiovascular / metabolic disorders / diseases, such as 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., N. Engl. J. Med. 2017, 377, 1119-31; Vandanmasgar et al., Nat. Med. 2011, 17, 179-88; Hu et al., Proc. Natl. Acad. Sci. 2015, 112, 11318-23; Antonopoulos et al., Curr. Opin. Pharmacol. 2017, 39, 1-8; Toldo ... S et al., Nat. Rev. Cardiol. [Nature Reviews Cardiology] 2018, 15, 203-214); wound healing and scar formation; inflammatory skin diseases, such as acne, suppurative hidradenitis (Sweeney et al., Br. J. Dermatol. [British Journal of Dermatology] 2015, 173, 1361), asthma, sarcoidosis, age-related macular degeneration; cancer-related diseases / disorders, such as myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis, lung cancer, colon cancer (Ridker et al., Lancet [Lancet] 2017, 390, 1833-42; Derangere et al., Cell. Death Differ. [Cell Death and Differentiation] 2014, 21, 1914-24; Gelfo et al., Oncotarget [Tumor Target] 2016, 7, 72167-83; Baiorka et al., Blood [Blood] 2016, 128, 2960-75; Carey et al., Cell. Rep. [Cell Report] 2017, 18, 3204-18). Diseases / disorders that are immune or inflammatory in nature are often difficult to diagnose or treat effectively. Most treatments include symptomatic treatment, slowing the progression of the disease / disorder, lifestyle changes, and surgery as a last resort (e.g., open heart surgery for advanced forms of atherosclerosis).Recent studies have linked mitochondrial dysfunction to NLRP3 activation in neuroinflammation-related diseases such as Parkinson's disease (Sarkar et al., npj Parkinson's disease 2017, 3:30; Zhou et al., Nature 2011, 469, 221). One of the major problems associated with mitochondrial modulators is their poor metabolic stability; therefore, there is a need for selective and stable inhibitors of neuroinflammation of this nature (Lee et al., Eur J. Org. Chem. 2017, 141, 240).

[0006] Thus, there is a need for inhibitors of the NLRP3 inflammasome pathway to provide new and / or alternative treatments for these inflammasome-associated diseases / disorders, as well as other diseases / disorders, such as autoinflammatory febrile syndromes cryptopyrin-associated periodic syndromes (e.g., CAPS), sickle cell disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, hyperoxaluria, pseudogout (chondrocalcinosis), type I / type II diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis). Summary of the invention

[0007] The present invention provides a compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and a combination thereof, wherein the compound inhibits the NLRP3 inflammasome pathway. The present invention further provides a method for treating or preventing a disease and / or disorder associated with NLRP3, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0008] Various embodiments of the invention are described herein.

[0009] In certain aspects, provided herein are compounds having formula (I), or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] R 1 is Cl, CH3, -OCF3 or CF3;

[0013] R2 is H, halo, C1-C4 alkyl or halo-C1-C4 alkyl;

[0014] R 3 , R 4 is H, CN, C1-C4 alkyl or halogenated C1-C4 alkyl;

[0015] Z is –O- or -NH-(CH2) n -, where n is 0, 1 or 2;

[0016] R 5 is a monocyclic or bicyclic heterocyclic group optionally substituted by 1 to 2 substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH, halo, oxo and -CO2H; or

[0017] R 5 is aryl or heteroaryl optionally substituted by 1 to 2 substituents independently selected from the group consisting of halo, halo-substituted C1-C4 alkyl, C1-C4 alkyl and -SO2NH2; or

[0018] R 5 is C3-C6 cycloalkyl optionally substituted by 1 to 3 substituents independently selected from C1-C4 alkyl, halo, halo-substituted C1-C4 alkyl and -OH; or

[0019] R 5 It is a C2-C6 alkyl group substituted by one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2.

[0020] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the definition of a compound of formula (I) or its subformula as disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition can be used to treat diseases and / or disorders associated with NLRP3 activity.

[0021] In another aspect, the present invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound according to the definition of a compound of formula (I) or its subformulae as disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents.

[0022] In another aspect, the present invention provides a combination, in particular a pharmaceutical combination, as disclosed herein for use as a medicament.

[0023] In another aspect, the present invention provides a compound of formula (I) or a subformula thereof as disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of the disease or disorder.

[0024] In another aspect, the present invention provides a method for treating a disease or disorder in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of the disease or disorder, comprising administering a therapeutically effective amount of a compound of Formula (I) or a subformula thereof as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0025] In another aspect, the present invention provides a method of inhibiting NLRP3 inflammasome activity in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a subformula thereof as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0026] Another aspect of the present invention relates to a compound of formula (I) or a subformula thereof as disclosed herein, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0027] Another aspect of the present invention relates to a compound of formula (I) or a subformulae thereof as disclosed herein, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0028] Another aspect of the present invention also provides a compound of formula (I) or its subformula as disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from the following: an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease. DETAILED DESCRIPTION

[0029] Therefore, the present invention provides compounds having (I):

[0030]

[0031] in

[0032] R 1 is Cl, CH3, -OCF3 or CF3;

[0033] R 2 is H, halo, C1-C4 alkyl or halo-C1-C4 alkyl;

[0034] R 3 , R 4 is H, CN, C1-C4 alkyl or halogenated C1-C4 alkyl;

[0035] Z is –O- or -NH-(CH2) n -, where n is 0, 1 or 2;

[0036] R 5 is a monocyclic or bicyclic heterocyclic group optionally substituted by 1 to 2 substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH, halo, oxo and -CO2H; or

[0037] R 5 is aryl or heteroaryl optionally substituted by 1 to 2 substituents independently selected from the group consisting of halo, halo-substituted C1-C4 alkyl, C1-C4 alkyl and -SO2NH2; or

[0038] R 5 is C3-C6 cycloalkyl optionally substituted by 1 to 3 substituents independently selected from C1-C4 alkyl, halo, halo-substituted C1-C4 alkyl and -OH; or

[0039] R 5 It is a C2-C6 alkyl group substituted by one or more substituents independently selected from -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2.

[0040] definition

[0041] For the purpose of interpreting this specification, the following definitions shall apply unless otherwise indicated and, where appropriate, terms used in the singular shall also include the plural and vice versa.

[0042] It must be noted that, unless the context clearly indicates otherwise or is clearly contradicted by the text, the singular forms "a", "an", "the" and similar terms used in the context of the present invention as used herein and in the appended claims (especially in the context of the appended claims) should be interpreted as including both the singular and the plural. Thus, for example, reference to "the compound" includes reference to one or more compounds; etc.

[0043] As used herein, the term "C2-C6 alkyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, the group containing no unsaturation, having from two to six carbon atoms, and connected to the rest of the molecule by a single bond. As defined herein, "C2-C6 alkyl" is optionally substituted with one or more substituents (preferably 1 to 13 substituents, more preferably 1 to 8 substituents). More preferably, up to 7 substituents. The term "C1-C4 alkyl" should be interpreted accordingly. Examples of C2-C6 alkyl include, but are not limited to, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (tert-butyl).

[0044] As used herein, the term "halogenated C1-C4 alkyl" or "halogen C1-C4 alkyl" refers to a C1-C4 alkyl group substituted with one or more halo groups as defined above. Examples of halogen C1-C4 alkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl and 1,4,4-trifluorobutan-2-yl.

[0045] As used herein, the term "C1-C4 alkoxy" refers to a group having the formula -OR a A group in which R a is a C1-C4 alkyl group generally as defined above. Examples of "C1-C4 alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy.

[0046] As used herein, the term "hydroxy C1-C4 alkyl" refers to a C1-C4 alkyl group in which one of the hydrogen atoms of the C1-C4 alkyl group is replaced by OH. Examples of hydroxy C1-C4 alkyl groups include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl and 4-hydroxy-butyl.

[0047] As used herein, the term "halogen" or "halo" refers to bromine, chlorine, fluorine, or iodine.

[0048] As used herein, the term "heterocyclyl" or "heterocyclic" refers to a stable 5- or 6-membered non-aromatic monocyclic or bicyclic or polycyclic ring group; having 3 to 24, preferably 4 to 16, most preferably 5 to 10 ring atoms; wherein one or more, preferably one to four, particularly one or two ring atoms are heteroatoms selected from, for example, oxygen, sulfur, and nitrogen (so that the remaining ring atoms are carbon). The term heterocyclyl does not include heteroaryl. The heterocyclic group can be connected to the remainder of the molecule by a heteroatom or a carbon atom selected from, for example, oxygen, sulfur, and nitrogen. The heterocyclic group can include, for example, fused or bridged rings and spirocycles. For example, the term "heterocyclyl" can refer to a 5-7 monocyclic ring containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur. Examples of monocyclic heterocyclyl groups include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolanyl, oxathianyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, piperazinyl, oxapinyl, oxaazepanyl, oxathiolanyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl. Preferably, the monocyclic heterocyclic group is morpholino, pyrrolidine or piperidinyl. The example of bicyclic heterocyclic group includes, for example, azabicyclooctanyl or safinoindolizine. According to the present invention, the term "heterocyclic group" substituted by "OH" substituent also includes "heterocyclic group", wherein heteroatoms (such as N or S) are oxidized to obtain, for example, heterocyclic group N-oxide, heterocyclic group S-oxide or heterocyclic group S-dioxide. The example of heterocyclic group N-oxide includes piperidinyl-N-oxide. 1-methylpyrrolidine 1-oxide. The example of heterocyclic group S-oxide or heterocyclic group S-dioxide includes tetrahydro-2H-thiopyran-1-oxide, tetrahydro-2H-thiopyran-1,1-dioxide and tetrahydrothiophene-1-oxide.

[0049] As used herein, the term "heteroaryl" refers to a 5- or 6-membered aromatic monocyclic ring group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The heteroaryl group can be bonded via a carbon atom or a heteroatom. Examples of heteroaryl include, but are not limited to, furanyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyridyl.

[0050] As used herein, the term "C3-C6 cycloalkyl" refers to a stable monocyclic, bicyclic or tricyclic saturated hydrocarbon group consisting only of carbon atoms and hydrogen atoms and having from three to ten carbon atoms. The term bicyclic cycloalkyl also includes spiro bicyclic cycloalkyl. Examples of monocyclic C3-C6 cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Bicyclic C3-C6 10 Examples of cycloalkyl groups include, but are not limited to, bicyclo[1.1.1]pentane.

[0051] As used herein, the term "aryl" refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, the aryl group is a monocyclic, bicyclic or tricyclic aromatic group having 6-20 carbon atoms. In a preferred embodiment, the aryl group is a phenyl group.

[0052] Unless otherwise indicated, the term "compounds of the present invention" refers to compounds of formula (I) and its subformulae (such as compounds of formula (II), compounds of formula (III) or compounds of formula (III-A) as described herein), and salts thereof, as well as all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers and isotopically labeled compounds (including deuterated substitutions). The term "compounds of the present invention" or "a compound of the present invention" refers to the compounds defined in any one of the Examples mentioned below.

[0053] Having described various embodiments of the present invention herein, it should be appreciated that specified features within each embodiment may be combined with other specified features to provide further embodiments of the present invention.

[0054] In embodiment 1, the present invention provides a compound having formula (I) as described above, or a pharmaceutically acceptable salt thereof.

[0055] In embodiment 2, the present invention provides a compound having formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II):

[0056]

[0057] Where R 1 , R 2 , R 3 , R 4 and R 5 As defined in Example 1.

[0058] In embodiment 3, the present invention provides a compound having formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III):

[0059]

[0060] wherein n is 0, 1 or 2; and R 1 , R 2 , R 3 , R 4 and R 5 As defined in Example 1.

[0061] In embodiment 3a, and according to embodiment 3, the present invention provides a compound having formula (III), or a pharmaceutically acceptable salt thereof, wherein the compound has formula (III-A):

[0062]

[0063] Where R 1 , R 2 , R 3 , R 4 and R 5 As defined in Example 1.

[0064] In embodiment 4, the present invention provides a compound according to any one of formula (I), (II), (III) and (III-A) as described in embodiment 1, 2, 3 or 3a, or a pharmaceutically acceptable salt thereof, wherein R 5 is a monocyclic or bicyclic heterocyclic group optionally substituted by 1 to 2 substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, hydroxy C1-C4 alkyl, -OH, halo, oxo and -CO2H.

[0065] In embodiment 5, the present invention provides a compound according to embodiment 4 having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Select from the following:

[0066]

[0067] Where R 5a are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl and H; and R 5b independently selected from -OH, hydroxyC1-C4alkyl, H, halo, oxo, haloC1-C4alkyl and -CO2H; X is O or CH2; and m is 0 or 1.

[0068] In embodiment 5a, and according to embodiment 5, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Select from the following:

[0069]

[0070] Where R 5a are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl and H; and R 5b independently selected from -OH, C1-C4 alkyl, hydroxyC1-C4 alkyl, H, halo, oxo, haloC1-C4 alkyl and -CO2H; X is O or CH2; and m is 0 or 1.

[0071] In embodiment 5b, and according to embodiments 5 and 5b, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 The stereochemistry of the carbon atom marked with "*" is as described above and is (R) or (S). Preferably, when Z is -NH-(CH2)n- and n=1 or 2, the stereochemistry of the carbon atom marked with "*" is (S). Preferably, Z is -O- or -NH-(CH2)n- and n=0, the stereochemistry of the carbon atom marked with "*" is (R).

[0072] In embodiment 5c, and according to embodiments 5, 5a and 5b, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Preferably selected from the following structures:

[0073]

[0074] Where R 5a are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl and H; and R 5b independently selected from -OH, C1-C4 alkyl, hydroxyC1-C4 alkyl, H, halo, oxo, haloC1-C4 alkyl and -CO2H; and m is 0 or 1.

[0075] In embodiment 5d, and according to embodiments 5, 5a, 5b and 5c, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Preferably selected from the following structures:

[0076]

[0077] Where R 5a are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl and H; and R 5b independently selected from -OH, C1-C4 alkyl, hydroxyC1-C4 alkyl, H, halo, oxo, haloC1-C4 alkyl and -CO2H; and m is 0 or 1.

[0078] In embodiment 5e, and according to embodiments 5, 5a, 5b, 5c and 5d, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Preferably the following structure:

[0079]

[0080] Where R 5a independently selected from C1-C4 alkyl, hydroxyC1-C4 alkyl and H.

[0081] In embodiment 6, the present invention provides a compound according to any one of formula (I), (II), (III) and (III-A) as described in embodiment 1, 2, 3 or 3a, or a pharmaceutically acceptable salt thereof, wherein R 5 is aryl or heteroaryl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, haloC1-C4 alkyl, C1-C4 alkyl and -SO2NH2.

[0082] In embodiment 6a, and according to embodiment 6, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Preferably selected from the following structures:

[0083]

[0084] Where R 5c is independently selected from H, C1-C4 alkyl and -SO2NH2; and s is 0, 1 or 2.

[0085] In embodiment 6b, and according to embodiment 6, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Preferably selected from the following structures:

[0086]

[0087] Where R 5c Independently selected from H, C1-C4 alkyl and -SO2NH2.

[0088] In embodiment 6c, and according to embodiments 6 and 6b, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Preferably selected from the following structures:

[0089]

[0090] Where R 5c Independently selected from H and C1-C4 alkyl.

[0091] In embodiment 7, the present invention provides a compound according to any one of formula (I), (II), (III) and (III-A) according to embodiment 1, 2, 3 or 3a, or a pharmaceutically acceptable salt thereof, wherein R 5 is a C3-C6 cycloalkyl group optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-C4 alkyl, halo, halo-substituted C1-C4 alkyl and -OH.

[0092] In embodiment 7a, and according to embodiment 7, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Preferred is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionally substituted by 1 to 3 substituents independently selected from: C1-C4 alkyl, halo, halo-C1-C4 alkyl and -OH.

[0093] In embodiment 7b, and according to embodiments 7 and 7a, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Select the following structures:

[0094]

[0095] Where R 5e , R 5e’ , R 5d , R 5d’ and R 5f Independently selected from H, C1-C4 alkyl, halo, halo-substituted C1-C4 alkyl and -OH.

[0096] In embodiment 7c, and according to embodiments 7, 7a and 7b, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Preferably selected from the following structures:

[0097]

[0098] Where R 5d and R 5d’ Independently selected from H, halo, haloC1-C4 alkyl and C1-C4 alkyl.

[0099] In embodiment 7d, and according to embodiments 7, 7a, 7b and 7c, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Preferably selected from the following structures:

[0100]

[0101] Where R 5d and R 5d’ Independently selected from H, halo, haloC1-C4 alkyl and C1-C4 alkyl.

[0102] In embodiment 8, the present invention provides a compound according to any one of formula (I), (II), (III) and (III-A) according to embodiment 1, 2 or 3, or a pharmaceutically acceptable salt thereof, wherein R 5 It is a C2-C6 alkyl group substituted by one or more substituents independently selected from the group consisting of: -OH, C1-C4 alkoxy, halo, -NH2, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2.

[0103] In embodiment 8a, and according to embodiment 8, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 5 Preferably selected from the following structures:

[0104]

[0105] Where R 5h Selected from -NH2, -OH, -NH(C1-C4alkyl) and -N(C1-C4alkyl)2.

[0106] In embodiment 9, the present invention provides a compound according to any one of embodiments 1, 2, 3, 3a, 4, 5, 5a-5e, 6, 6a-6c, 7, 7a-7d, 8 and 8a having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 At least one of them is H.

[0107] In embodiment 9a, and according to embodiment 9, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 2 is halogenated, C1-C4 alkyl or halogenated C1-C4 alkyl; and R 3 It's H.

[0108] In embodiment 9b, and according to embodiment 9, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 2 is H; and R 3 It is CN, C1-C4 alkyl or halogenated C1-C4 alkyl.

[0109] In embodiment 10, the present invention provides a compound according to any one of formula (I), (II), (III) and (III-A) according to embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 1 It is -OCF3 or -CF3.

[0110] In embodiment 10a, and according to embodiment 10, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein R 1 It's CF3.

[0111] In embodiment 11, the present invention provides a compound according to any one of formula (I), (II), (III) and (III-A) according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0112] 2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0113] (S)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0114] (R)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0115] 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0116] 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0117] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0118] 2-(6-((3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0119] 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0120] 2-(6-(((1S,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0121] 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0122] 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0123] 2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0124] (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0125] (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0126] 3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0127] (S)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0128] (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0129] 2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0130] (S)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0131] (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0132] 2-(6-((1-isopropylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0133] 2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0134] (R)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0135] (S)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0136] 2-(6-((5,5-difluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0137] 3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0138] 3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile;

[0139] (S)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile;

[0140] (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile;

[0141] 3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0142] (S)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0143] (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0144] 2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0145] (S)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0146] (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0147] 3-methyl-2-(6-((pyrrolidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0148] (S)-3-methyl-2-(6-((pyrrolidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0149] (R)-3-methyl-2-(6-((pyrrolidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0150] 2-(6-((2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0151] 2-(6-((2-(dimethylamino)-2-methylpropyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0152] (R)-3-methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0153] 3-Methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-Methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0154] 2-(6-(2-hydroxy-2-methylpropoxy)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0155] (R)-3-methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0156] 3-methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0157] (S)-3-methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0158] (S)-2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0159] 2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0160] (R)-2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0161] 2-(6-((2-hydroxycyclopentyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0162] (cis)-2-(6-((2-hydroxycyclopentyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0163] (trans)-2-(6-((2-hydroxycyclopentyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0164] 3,5-Dichloro-2-(6-((2-hydroxyethyl)amino)pyridazin-3-yl)phenol;

[0165] 2-(6-((2-hydroxyethyl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0166] 3,5-Dichloro-2-(6-((2,2,2-trifluoroethyl)amino)pyridazin-3-yl)phenol;

[0167] 3-methyl-2-(6-((pyridin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0168] 2-(6-((2-amino-2-methylpropyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0169] 3-Chloro-2-(6-((2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0170] 3-Chloro-2-(6-((cis-3-hydroxycyclobutyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0171] 3-Chloro-2-(6-((3-hydroxycyclobutyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0172] 3-Chloro-2-(6-((trans-3-hydroxycyclobutyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0173] 3-methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0174] (R)-3-methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0175] (S)-3-methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0176] 3-Chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0177] 5-chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridazin-3-yl)-3-(trifluoromethyl)phenol;

[0178] 3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0179] (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0180] (S)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0181] 3-Chloro-2-(6-((2-hydroxyethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0182] 5-Chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0183] (S)-5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0184] (R)-5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0185] 5-Chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol TFA-salt;

[0186] (S)-5-Chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol TFA-salt;

[0187] (R)-5-Chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol TFA-salt;

[0188] 2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3,5-bis(trifluoromethyl)phenol;

[0189] (S)-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3,5-bis(trifluoromethyl)phenol;

[0190] (R)-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3,5-bis(trifluoromethyl)phenol;

[0191] 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0192] 2-(4,5-dimethyl-6-(((S)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0193] 2-(4,5-dimethyl-6-(((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0194] 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA-salt;

[0195] 2-(4,5-dimethyl-6-(((S)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA-salt;

[0196] 2-(4,5-dimethyl-6-(((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA-salt;

[0197] 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-2-carboxylic acid;

[0198] 3-methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0199] (S)-3-methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0200] (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0201] 3-methyl-2-(6-(pyrimidin-5-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0202] 3,5-Dichloro-2-(6-(cyclopropylamino)pyridazin-3-yl)phenol;

[0203] 3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0204] (S)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0205] (R)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0206] 3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol TFA-salt;

[0207] (S)-3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol TFA-salt;

[0208] (R)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol TFA-salt;

[0209] 3-methyl-2-(6-(pyridin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0210] 3,5-Dimethyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0211] (S)-3,5-dimethyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0212] (R)-3,5-dimethyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0213] 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0214] (S)-2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0215] (R)-2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0216] 3-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0217] (S)-3-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0218] (R)-3-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0219] 5-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol;

[0220] (S)-5-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol;

[0221] (R)-5-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol;

[0222] 5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-(trifluoromethyl)phenol;

[0223] (S)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-(trifluoromethyl)phenol;

[0224] (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-(trifluoromethyl)phenol;

[0225] 2-(6-((1,3-dimethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0226] 2-(6-((1,3-dimethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA-salt;

[0227] 2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0228] (S)-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0229] (R)-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0230] 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0231] 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0232] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0233] 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0234] 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0235] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0236] 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0237] 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0238] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0239] 2-(6-((3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0240] 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0241] 2-(6-(((1S,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0242] 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0243] 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0244] 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-2-one;

[0245] (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-2-one;

[0246] (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-2-one;

[0247] 2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0248] (S)-2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0249] (R)-2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0250] 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidin-2-one;

[0251] (S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidin-2-one;

[0252] (R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidin-2-one;

[0253] 3-methyl-5-(trifluoromethyl)-2-(6-((6-(trifluoromethyl)piperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0254] 3-methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0255] (S)-3-methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0256] (R)-3-methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0257] 3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0258] (S)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0259] (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0260] 2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0261] (S)-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0262] (R)-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0263] 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoro

[0264] Methyl)phenol;

[0265] 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0266] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0267] 2-(6-((3-hydroxy-3-(trifluoromethyl)cyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0268] 2-(6-(((trans)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0269] 2-(6-(((cis)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0270] 5-Chloro-2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)phenol;

[0271] 5-Chloro-2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)phenol; 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)phenol;

[0272] 5-Chloro-2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol;

[0273] 5-Chloro-2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol;

[0274] 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol;

[0275] 5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol;

[0276] (S)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol;

[0277] (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol;

[0278] 5-Chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0279] (S)-5-chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0280] (R)-5-chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0281] 2-(6-((2-hydroxy-2-methylpropyl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0282] 2-(6-((2-hydroxy-2-methylpropyl)amino)-4-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0283] 3-methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0284] (S)-3-methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0285] (R)-3-methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0286] 2-(6-(((4-fluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0287] 2-(6-((((2S,4S)-4-fluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0288] 2-(6-((((2R,4S)-4-fluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0289] 2-(6-((((2R,4R)-4-fluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0290] 2-(6-((((2S,4R)-4-fluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0291] (S)-3-methyl-2-(6-(((4-methylmorpholin-3-yl)methyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0292] (R)-3-methyl-2-(6-(((4-methylmorpholin-3-yl)methyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0293] (rac)-3-methyl-2-(6-(((4-methylmorpholin-3-yl)methyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0294] 3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0295] (S)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0296] (R)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0297] 3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol HCl-salt;

[0298] (R)-3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol HCl-salt;

[0299] (S)-3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol HCl-salt;

[0300] 2-(6-((1-hydroxy-2-methylpropan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0301] 2-(6-((1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0302] (S)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0303] (R)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0304] 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethoxy)phenol;

[0305] 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethoxy)phenol;

[0306] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethoxy)phenol;

[0307] 2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenol;

[0308] (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenol;

[0309] (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenol;

[0310] 3-methyl-2-(6-((octahydroindolizin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0311] 3-methyl-2-(6-(((8R,8aR)-octahydroindolizin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0312] 3-methyl-2-(6-(((8R,8aS)-octahydroindolizin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0313] 3-methyl-2-(6-(((8S,8aR)-octahydroindolizin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0314] 3-methyl-2-(6-(((8S,8aS)-octahydroindolizin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0315] (R)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0316] 2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0317] (S)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0318] 3-methyl-2-(6-((8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0319] 3-methyl-2-(6-(((1S,2S,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0320] 3-methyl-2-(6-(((1S,2R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0321] 3-methyl-2-(6-(((1S,2R,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0322] 3-methyl-2-(6-(((1S,2S,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0323] 3-methyl-2-(6-(((1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0324] 3-methyl-2-(6-(((1R,2S,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0325] 3-methyl-2-(6-(((1R,2S,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0326] 3-methyl-2-(6-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0327] 2-(6-((8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0328] 2-(6-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0329] 2-(6-(((1R,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0330] 2-(6-(((1R,2S,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0331] 2-(6-(((1R,2R,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0332] 2-(6-(((1S,2S,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0333] 2-(6-(((1S,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0334] 2-(6-(((1S,2R,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0335] 2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0336] 2-(6-((6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0337] 2-(6-(((3R,6R)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0338] 2-(6-(((3S,6R)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0339] 2-(6-(((3R,6S)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0340] 2-(6-(((3S,6S)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0341] (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol;

[0342] 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol;

[0343] (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol;

[0344] 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol;

[0345] (1S,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol;

[0346] (1S,2R,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol;

[0347] (1S,2S,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol;

[0348] (1S,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol;

[0349] (1R,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol;

[0350] (1R,2S,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol;

[0351] (1R,2R,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol;

[0352] (1R,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol;

[0353] (S)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0354] 2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0355] (R)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0356] 3-Methyl-2-(6-((2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-(((2S,3S)-2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0357] 3-methyl-2-(6-(((2R,3S)-2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0358] 3-methyl-2-(6-(((2S,3R)-2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0359] 3-methyl-2-(6-(((2R,3R)-2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0360] 2-(6-((2-hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0361] 2-(6-(((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0362] 2-(6-(((S)-1-((R)-2-hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0363] 2-(6-(((S)-1-((S)-2-hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0364] 2-(6-(((R)-1-((R)-2-hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0365] 2-(6-((5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0366] 2-(6-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0367] 2-(6-(((3S,5R)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0368] 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0369] 2-(6-(((3R,5R)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0370] 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0371] 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0372] 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0373] 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0374] 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0375] 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)

[0376] phenol;

[0377] 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0378] 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0379] 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0380] 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0381] 2-(6-((5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0382] 2-(6-(((3S,5R)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0383] 2-(6-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0384] 2-(6-(((3R,5R)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0385] 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0386] 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol;

[0387] (3S,5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol;

[0388] (3R,5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol;

[0389] (3R,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol;

[0390] (3S,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol;

[0391] 2-(6-(((1-hydroxycyclopentyl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0392] 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one;

[0393] 3-methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0394] (S)-3-methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0395] (R)-3-methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0396] 2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)-phenol;

[0397] (S)-2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)-phenol;

[0398] (R)-2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)-phenol;

[0399] 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one;

[0400] (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one;

[0401] (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one;

[0402] 4-(2-((6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl)amino)ethyl)benzenesulfonamide;

[0403] 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide;

[0404] (3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide;

[0405] (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide;

[0406] 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide TFA-salt;

[0407] (3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide TFA salt;

[0408] (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide TFA salt;

[0409] or a pharmaceutically acceptable salt thereof.

[0410] In embodiment 11a, and according to embodiment 11, the present invention provides a compound according to embodiment 1 having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein the compound is preferably selected from:

[0411] (R)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0412] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0413] 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0414] (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0415] (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0416] (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0417] 2-(6-((1-isopropylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0418] (S)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0419] 2-(6-((5,5-difluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0420] 3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0421] (R)-3-((1-ethylpiperidin-3-yl)amino)-6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile;

[0422] (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0423] (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0424] (R)-3-methyl-2-(6-((pyrrolidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0425] 2-(6-((2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0426] 2-(6-((2-(dimethylamino)-2-methylpropyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0427] (R)-3-methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0428] (S)-3-methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0429] 2-(6-(2-hydroxy-2-methylpropoxy)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0430] (R)-3-methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0431] (S)-3-methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0432] (S)-2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0433] (R)-2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0434] (trans)-2-(6-((2-hydroxycyclopentyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0435] 3,5-Dichloro-2-(6-((2-hydroxyethyl)amino)pyridazin-3-yl)phenol;

[0436] 2-(6-((2-hydroxyethyl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0437] 3,5-Dichloro-2-(6-((2,2,2-trifluoroethyl)amino)pyridazin-3-yl)phenol;

[0438] 3-methyl-2-(6-((pyridin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0439] 2-(6-((2-amino-2-methylpropyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0440] 3-Chloro-2-(6-((2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0441] 3-Chloro-2-(6-((cis-3-hydroxycyclobutyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0442] 3-Chloro-2-(6-((trans-3-hydroxycyclobutyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0443] (S)-3-methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0444] 3-Chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0445] 5-chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridazin-3-yl)-3-(trifluoromethyl)phenol;

[0446] (S)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0447] 3-Chloro-2-(6-((2-hydroxyethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0448] (R)-5-Chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol TFA-salt;

[0449] (R)-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3,5-bis(trifluoromethyl)phenol;

[0450] 2-(4,5-dimethyl-6-(((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA-salt;

[0451] 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-2-carboxylic acid;

[0452] (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0453] 3-methyl-2-(6-(pyrimidin-5-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0454] 3,5-Dichloro-2-(6-(cyclopropylamino)pyridazin-3-yl)phenol;

[0455] (R)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol TFA-salt;

[0456] 3-methyl-2-(6-(pyridin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0457] (R)-3,5-dimethyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0458] (R)-2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0459] (R)-3-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0460] (R)-5-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol;

[0461] (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-(trifluoromethyl)phenol;

[0462] 2-(6-((1,3-dimethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol TFA-salt;

[0463] (R)-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0464] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0465] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0466] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0467] 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0468] 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0469] (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-2-one;

[0470] (R)-2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0471] (R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidin-2-one;

[0472] 3-methyl-5-(trifluoromethyl)-2-(6-((6-(trifluoromethyl)piperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0473] (R)-3-methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0474] (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0475] (R)-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0476] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0477] 2-(6-(((cis)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0478] 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)phenol;

[0479] 5-Chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol;

[0480] (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol;

[0481] (R)-5-chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

[0482] 2-(6-((2-hydroxy-2-methylpropyl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0483] 2-(6-((2-hydroxy-2-methylpropyl)amino)-4-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0484] (R)-3-methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0485] 2-(6-((((2S,4S)-4-fluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0486] 2-(6-((((2S,4R)-4-fluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0487] (rac)-3-methyl-2-(6-(((4-methylmorpholin-3-yl)methyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0488] (S)-3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol HCl-salt;

[0489] 2-(6-((1-hydroxy-2-methylpropan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0490] (R)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0491] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethoxy)phenol;

[0492] (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenol;

[0493] 3-methyl-2-(6-(((8R,8aR)-octahydroindolizin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0494] 3-methyl-2-(6-(((8S,8aS)-octahydroindolizin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0495] (R)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0496] (S)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0497] 3-methyl-2-(6-(((1S,2S,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0498] 3-methyl-2-(6-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0499] 2-(6-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0500] 2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0501] 2-(6-(((3R,6R)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0502] 2-(6-(((3S,6S)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol;

[0503] (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol;

[0504] (1S,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol;

[0505] (1R,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol;

[0506] (S)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0507] (R)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0508] 3-methyl-2-(6-(((2S,3S)-2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0509] 3-methyl-2-(6-(((2R,3R)-2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0510] 2-(6-(((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0511] 2-(6-(((R)-1-((R)-2-hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0512] 2-(6-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0513] 2-(6-(((3R,5R)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0514] 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0515] 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0516] 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0517] 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0518] 2-(6-(((3S,5R)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0519] 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0520] (3S,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol;

[0521] 2-(6-(((1-hydroxycyclopentyl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

[0522] 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one;

[0523] (R)-3-methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

[0524] (R)-2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)-phenol;

[0525] (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one;

[0526] 4-(2-((6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl)amino)ethyl)benzenesulfonamide;

[0527] (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide TFA salt;

[0528] or a pharmaceutically acceptable salt thereof.

[0529] In embodiment 11b, the present invention relates to a compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is 3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In one example, the compound is (S)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In a preferred example, the compound is (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof

[0530] In embodiment 11c, the present invention relates to a compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In one example, the compound is (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In a preferred example, the compound is (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

[0531] In embodiment 11d, the present invention relates to a compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In one example, the compound is (S)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In a preferred example, the compound is (R)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

[0532] In embodiment 11e, the present invention relates to a compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In one example, the compound is 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In a preferred example, the compound is 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

[0533] In embodiment 11f, the present invention relates to a compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is 2-(6-((3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In one example, the compound is 2-(6-(((1S, 3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In one example, the compound is 2-(6-(((1R, 3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In one example, the compound is 2-(6-(((1S, 3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof. In a preferred example, the compound is 2-(6-(((1R, 3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof.

[0534] In embodiment 11g, the present invention relates to a compound of formula (I) according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol, or a pharmaceutically acceptable salt thereof. In one example, the compound is (3R,5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol, or a pharmaceutically acceptable salt thereof. In one example, the compound is (3R,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol, or a pharmaceutically acceptable salt thereof. In one example, the compound is (3S, 5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol, or a pharmaceutically acceptable salt thereof. In a preferred example, the compound is (3S, 5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol, or a pharmaceutically acceptable salt thereof.

[0535] In Example 12, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of formula (I), (II), (III) and (III-A) according to any one of Examples 1 to 11g, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0536] In Example 13, the present invention relates to a combination comprising a therapeutically effective amount of a compound of any one of formula (I), (II), (III) and (III-A) according to any one of Examples 1 to 11g, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0537] In embodiment 14, the present invention relates to a combination according to embodiment 13, comprising a therapeutically effective amount of a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein one or more therapeutic agents are independently selected from: farnesoid X receptor (FXR) agonists; anti-steatotic agents; anti-fibrotic agents; JAK inhibitors; checkpoint inhibitors, including anti-PD1 inhibitors, anti-LAG-3 inhibitors, anti-TIM-3 inhibitors, or anti-PDL1 inhibitors; chemotherapy , radiation therapy and surgery; urate-lowering therapy; anabolic agents and cartilage regeneration therapy; IL-17 blockers; complement inhibitors; Bruton's tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors (TLR7 / 8 inhibitors); CAR-T therapy; antihypertensive agents; cholesterol-lowering agents; leukotriene A4 hydrolase (LTAH4) inhibitors; SGLT2 inhibitors; beta2-agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs ("NSAIDs"); acetylsalicylic acid drugs (ASA), including aspirin; paracetamol; regenerative therapy treatments; cystic fibrosis treatments; or atherosclerosis treatments.

[0538] In one embodiment, the present invention relates to a method of inhibiting NLRP3 activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (II), (III) or (III-A) according to any one of Embodiments 1, 2, 3, 3a, 4, 5, 5a-5e, 6, 6a-6c, 7, 7a-7d, 8, 8a, 9, 9a-9b, 10, 10a, 11, 11a-11g, 12, 13 and 14, or a pharmaceutically acceptable salt thereof.

[0539] In embodiment 15, the present invention relates to a compound according to any one of embodiments 1 to 11g having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, or a combination according to any one of embodiments 13 to 14, for use as a medicament. In particular, the present invention relates to a compound according to any one of embodiments 1 to 11g having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, for use as a medicament. In particular, the present invention relates to a compound according to any one of embodiments 1 to 11g having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, for use as a medicament for inhibiting the NLRP3 pathway. In another specific embodiment, the present invention relates to a combination according to any one of embodiments 13 to 14, for use as a medicament.

[0540] In Example 16, the present invention relates to a compound of any one of Formula (I), (II), (III) and (III-A) according to any one of Examples 1 to 11g, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of the disease or disorder.

[0541] In Example 17, the present invention relates to a method of treating a disease or disorder in which NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of the disease or disorder, comprising administering a therapeutically effective amount of a compound of any one of Formula (I), (II), (III) and (III-A) according to any one of Examples 1 to 11g, or a pharmaceutically acceptable salt thereof.

[0542] In embodiment 18, the present invention relates to a compound of any one of formula (I), (II), (III) and (III-A) according to any one of embodiments 1 to 11g, or a pharmaceutically acceptable salt thereof for use according to embodiment 16, or to a method of treatment according to embodiment 17, wherein the disease or disorder is selected from: an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), a liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), an inflammatory arthritis-related disorder (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthritis such as acute, chronic joint disease), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammatory-related diseases (e.g., multiple sclerosis, brain infection, acute injury, 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, 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). In a specific aspect of Example 16, the present invention relates to a compound having any one of Formula (I), (II), (III), and (III-A), or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is preferably selected from autoinflammatory febrile syndrome (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, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0543] In one embodiment, the present invention relates to a compound of any one of formula (I), (II), (III) and (III-A) according to any one of embodiments 1 to 11g, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from the following: an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), a liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), an inflammatory arthritis-related disorder (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute, chronic joint diseases), kidney disease, related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammation-related diseases (e.g., multiple sclerosis, brain infection, acute injury, 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, 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). In a specific aspect of Example 18, the present invention relates to a compound having any one of Formula (I), (II), (III), and (III-A), or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is preferably selected from autoinflammatory febrile syndrome (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, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0544] In Example 19, the present invention relates to a method of inhibiting NLRP3 inflammasome activity in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Formulas (I), (II), (III) and (III-A) according to any one of Examples 1 to 11g, or a pharmaceutically acceptable salt thereof.

[0545] In one embodiment, the present invention relates to a method of inhibiting NLRP3 activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of any one of Formula (I), (II), (III) and (III-A) according to any one of Embodiments 1, 2, 3, 3a, 4, 5, 5a-5e, 6, 6a-6c, 7, 7a-7d, 8, 8a, 9, 9a-9b, 10, 10a, 11, 11a-11g, 12, 13 and 14, or a pharmaceutically acceptable salt thereof.

[0546] In one embodiment, the present invention relates to a method of treating a disease or disorder selected from the group consisting of an inflammasome-associated disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, e.g., an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), a liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), an inflammatory arthritis-related disorder (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, acute or chronic arthropathy), a kidney-related disease (e.g., hyperoxaluria, lupus nephritis, diabetic nephropathy, hypertensive nephropathy, hemodialysis-associated inflammation), a neuroinflammation-related disease (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative disease, Alzheimer's disease), a cardiovascular / Metabolic 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., 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis), wherein the method comprises administering to the subject a therapeutically effective amount of a compound of any one of Formula (I), (II), (III) and (III-A) as described in any one of Embodiments 1, 2, 3, 3a, 4, 5, 5a-5e, 6, 6a-6c, 7, 7a-7d, 8, 8a, 9, 9a-9b, 10, 10a, 11, 11a-11g, 12, 13 and 14, or a pharmaceutically acceptable salt thereof. In particular, the disease or disorder is preferably selected from autoinflammatory febrile 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, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0547] Depending on the choice of starting materials and procedures, the compounds may exist in the possible stereoisomeric forms or as mixtures thereof (e.g., as pure optical isomers or as stereoisomer mixtures, such as racemates and diastereomeric mixtures), depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible isomers, including racemic mixtures, diastereomeric mixtures and optically pure forms. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included. The present invention is also intended to include any pseudo-asymmetric carbon atoms, which are represented herein as (r)- and (s)-, and which are unchanged when reflected in a mirror but can be reversed by exchanging any two entities (PAC 1996, 68, 2193, Basic terminology of stereochemistry IUPAC recommendations 1996).

[0548] As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of a compound of the present invention. "Salts" particularly include "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0549] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0550] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0551] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0552] Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.

[0553] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0554] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0555] In another aspect, the present invention provides a compound of any one of formula (I), (II), (III) and (III-A) in the form of acetate, ascorbate, adipate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, decanoate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate

[0013] The invention can be in the form of a hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate, hydroxyethylate

[0556] In another aspect, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A) in the form of a sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine penicillin, choline salt, diethanolamine, diethylamine, lysine, meglumine, piperazine or tromethamine salt.

[0557] Any formula given herein is also intended to represent the non-labeled form of the compound as well as the isotope-labeled form. In addition to one or more atoms being replaced by atoms with a selected atomic mass or mass number, the isotope-labeled compound has the structure described by the formula given herein. The isotope that can be incorporated into the compounds of the invention includes, for example, isotopes of hydrogen.

[0558] In addition, the incorporation of certain isotopes, especially deuterium (i.e. 2H or D) can provide certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improvements in therapeutic index or tolerability. It should be understood that deuterium in this context is considered to be a substituent of a compound of formula (I). The concentration of deuterium can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a particular isotope. If a substituent in a compound of the invention indicates deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation on each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0559] In another aspect, the invention provides a compound of formula (I) as defined herein,

[0560]

[0561] or a pharmaceutically acceptable salt thereof, wherein when R 5 When selected from:

[0562]

[0563] Where R 5a , R 5b , X and m are as defined in Examples 5, 5a-5e, and R 5a and / or R 5b One or more hydrogen atoms present in the 5a or R 5b ) is substituted. For example (but not limited to), deuterium can be incorporated as follows:

[0564]

[0565]

[0566] In another aspect, the invention provides a compound of formula (I) as defined herein,

[0567]

[0568] or a pharmaceutically acceptable salt thereof, wherein when R2 , R 3 , R 4 When selected from the following H, C1-C4 alkyl or halogenated C1-C4 alkyl, one or more hydrogen atoms present in the group may be replaced by deuterium atoms. For example (but not limited to), deuterium can be incorporated as follows:

[0569]

[0570] Other examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 3 H. 11 C. 13 C. 14 C. 15 N. 18 F 31 P. 32 P. 35 S. 36 Cl, 123 I. 124 I. 125 I. Thus, it should be understood that the present invention includes the incorporation of one or more of any of the foregoing isotopes (including, for example, radioactive isotopes (such as 3 H and 14 C)) or compounds in which non-radioactive isotopes (such as 2 H and 13 C). Such isotope-labeled compounds can be used for metabolic studies (using 14 C) reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or radiation therapy for patients. In particular, 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I), or pharmaceutically acceptable salts thereof, can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations, using an appropriate isotopically labeled reagent in place of the unlabeled previously used reagent.

[0571] Pharmaceutical composition

[0572] As used herein, the term "pharmaceutical composition" refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, in a form suitable for oral or parenteral administration, and at least one pharmaceutically acceptable carrier.

[0573] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that can be used to prepare or use a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, 2013, pp. 1049-1070).

[0574] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will cause a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity, or an improvement in symptoms, relief of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, effectively (1) at least partially alleviates, inhibits, prevents and / or improves (i) a condition, disorder or disease mediated by NLRP3, or (ii) associated with NLRP3 activity, or (iii) characterized by the activity (normal or abnormal) of NLRP3; or (2) reduces or inhibits the activity of NLRP3; or (3) reduces or inhibits the expression of NLRP3. In another non-limiting embodiment, the term "therapeutically effective amount" of a compound of the present invention refers to an amount that, when administered to a cell, or tissue, or non-cellular biological material or medium, effectively at least partially reduces or inhibits the activity of NLRP3; or at least partially reduces or inhibits the expression of NLRP3.

[0575] As used herein, the term "subject" refers to primates (e.g., humans (male or female)), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet another embodiment, the subject is a human.

[0576] As used herein, the term "inhibit, inhibition or inhibiting" refers to reducing or inhibiting a given condition, symptom, disorder, or disease, or significantly reducing the baseline activity of a biological activity or process. Specifically, inhibiting NLRP3 or inhibiting the NLRP3 inflammasome pathway includes reducing the ability of NLRP3 or the NLRP3 inflammasome pathway to induce the production of IL-1β and / or IL-18. This can be achieved by mechanisms including, but not limited to, inactivating, destabilizing NLRP3, and / or changing the distribution of NLRP3.

[0577] As used herein, the term "NLRP3" is meant to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0578] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one clinical symptom thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible by the patient.

[0579] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0580] As used herein, a subject is "in need of" or "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0581] All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention, without limiting the scope of the present invention otherwise claimed.

[0582] Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the invention may exist in a racemic or enantiomerically enriched form, e.g., (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration.

[0583] Thus, as used herein, the compounds of the invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[0584] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the components, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0585] Any resulting racemate of the compounds of the present invention or intermediate can be split into optical antipodes by known methods, for example, by separating its diastereomeric salts obtained with optically active acids or bases, and releasing optically active acidic or basic compounds. In particular, the basic part can be used to split the compounds of the present invention into its optical antipodes, for example, by fractional crystallization with optically active acids such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O, O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid formed salts to split. The racemic product can also be split by chiral chromatography, for example, using high performance liquid chromatography (HPLC) using a chiral adsorbent.

[0586] Methods for synthesizing the compounds of the present invention

[0587] The compounds of the present invention can be prepared according to the definition of compounds of formula (I) or pharmaceutically acceptable salts thereof by the routes described in the following schemes or examples. All methods described herein can be carried out in any suitable order unless otherwise indicated herein or clearly contradictory to the context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention and does not limit the scope of the invention otherwise claimed. In the following general method, R 1 , R 2 , R 3 , R 4 , R 5 , halo and Z are as previously defined in the above examples, or limited to those specified in the schemes. Unless otherwise stated, starting materials are either commercially available or prepared by known methods.

[0588] Reaction Scheme 1

[0589] As described herein, compounds of the invention can be prepared by the reaction sequence shown in Scheme 1 (below), wherein an appropriately substituted 3,6-dihalopyridazine (M1) is reacted with an appropriate amine (M2a) in the presence of a base (e.g., DIPEA) at elevated temperatures, typically between 150° C. and 180° C. (optionally under microwave irradiation) to afford a 6-halopyridazine-3-amine (M3a), or with an appropriate alcohol (M2b) in the presence of a base (e.g., NaH) at low temperatures (typically 0° C.) to afford a 3-halo-6-alkoxypyridazine (M3b). The two intermediates (M3a) or (M3b) are then subjected to a Suzuki-type cross-coupling reaction with a borate (M4) in the form of an appropriate boronic acid or boronic ester (e.g. 4,4,5,5-tetramethyl-1,3,2-dioxaborolane) using a suitable palladium catalyst (e.g. Pd(PPh3)4 and an aqueous base solution (typically Na2CO3 or NaHCO3) in a miscible solvent such as DME or dioxane to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0590]

[0591] Reaction Scheme 2

[0592] Alternatively, as described herein, compounds of the invention can be prepared by the reaction sequence shown in Scheme 2 (below), wherein an appropriately substituted 3,6-dihalopyridazine (M1) is subjected to a Suzuki-type cross-coupling reaction (route A) with a borate (M4) in the form of an appropriate boronic acid or borate ester (e.g., 4,4,5,5-tetramethyl-1,3,2-dioxaborolane) using a suitable palladium catalyst (e.g., Pd(PPh3)4 or XantPhos-Pd-G2), and an aqueous base solution (typically Na2CO3 or NaHCO3) in a miscible solvent (e.g., DME or dioxane) to give 3-halo-pyridazines (M5), or reacted in the same manner with a borate (M6) bearing a phenol protecting group P (e.g., methyl or benzyl) (route B) to provide compounds having the formula 3-halo-pyridazines (M7). Intermediate (M5) is then reacted with an appropriate amine (M2a) in the presence of a base (e.g. DIPEA) at elevated temperature, typically between 150°C and 180°C (optionally under microwave irradiation) to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof, while intermediate (M7) is treated in the same manner to give a protected form (M8), which is further subjected to typically cleavage treatment (e.g. BBr3, or catalytic hydrogenation) to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0593]

[0594] Reaction Scheme 3

[0595] Alternatively, as described herein, compounds of the invention can be prepared by the reaction sequence shown in Scheme 3 (below), wherein an appropriately substituted intermediate (M5) is subjected to a Buchwald-type amination reaction with an appropriate amine (M2a) over a suitable palladium catalyst (e.g., PdCl2(dppf)) and a base (typically LiOtBu) in an aprotic solvent (e.g., toluene) to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0596]

[0597] The method can be extended to prepare compounds of any one of formula (I), (II), (III) and (III-A) as described herein, or pharmaceutically acceptable salts thereof. Based on the starting materials and the selected approach as mentioned in Scheme 1, Scheme 2 or Scheme 3 above, one skilled in the art will know how to prepare compounds of formula (I), or pharmaceutically acceptable salts thereof. Certain variations or alternative methods are described in the experimental section below.

[0598] The present invention further includes any variant of the inventive method, wherein the intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or wherein the starting material is formed in situ under the reaction conditions, or wherein the reaction components are used in the form of their salts or optically pure substances. The compounds of the present invention and the intermediates can also be converted into each other according to methods generally known to those skilled in the art.

[0599] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers (such as those described herein). The pharmaceutical composition can be formulated for a specific route of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical composition of the present invention may be in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including but not limited to solutions, suspensions or emulsions). Tablets may be film-coated or enteric-coated according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient and one or more of the following:

[0600] a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0601] b) lubricants, such as silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; in the case of tablets, also

[0602] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired,

[0603] d) disintegrants, for example starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and

[0604] e) absorbents, colorants, flavorings and sweeteners.

[0605] Methods of using the present invention

[0606] There is evidence for a role for NLRP3-induced IL-1 and IL-18 in inflammatory responses associated with or due to a variety of different disorders (Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15; Strowig et al., Nature, 2012, 481, 278-286). NLRP3 mutations have been found to cause a group of rare autoinflammatory diseases known as CAPS (Ozaki et al., J. Inflammation Research, 2015, 8, 15-27; Schroder et al., Cell, 2010, 140: 821-832; Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15). CAPS is a genetic disease characterized by recurrent fever and inflammation and consists of three autoinflammatory disorders that form a clinical continuum. These diseases are, in order of increasing severity: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurocutaneous arthritis syndrome (CINCA; also known as neonatal onset multisystem inflammatory disease NOMID), and all have been shown to be caused by gain-of-function mutations in the NLRP3 gene that result in increased secretion of IL-1β. NLRP3 has also been implicated in a number of autoinflammatory diseases, including suppurative arthritis, pyoderma gangrenosum, and acne (PAPA), Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris (Cook et al., Eur. J. Immunol. [European Journal of Immunology], 2010, 40, 595-653).

[0607] NLRP3 has been implicated in a number of autoimmune diseases, including multiple sclerosis, type 1 diabetes (T1D), psoriasis, rheumatoid arthritis (RA), Behcet's disease, Schnitzler syndrome, and syndrome), macrophage activation syndrome (Braddock et al., Nat. Rev. Drug Disc. 2004, 3, 1-10; Inoue et al., Immunology, 2013, 139, 11-18; Coll et al., Nat. Med. 2015, 21(3), 248-55; Scott et al., Clin. Exp. Rheumatol. 2016, 34(1), 88-93), systemic lupus erythematosus and its complications such as lupus nephritis (Lu et al., J. Immunol. 2017, 198(3), 1119-29), and systemic sclerosis (Artlett et al., Arthritis Rheum. 2011, 63(11), 3563-74). NLRP3 has also been shown to play a role in many lung diseases, including chronic obstructive pulmonary disorder (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al., Am. J. Pathol., 2014, 184:42-54; Kim et al., Am. J. Respir. Crit. Care Med, 2017, 196(3), 283-97). NLRP3 is also thought to play a role in a variety of central nervous system disorders, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, brain damage caused by pneumococcal meningitis (Walsh et al., Nature Reviews, 2014, 15, 84-97; and Dempsey et al., Brain. Behav. Immun. 2017, 61, 306-16), intracranial aneurysms (Zhang et al., J. Stroke and Cerebrovascular Dis., 2015, 24, 5, 972-9), and traumatic brain injury (Ismael et al., J. Neurotrauma., 2018, 35(11), 1294-1303).NRLP3 activity has also been shown to be involved in a variety of metabolic diseases, including type 2 diabetes (T2D) and its organ-specific complications, atherosclerosis, obesity, gout, pseudogout, metabolic syndrome (Wen et al., Nature Immunology, 2012, 13, 352-357; Duewell et al., Nature, 2010, 464, 1357-1361; Strowig et al., Nature, 2014, 481, 278-286), and non-alcoholic steatohepatitis (Mridha et al., J. Hepatol. 2017, 66(5), 1037-46). A role for NLRP3 via IL-1β production has also been proposed in the following diseases: atherosclerosis, myocardial infarction (van Hout et al., Eur. Heart J. 2017, 38(11), 828-36), heart failure (Sano et 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 events (Ridker et al., N. Engl. J. Med. 2017, 377(12), 1119-31).

[0608] Other diseases in which NLRP3 has been implicated include: eye diseases such as wet and dry age-related macular degeneration (Doyle et al., Nature Medicine, 2012, 18, 791-798; Tarallo et al., Cell, 2012, 149(4), 847-59), diabetic retinopathy (Loukovaara et al., Acta Ophthalmol. [Acta Ophthalmol.], 2017, 95(8), 803-8), noninfectious uveitis and optic nerve damage (Puyang et al., Sci. Rep. [Science and Technology Report] 2016, 6, 20998); liver diseases, including nonalcoholic steatohepatitis (NASH) and acute alcoholic hepatitis (Henao-Meija et al., Nature [Nature], 2012, 482, 179-185); inflammatory reactions in the lungs and skin (Primiano et al., J. Immunol. [Journal of Immunology] 2016, 197(6), 2421-33), including contact hypersensitivity reactions (such as bullous pemphigoid (Fang et al., J Dermatol ... Sci. [Journal of Dermatology] 2016, 83(2), 116-23)), atopic dermatitis (Niebuhr et al., Allergy [Allergy], 2014, 69(8), 1058-67), suppurative hidradenitis (Alikhan et al., J. Am. Acad. Dermatol. [Journal of the American Academy of Dermatology], 2009, 60(4), 539-61), and sarcoidosis (Jager et al., Am. J. Respir. Crit. Care Med. [American Journal of Respiratory and Critical Care Medicine], 2015, 191, A5816); inflammatory reactions in joints (Braddock et al., Nat. Rev. Drug Disc [Nature Reviews Drug Discovery], 2004, 3, 1-10); amyotrophic lateral sclerosis (Gugliandolo et al., Int. J. Mol. Sci. [International Journal of Molecular Sciences], 2018, 19(7), E1992); cystic fibrosis (Iannitti et al., Nat. Commun. [Nature Communications], 2016, 7, 10791); stroke (Walsh et al., Nature Reviews [Nature Reviews], 2014, 15, 84-97); chronic kidney disease (Granata et al., PLoS One [Public Library of Science One] 2015, 10(3), eoi22272); and inflammatory bowel disease, including ulcerative colitis and Crohn's disease (Braddock et al., Nat. Rev. Drug Disc [Nature Reviews Drug Discovery], 2004, 3, 1-10; Neudecker et al., J. Exp. Med.[Journal of Experimental Medicine] 2017, 214(6), 1737-52; Lazaridis et al., Dig. Dis. Sci. [Digestive Diseases and Sciences] 2017, 62(9), 2348-56). The NLRP3 inflammasome has been found to be activated in response to oxidative stress. NLRP3 has also been shown to be involved in inflammatory hyperalgesia (Dolunay et al., Inflammation, 2017, 40, 366-86). .

[0609] Activation of the NLRP3 inflammasome has been shown to enhance certain pathogenic infections, such as influenza and leishmaniasis (Tate et al., Sci Rep., 2016, 10(6), 27912-20; Novias et al., PLOS Pathogens 2017, 13(2), e1006196).

[0610] NLRP3 has also been implicated in the pathogenesis of many cancers (Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15). For example, several previous studies have shown a role for IL-1β in cancer invasion, growth, and metastasis, and inhibition of IL-1β with canakinumab has been shown to reduce the incidence of lung cancer and total cancer mortality in a randomized, double-blind, placebo-controlled trial (Ridker et al., Lancet., 2017, 390(10105), 1833-42). Inhibition of NLRP3 inflammasomes or IL-1β has also been shown in vitro to inhibit the proliferation and migration of lung cancer cells (Wang et al., Oncol Rep., 2016, 35(4), 2053-64). A role for the NLRP3 inflammasome has been proposed in myelodysplastic syndrome, myelofibrosis and other myeloproliferative neoplasms, and acute myeloid leukemia (AML) (Basiorka et al., Blood, 2016, 128(25), 2960-75.), as well as in the carcinogenesis of various other cancers, including gliomas (Li et al., Am. J. Cancer Res. 2015, 5(1), 442-9), inflammation-induced tumors (Allen et al., J. Exp. Med. 2010, 207(5), 1045-56; Hu et al., PNAS. 2010, 107(50), 21635-40), multiple myeloma (Li et al., Hematology 2016, 128(25), 2960-75.), and in the development of various other cancers, including gliomas (Li et al., Am. J. Cancer Res. 2015, 5(1), 442-9), inflammation-induced tumors (Allen et al., J. Exp. Med. 2010, 207(5), 1045-56; Hu et al., PNAS. 2010, 107(50), 21635-40), multiple myeloma (Li et al., Hematology 2016, 128(25), 2960-75.). 21(3), 144-51), and head and neck squamous cell carcinoma (Huang et al., J. Exp. Clin. Cancer Res. [Journal of Experimental and Clinical Cancer Research], 2017, 36(1), 116). Activation of the NLRP3 inflammasome has also been shown to mediate chemoresistance of tumor cells to 5-fluorouracil (Feng et al., J. Exp. Clin. Cancer Res. [Journal of Experimental and Clinical Cancer Research], 2017, 36(1), 81), and activation of the NLRP3 inflammasome in peripheral nerves contributes to chemotherapy-induced neuropathic pain (Jia et al., Mol. Pain. [Molecular Pain], 2017, 13, 1-11). NLRP3 has also been shown to be required for efficient control of viruses, bacteria, and fungi.

[0611] Activation of NLRP3 leads to apoptosis and this feature plays an important role in the manifestation of clinical diseases (Yan-gang et al., Cell Death and Disease, 2017, 8(2), 2579; Alexander et al., Hepatology, 2014, 59(3), 898-910; Baldwin et al., J. Med. Chem., 2016, 59(5), 1691-1710; Ozaki et al., J. Inflammation Research, 2015, 8, 15-27; Zhen et al., Neuroimmunology Neuroinflammation, 2014, 1(2), 60-65; Mattia et al., J. Med. Chem., 2014, 57(24), 10366-82; Satoh et al., Cell Death and Disease, 2013, 4, 644). Therefore, inhibitors of NLRP3 are expected to block pyroptosis and the release of proinflammatory cytokines such as IL-1β.

[0612] Compounds of any of Formulae (I), (II), (III) and (III-A), or compounds according to any of the preceding embodiments, or compounds according to any of the illustrative examples (e.g. Ex 001 to Ex 104 as disclosed herein), in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, such as NRLP3 inhibitory properties with respect to the NLRP3 pathway (e.g. as indicated by the in vitro tests provided in the sections below), and are therefore indicated for use in therapy or as research chemicals, e.g. as tool compounds.

[0613] The compounds of the invention are useful for treating an indication selected from the group consisting of: inflammasome-associated diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases, e.g., diseases, disorders or conditions in which NLRP3 signaling contributes to pathology, and / or symptoms, and / or progression, and which are responsive to NLRP3 inhibition and which can be treated or prevented according to any one of Examples 1 to 19, or according to any one of the illustrative examples of the invention (e.g., Ex 001 to Ex 104 as disclosed herein), including:

[0614] I. Inflammation, including inflammation that occurs due to an inflammatory disorder such as an autoinflammatory disease, inflammation that occurs as a symptom of a non-inflammatory disorder, inflammation that occurs due to infection, or inflammation that is secondary to trauma, injury, or autoimmunity. Examples of inflammation that can be treated or prevented include inflammatory responses associated with or due to the following conditions:

[0615] (a) Skin disorders such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia;

[0616] (b) joint disorders such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, crystal-induced arthritis (pseudogout, gout) or seronegative spondyloarthropathies (e.g. ankylosing spondylitis, psoriatic arthritis or Reiter's disease);

[0617] (c) muscle disorders such as polymyositis or myasthenia gravis;

[0618] (d) gastrointestinal disorders, such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that may have effects distal to the intestine (e.g., migraine, rhinitis, or eczema);

[0619] (e) respiratory disorders such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, exogenous or dust asthma, and in particular chronic or long-standing asthma, such as late-onset asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, sicca rhinitis, medicamentous rhinitis, membranous rhinitis, seasonal rhinitis (e.g. hay fever and vasomotor rhinitis)), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia;

[0620] (f) vascular disorders, such as atherosclerosis, Behcet's disease, vasculitis, or Wegener's granulomatosis;

[0621] (g) immune disorders, for example, autoimmune diseases such as systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or Graves' disease;

[0622] (h) eye diseases, such as uveitis, allergic conjunctivitis, or vernal conjunctivitis;

[0623] (i) Neurological disorders, such as multiple sclerosis or encephalomyelitis;

[0624] (j) infection or infection-related condition, such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infection, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis, Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis / epidydimitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease;

[0625] (k) renal disorders, such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, acute renal failure, uremia, or nephrotic syndrome;

[0626] (l) Lymphatic disorders, such as Castleman's disease;

[0627] (m) disorders of or involving the immune system, such as hyper-IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease;

[0628] (n) liver disorders such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcohol-induced hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), or primary biliary cirrhosis;

[0629] (o) cancer, including those listed below;

[0630] (p) burns, wounds, trauma, hemorrhage or stroke;

[0631] (q) radiation exposure; and / or

[0632] (r) obesity; and / or

[0633] (s) Pain, such as inflammatory hyperalgesia.

[0634] II. Inflammatory diseases, including inflammation that occurs due to inflammatory disorders, such as autoinflammatory diseases, such as cryptopyrin-associated periodic syndrome (CAPS), Muckler-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal-onset multisystem inflammatory disease (NOMID), Majeed syndrome, suppurative arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), adult-onset Still's disease (AOSD), A20 haploinsufficiency (HA20), pediatric granulomatous arthritis (PGA), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammatory, antibody deficiency and immune dysregulation (APLAID), or sideroblastic anemia with B-cell immunodeficiency, periodic fever and developmental delay (SIFD).

[0635] III. Immune diseases, such as autoimmune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), antisynthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki's disease disease), lupus including systemic lupus erythematosus (SLE), multiple sclerosis (MS) (including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRMS)), myasthenia gravis, opsoclonus-myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, refractory gouty arthritis, Rett's syndrome, Sjögren's syndrome, systemic sclerosis, systemic connective tissue disorders, Takayasu's arteritis arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Beliefs disease, Chagas' disease, dysautonomia, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis, vitiligo, or vulvodynia;

[0636] IV. Cancer, including lung cancer, renal cell carcinoma, non-small cell lung cancer (NSCLC), Langerhans cell histiocytosis (LCH), myeloproliferative neoplasms (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndrome (MDS), leukemia including acute lymphocytic leukemia (ALL) and 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, endometrial cancer, esophageal cancer, Ewing family tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease disease, glioma, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumors, lymphoma (including cutaneous T-cell lymphoma), malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymic cancer, thyroid cancer (including anaplastic thyroid cancer), uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor;

[0637] V. Infections, including viral infections (e.g., from influenza virus, human immunodeficiency virus (HIV), alphaviruses (such as chikungunya virus and Ross River virus), flaviviruses (such as dengue virus and Zika virus), herpesviruses (such as Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and KSHV), poxviruses (such as vaccinia virus (modified vaccinia virus Ankara) and myxoma virus), adenoviruses (such as adenovirus 5), or papillomaviruses), bacterial infections (e.g., from Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordatella pertussis, Burkholderia pseudomallei, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Haemophilus influenzae, Pasteurella multocida multicida), Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae, Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi, or Yersinia pestis pestis), fungal infections (e.g., from Candida or Aspergillus species), protozoan infections (e.g., from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania, or Trypanosoma), helminthic infections (e.g., from Schistosoma, Ascaris, Tapeworms, or Trematodes), and prion infections;

[0638] VI. Central nervous system diseases, such as Parkinson's disease, Alzheimer's disease, dementia, motor neurone disease, Huntington's disease, cerebral malaria, brain damage caused by pneumococcal meningitis, intracranial aneurysm, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis;

[0639] VII. Metabolic diseases, such as type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudogout;

[0640] VIII. Cardiovascular diseases, such as hypertension, ischemia, reperfusion injury (including ischemia-reperfusion injury after MI), stroke (including ischemic stroke), transient ischemic attack, myocardial infarction (including recurrent myocardial infarction), heart failure (including congestive heart failure and heart failure with preserved ejection fraction), embolism, aneurysm (including abdominal aortic aneurysm), cardiovascular risk reduction (CvRR), and pericarditis (including Dressler's syndrome);

[0641] IX. Respiratory diseases, including chronic obstructive pulmonary disorder (COPD), asthma (such as allergic asthma and steroid-resistant asthma), asbestosis, silicosis, nanoparticle-induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis;

[0642] X. Liver diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) (including advanced fibrosis stages F3 and F4), alcoholic fatty liver disease (AFLD), and alcoholic steatohepatitis (ASH);

[0643] XI. Renal disease, including acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy;

[0644] XII. Eye diseases, including eye diseases of the ocular epithelium, age-related macular degeneration (AMD) (dry and wet), uveitis, corneal infection, diabetic retinopathy, optic nerve damage, dry eyes, and glaucoma;

[0645] XIII. Skin disorders, including dermatitis (such as contact dermatitis and atopic dermatitis), contact hypersensitivity reactions, sunburn, skin lesions, hidradenitis suppurativa (HS), other skin disorders causing cysts, and acne conglobata;

[0646] XIV. Lymphatic disorders, such as lymphangitis and Castleman's disease;

[0647] XV. Psychological disorders, such as depression and psychological stress;

[0648] XVI. Graft versus host disease;

[0649] XVII. Bone diseases, including osteoporosis and osteosclerosis;

[0650] XVIII. Blood disorders, including sickle cell disease;

[0651] XVIX. Allodynia, including mechanical allodynia; and

[0652] XVX. Any disease in which the individual has been identified to carry a germline or somatic non-silent mutation in NLRP3.

[0653] More specifically, the compounds of the present invention can be used to treat an indication selected from the following: inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases, for example, autoinflammatory fever syndromes (e.g., cryptopyrin-associated periodic syndromes), 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 disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute, chronic joint diseases), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes and related complications (e.g., nephropathy, retinopathy, hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammation-related diseases (e.g., multiple sclerosis, brain infection, acute injury, 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, 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). In particular, autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (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 suppurativa, wound healing and scarring, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).

[0654] In particular, the compounds of the present invention, or a pharmaceutically acceptable salt thereof, can be used to treat a disease or disorder preferably selected from the group consisting of autoinflammatory febrile 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, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0655] Therefore, as another aspect, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a compound according to any one of the preceding embodiments (i.e., any one of embodiments 1 to 11g), or a compound according to any one of the exemplary embodiments (e.g., Ex 001 to Ex 104 as disclosed herein), or a pharmaceutically acceptable salt thereof for use in therapy. In another embodiment, the therapy is selected from a disease that can be treated by inhibiting the NLRP3 inflammasome pathway. In another embodiment, the disease is selected from the aforementioned list, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute, chronic joint diseases), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II diabetes Diseases / disorders related to diabetes (e.g., diabetes and related complications (e.g., nephropathy, retinopathy, hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammation-related diseases (e.g., multiple sclerosis, brain infection, acute injury, 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, 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). In particular, autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0656] Therefore, as another aspect, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a compound according to any one of the preceding embodiments (i.e., any one of embodiments 1 to 11g), or a compound according to any one of the illustrative examples (e.g., Ex 001 to Ex 104 as disclosed herein), or a pharmaceutically acceptable salt thereof, for use in therapy. In another embodiment, the therapy is selected from a disease that can be treated by inhibiting the NLRP3 inflammasome pathway. In another embodiment, the disease is selected from the aforementioned list, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute, chronic joint diseases), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II diabetes Diseases / disorders related to diabetes (e.g., diabetes and related complications (e.g., nephropathy, retinopathy, hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammation-related diseases (e.g., multiple sclerosis, brain infection, acute injury, 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, 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). In particular, autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0657] In another aspect, the present invention provides a method for treating a disease by inhibiting NLRP3, the method comprising administering a therapeutically effective amount of a compound having any one of formula (I), (II), (III) and (III-A), or a compound according to any one of the preceding embodiments (i.e., any one of Embodiments 1 to 11g), or a compound according to any one of the illustrative examples (e.g., Ex 001 to Ex 104 as disclosed herein), or a pharmaceutically acceptable salt thereof. In another embodiment, the disease is selected from the aforementioned list, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute, chronic joint diseases), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II diabetes Diseases / disorders related to diabetes (e.g., diabetes and related complications (e.g., nephropathy, retinopathy, hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammation-related diseases (e.g., multiple sclerosis, brain infection, acute injury, 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, 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). In particular, autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0658] In another aspect, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a compound according to any of the preceding embodiments (i.e., any of embodiments 1 to 11g), or a compound according to any of the exemplary embodiments (e.g., Ex 001 to Ex 104 as disclosed herein), or a pharmaceutically acceptable salt thereof, for use in treating a disease, condition or symptom mediated substantially or entirely by NLRP3 inflammasome activity, and / or NLRP3-induced IL-1β and / or NLRP3-induced IL-18 as disclosed herein. Some of the diseases, disorders or conditions mentioned herein are caused by mutations in NLRP3 (particularly resulting in increased NLRP3 activity).

[0659] Therefore, as another aspect, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a compound according to any one of the preceding embodiments (i.e., any one of embodiments 1 to 11g), or a compound according to any one of the exemplary embodiments (e.g., Ex 001 to Ex 104 as disclosed herein), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament. In another embodiment, the medicament is for treating a disease treated by inhibiting the NLRP3 inflammasome pathway. In another embodiment, the disease is selected from the aforementioned list, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute, chronic joint diseases), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II diabetes Diseases / disorders related to diabetes (e.g., diabetes and related complications (e.g., nephropathy, retinopathy, hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammation-related diseases (e.g., multiple sclerosis, brain infection, acute injury, 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, 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). In particular, autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0660] In another embodiment of the present invention, 3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In another embodiment of the present invention, (S)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In a preferred embodiment of the present invention, (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. For example, the disease or disorder is selected from the aforementioned list, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute, chronic joint diseases), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II diabetes mellitus), 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., 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).In particular, the compounds of the invention are useful for treating autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0661] In one embodiment of the present invention, 2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In another embodiment of the present invention, (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In a preferred embodiment of the present invention, (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. For example, the disease or disorder is selected from the aforementioned list, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute, chronic joint diseases), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II diabetes mellitus), 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., 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).In particular, the compounds of the invention are useful for treating autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0662] In another embodiment of the present invention, 2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. 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 pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In a preferred embodiment of the present invention, (R)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. For example, the disease or disorder is selected from the aforementioned list, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute, chronic joint diseases), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II diabetes mellitus), Diseases / disorders related to cardiovascular disease (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., 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).In particular, the compounds of the invention are useful for treating autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0663] In another embodiment of the present invention, 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In another embodiment of the present invention, 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In a preferred embodiment of the present invention, 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. For example, the disease or disorder is selected from the aforementioned list, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute, chronic joint diseases), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II diabetes mellitus), 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., 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).In particular, the compounds of the invention are useful for treating autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0664] In another embodiment of the present invention, 2-(6-((3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In another embodiment of the present invention, 2-(6-(((1S,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In another embodiment of the present invention, 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In another embodiment of the present invention, 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In a preferred embodiment of the present invention, 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway.For example, the disease or disorder is selected from the aforementioned list, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute, chronic joint diseases), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II diabetes mellitus), 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., 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). In particular, the compounds of the invention are useful for treating autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0665] In another embodiment of the present invention, 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In another embodiment of the present invention, (3R,5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In another embodiment of the present invention, (3R,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In another embodiment of the present invention, (3S, 5S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway. In a preferred embodiment of the present invention, (3S, 5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol, or a pharmaceutically acceptable salt thereof, is provided for use in treating a disease or disorder treated by inhibiting the NLRP3 pathway.For example, the disease or disorder is selected from the aforementioned list, suitably an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease, for example, an autoinflammatory fever syndrome (e.g., cryptopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases / disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, joint diseases such as acute, chronic joint diseases), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / type II diabetes mellitus), 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., 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, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). In particular, the compounds of the invention are useful for treating autoinflammatory febrile syndromes (e.g., CAPS), sickle cell disease, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative 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 syndrome (MDS), myelofibrosis).

[0666] For a subject of about 50-70kg, the pharmaceutical composition of the present invention or combination can be in a unit dose of one or more active ingredients of about 1-1000mg, or about 1-500mg, or about 1-250mg, or about 1-150mg, or about 1-100mg, or about 1-50mg of active ingredients. The therapeutically effective dose of a compound, a pharmaceutical composition, or a combination thereof depends on the species, body weight, age, and individual condition, disorder, or disease or the degree of severity of the subject. A physician, clinician, or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient necessary for preventing, treating, or suppressing the progress of the disorder or disease.

[0667] The above dosage characteristics are demonstrated in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues and preparations. The compounds of the invention can be applied in vitro in the form of solutions (e.g., aqueous solutions), and in vivo in the form of enteral, parenteral (advantageously, intravenous) suspensions or aqueous solutions. In vitro doses can be administered at about 10 -3 Molar concentration and 10 -9 Depending on the route of administration, the in vivo therapeutically effective amount may range from about 0.1-500 mg / kg, or from about 1-100 mg / kg.

[0668] Combination products and combination therapies of the invention

[0669] "Combination" refers to a fixed combination in the form of a dosage unit, or a combined administration (wherein the compound of the invention and a combination partner (e.g., another drug explained below, also referred to as a "therapeutic agent" or "co-agent") can be administered independently at the same time or separately at time intervals, particularly where these time intervals allow the combination partners to exhibit a synergistic (e.g., synergistic) effect). The individual components can be packaged in one kit or packaged separately. One or both components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose prior to administration. As used herein, the terms "co-administration" or "combined administration" and the like are meant to encompass administration of the selected combination partner to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or are administered simultaneously. As used herein, the term "pharmaceutical combination" means a product resulting from a mixture or combination of more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. As used herein, the term "drug combination" refers to a fixed combination in the form of a dosage unit; or a non-fixed combination or a complete kit for combined administration, wherein two or more therapeutic agents can be administered independently at the same time or separately at time intervals, especially wherein these time intervals allow the combination partner to show cooperation such as synergistic effects. The term "fixed combination" means that therapeutic agents (e.g., compounds of the invention and combination partners) are administered to patients simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that therapeutic agents (e.g., compounds of the invention and combination partners) are administered to patients simultaneously, in parallel or sequentially as separate entities (without specific time limits), wherein such administration provides two compounds at therapeutically effective levels in the patient. The latter is also applicable to cocktail therapy, such as the administration of three or more therapeutic agents.

[0670] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described in this disclosure. This administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as with a single capsule of active ingredients with a fixed ratio. Alternatively, this administration encompasses the co-administration of multiple or separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. The powder and / or liquid can be reconstituted or diluted to a desired dose before administration. In addition, this administration also encompasses the use of each type of therapeutic agent in a sequential manner at approximately the same time or at different times. In either case, the treatment regimen will provide the beneficial effects of the drug combination in terms of treating the conditions or disorders described herein.

[0671] The compounds of this invention can be administered simultaneously with one or more other therapeutic agents, or before or after them. The compounds of this invention can be administered separately by the same or different administration routes as other medicaments, or administered together in the same pharmaceutical composition. The therapeutic agent is, for example, a chemical compound, a peptide, an antibody, an antibody fragment or a nucleic acid, which has therapeutic activity or enhances therapeutic activity when administered to a patient in combination with the compounds of this invention.

[0672] In one embodiment, the present invention provides a product comprising a compound of any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent as a combination preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is for the treatment of a disease or disorder mediated by NLRP3. Products provided as combination preparations include compositions comprising a compound of any one of formula (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents together in the same pharmaceutical composition, or comprising a compound of any one of formula (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents in separate form (e.g., in the form of a kit).

[0673] In one embodiment, the present invention provides a drug combination comprising a compound having any one of formula (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments (i.e., according to any one of embodiments 1 to 11g) or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. Optionally, the drug combination may comprise a pharmaceutically acceptable carrier as described above.

[0674] In one embodiment, the invention provides a medicine box comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound having any one of formula (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments (i.e., according to any one of embodiments 1 to 11g) or a pharmaceutically acceptable salt thereof. In one embodiment, the medicine box comprises a device for separately retaining the composition, such as a container, a separate bottle or a separate foil package. An example of such a medicine box is a blister package, such as typically used for packaging tablets, capsules, etc.

[0675] The kit of the invention can be used for administering different dosage forms (eg, oral and parenteral), for administering separate compositions at different dosage intervals or for titrating the separate compositions relative to each other. To aid compliance, the kit of the invention typically comprises instructions for administration.

[0676] In the combination therapy of the present invention, the compounds of the present invention and other therapeutic agents may be produced and / or formulated by the same or different manufacturers. In addition, the compounds of the present invention and another therapeutic agent may be used together to form a combination therapy: (i) before the combination product is presented to a physician (e.g., in the case of a kit comprising the compounds of the present invention and another therapeutic agent); (ii) by the physician himself (or under the guidance of a physician) just before administration; (iii) by the patient himself, e.g., during the continuous administration of the compounds of the present invention and another therapeutic agent.

[0677] Therefore, the present invention provides a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof for treating a disease or condition mediated by NLRP3, wherein the drug is prepared for administration with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating a disease or condition mediated by NLRP3, wherein the drug is administered together with a compound having any one of formula (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments (i.e., according to any one of embodiments 1 to 11g), or a pharmaceutically acceptable salt thereof.

[0678] The present invention also provides a compound having any one of formula (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments (i.e., according to any one of embodiments 1 to 11g) or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition mediated by NLRP3, wherein the compound having any one of formula (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments (i.e., according to any one of embodiments 1 to 11g) or a pharmaceutically acceptable salt thereof is prepared for administration with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by NLRP3, wherein the other therapeutic agent is prepared for administration with a compound having any one of formula (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments (i.e., according to any one of embodiments 1 to 11g) or a pharmaceutically acceptable salt thereof. The present invention also provides a compound having any one of formula (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments (i.e., according to any one of embodiments 1 to 11g) or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition mediated by NLRP3, wherein the compound having any one of formula (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments (i.e., according to any one of embodiments 1 to 11g) or a pharmaceutically acceptable salt thereof is administered with an additional therapeutic agent. The present invention also provides an additional therapeutic agent for use in a method of treating a disease or condition mediated by NLRP3, wherein the other therapeutic agent is administered with a compound having any one of formula (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments (i.e., according to any one of embodiments 1 to 11g) or a pharmaceutically acceptable salt thereof.

[0679] The present invention also provides a compound of any one of formula (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments (i.e., according to any one of embodiments 1 to 11g) or a pharmaceutically acceptable salt thereof for treating a disease or condition mediated by NLRP3, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the NLRP3 inflammasome pathway, wherein the patient has previously (e.g., within 24 hours) been treated with a compound of any one of formula (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any one of the preceding embodiments (i.e., according to any one of embodiments 1 to 11g) or a pharmaceutically acceptable salt thereof.

[0680] In one embodiment, the additional therapeutic agent is a therapeutic agent useful for treating an inflammasome-associated disease / disorder, immune disease, inflammatory disease, autoimmune disease, or autoinflammatory disease as disclosed herein.

[0681] In one embodiment, the other therapeutic agent that can be used in the combination therapy is selected from farnesoid X receptor (FXR) agonists; anti-steatosis agents; anti-fibrotic agents; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiotherapy and surgery; urate-lowering therapy; anabolic agents and cartilage regeneration therapy; blockers of IL-17; complement inhibitors; Bruton's tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors (TLR7 / 8 inhibitors); CAR-T therapy; antihypertensive agents; cholesterol-lowering agents; leukotriene A4 hydrolase (LTAH4) inhibitors; SGLT2 inhibitors; β2-agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs ("NSAIDs"); acetylsalicylic acid drugs (ASA), including aspirin; paracetamol; regenerative therapy treatments; cystic fibrosis treatments; and atherosclerosis treatments.

[0682] Suitable leukotriene A4 hydrolase (LTA4H) inhibitors for use in the combination include, but are not limited to, compounds disclosed in WO2015 / 092740 (Attorney Docket No. PAT056044-WO-PCT).

[0683] Suitable sodium-dependent glucose transporter 2 (SGLT2) inhibitors for use in combination include, but are not limited to, compounds disclosed in US 8,163,704 (Attorney Docket No. PAT053854-WO-PCT), WO 2011 / 048112, WO 2011 / 048148, or WO 2010 / 128152.

[0684] Suitable beta2-agonists for use in combination include, but are not limited to, arformoterol, bambuterol, bitolterol, bromosatrol, carbuterol, clenbuterol, dopexamine, fenoterol, formoterol, hexoprenaline, ibuterol, neoproterenol, isoproterenol, levalbuterol, mabuterol, meluadrine, metaprotenol, nolomirole, metaprotenol, pirbuterol, procaterol, reproterol, ritodrine (ritodrine), rimoterol, salbutamol, salmethamine, salmeterol, sibenadet, sotenerot, sulfonterol, terbutaline, tiaramide, tulobuterol, GSK-597901, GSK-159797, GSK-678007, 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-dimethylacetamide hydrochloride monohydrate, carmoterol, QAB-149 and 5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-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-methoxybenzylamino)-4-hydroxyphenyl]-2-[4(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-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 which is optionally in the form of a racemate, enantiomer, diastereomer or mixture thereof, and is also optionally in the form of a pharmacologically compatible acid addition salt. ,

[0685] Suitable cartilage regeneration therapies for use in combination include, but are not limited to, the ANGPTL3 mimetic peptides disclosed in WO 2014 / 138687 (Attorney Docket No. PAT055625-WO-PCT), or the chondrogenesis activators disclosed in WO 2015 / 175487 (Attorney Docket No. PAT055940-WO-PCT).

[0686] Suitable checkpoint inhibitors for use in combination include, but are not limited to, anti-PD1 inhibitors, anti-LAG-3 inhibitors, anti-TIM-3 inhibitors, and anti-PDL1 inhibitors. Suitable anti-PD1 inhibitors include, but are not limited to, antibody molecules disclosed in WO 2015 / 112900. Suitable anti-LAG-3 inhibitors include, but are not limited to, antibody molecules disclosed in WO 2015 / 138920. Suitable anti-TIM-3 inhibitors include, but are not limited to, antibody molecules disclosed in WO 2015 / 117002. Suitable anti-TIM-3 inhibitors include, but are not limited to, antibody molecules disclosed in WO 2015 / 117002. Suitable anti-PDL1 inhibitors include, but are not limited to, antibody molecules disclosed in WO / 2016 / 061142.

[0687] Suitable Toll-like receptor inhibitors (TLR7 / 8 inhibitors) for use in combination include, but are not limited to, compounds disclosed in WO2018 / 04081.

[0688] Suitable FXR agonists for use in combination include, but are not limited to, obeticholic acid (also known as OCA, Intercept Pharmaceuticals), GS9674, elafibranor (GFT505), GW4064, UPF987, FXR-450, fexar amine, methylcolate, methyl deoxycholate, 5β-cholanic acid, 5β-cholanic acid 7α,12α diol, NIHS700, marchantin A, marchantin E, MFA-1INT767 (also known as WO 2014 / 085474), MET409 (Metacrine), EDP-305 (Enanta), 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]oct-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid (also known by the name Tropifexor), or a pharmaceutically acceptable salt thereof, or a compound disclosed in WO 2012 / 087519, or a compound disclosed in WO 2015 / 069666.

[0689] Suitable JAK inhibitors for use in combination include, but are not limited to, Ruxolitinib.

[0690] Suitable NSAIDs for use in combination include, but are not limited to, aceclofenac, acemetacin, acetylsalicylic acid, alclofenac, alminofen, amfenac, ampiroxicam, antolmetinguacil, anirolac, antrafenin, azapropazone, benolate, bermoprofen, bindarit, bromfenac, buclofen, bucolom, bufenac, bumadizon, butibufen, butixirat, carbasalat calcium, carprofen, choline magnesium trisalicylate, and choline magnesium trisalicylate.trisalicylate, celecoxib, Cinmetacin, Cinnoxicam, clidanac, Clobuzarit, Deboxamet, dexibuprofen, Dexketoprofen, diclofenac, diflunisal, droxicam, Eltenac, Enfenamins aure), Etersalat, etodolac, etofenamate, etoricoxib, Feclobuzon, felbinac, fenbufen, fenclofenac, fenoprofen, fentiazac, fepradinol, feprazone, flobufen, floctafenin e), flufenamic acid, flufenisal, flunoxaprofen, flurbiprofen, flurbiprofenaxetil, furofenac, furprofen, glucametacin, ibufenac, ibuprofen, indobufen, indomethacin, indomethacin farnesate, dometacinfarnesil, indoprofen, Isoxepac, Isoxicam, ketoprofen, ketorolac, lobenzarit, Lonazolac, lornoxicam, Loxoprofen, lumiracoxib, meclofenamic, Meclofen, mefenamicacid, meloxicam, mesalazine, miroprofen, mofezolac, nabumeton, naproxen, niflumic acid, olsalazine, oxaprozin, oxipinacin, oxyphenbutazone, parecoxib, phenylbutazone, pelubiprofen, pimecrofen, Pimeprofen, Pirazolac, Priroxicam, pirprofen, Pranoprofen, Prifelon, Prinomod, Proglumetacin, Proquazon, Protizininsaure, rofecoxib, Romazarit, salicylamide, salicylic acid acid, Salmi Stein, Salnacedin, salsalate, sulindac, sudoxicam, suprofen, Talniflumate, tenidap, Tenosal, tenoxicam, tepoxalin, tiaprofenic acid, Taramid, Tilnoprofenarbamel, timegadine, Tinoridin, Tiopinac, tolfenamic acid acid, tolmetin, Ufenamat, valdecoxib, Ximoprofen, zaltoprofen, Zoliprofen, and combinations thereof.

[0691] Suitable BTK inhibitors include, for example, Ibrutinib, Acalabrutinib (ACP-196), Evobrutinib; Fenebrutinib; Tirabrutinib (ONO-4059, GS-4059); Zanubrutinib (BGB-3111), Spebrutinib (CC-292, AVL-292), Poseltinib (HM-71224, LY3337641), Vecabrutinib (SNS-062), BMS-986142; BMS986195; PRN2246; PRN1008, M7583, CT1530, BIIBO68, AC-0058TA, ARQ-531, TAK-020, TG1701 or WO 2015 / 079417, WO 2015 / 083008, WO 2015 / 110923, WO 2014 / 173289, WO 2012 / 021444, WO 2013 / 081016, WO 2013 / 067274, WO 2012 / 170976, WO 2011 / 162515, US2017 / 119766, WO 2016 / 065226, US9,688,676, WO 2016 / 201280, WO 2017 / 059702, US9,630,968, US2014 / 0256734, WO 2017118277, WO2014 / 039899, ​​WO / 16 / 105531, WO 2018 / 005849, WO 2013 / 185082 or compounds described in J. Med. Chem. [Journal of Medicinal Chemistry], 2016, 59(19), 9173–9200. Of particular interest, BTK inhibitors include compounds of Example 31 described in WO 2014 / 039899, ​​compounds having the following structure:

[0692]

[0693] As described in Journal of Medicinal Chemistry, 2016, 59(19), 9173-9200 as compound 14f; the compound of Example 2 described in US2017 / 119766, and Example 223 described in WO 2016 / 065226 are the following compounds:

[0694]

[0695] Or compound 1 described in WO 2016 / 201280, compound 1 described in WO 2017 / 059702, or compound 1 described in WO2017 / 118277; or a pharmaceutically acceptable salt thereof.

[0696] Among other particular interests, BTK inhibitors include compounds described in WO 2015 / 079417, such as compounds selected from the group consisting of N-(3-(5-((1-acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-((1-propyloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; -(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylpropionylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylbut-2-enoylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide Benzamide; N-(3-(6-amino-5-(2-(N-ethylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; 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-enylamide)propoxy)pyrimidin-4 -yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(N-methylbut-2-ynylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N-(3-(6-amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; or a pharmaceutically acceptable salt thereof.

[0697] Examples

[0698] Examples of the present invention

[0699] This disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that these examples are provided to illustrate certain embodiments, and are not intended to limit the scope of this disclosure thereto. It should be further understood that various other embodiments, modifications and their equivalents that can be thought of by those skilled in the art themselves can be adopted without departing from the spirit of this disclosure and / or the scope of the appended claims.

[0700] The compounds disclosed herein can be prepared by methods known in the field of organic synthesis. In all methods, it should be understood that, according to general chemical principles, the protecting groups of sensitive groups or reactive groups can be used when necessary. According to the standard method of organic synthesis (TW Green and PGM Wuts (2014) Protective Groups in Organic Synthesis [protective groups in organic synthesis], the 5th edition, John Wiley & Sons [John Wiley & Sons Publishing Company]) operating protecting groups. Using methods obvious to those skilled in the art, these groups are removed at a convenient stage of compound synthesis.

[0701] Unless otherwise stated, reagents and solvents were used as received from commercial suppliers.

[0702] Chemical names were generated using ChemBioDraw Ultra v14 from CambridgeSoft.

[0703] Temperatures are given in degrees Celsius. If not otherwise mentioned, all evaporations are carried out under reduced pressure, typically between about 15 mmHg and 100 mm Hg (=20-133 mbar). The structures of final products, intermediates and starting materials are confirmed by standard analytical methods (e.g., microanalysis and spectral characteristics (e.g., MS, IR, NMR)). The abbreviations used are those conventional in the art.

[0704] abbreviation

[0705] AcOH Acetic acid

[0706] ASC apoptosis-associated speck-like protein

[0707] BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl)

[0708] BippyPhos 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-1,4-dipyrazole

[0709] Boc tert-Butyloxycarbonyl

[0710] CAPS Cryopyrin-associated periodic syndrome

[0711] DAMP Danger Activated Molecular Pattern

[0712] DIAD Diisopropyl azodicarboxylate

[0713] DIPEA N-Diisopropylethylamine

[0714] DME 1,2-Dimethoxyethane

[0715] DMF N,N-Dimethylformamide

[0716] DMSO Dimethyl sulfoxide

[0717] dppf 1,1'-Bis(diphenylphosphino)ferrocene

[0718] EtOAc Ethyl acetate

[0719] EtOH

[0720] h hour

[0721] HCl Hydrogen chloride

[0722] HTRF Homogeneous Time Resolved Fluorescence

[0723] Hz / MHz Hertz / Megahertz

[0724] IC 50 Half maximum inhibitory concentration

[0725] IL-1β Interleukin 1β

[0726] IR

[0727] LC-MS liquid chromatography-mass spectrometry

[0728] LPS Lipopolysaccharide from Escherichia coli O111:B4

[0729] LRR Leucine-rich repeat

[0730] M Moore

[0731] mCPBA 3-Chloroperoxybenzoic acid

[0732] MEK Methyl Ethyl Ketone; Butan-2-one

[0733] MeOH Methanol

[0734] min

[0735] mL / L milliliters / liter

[0736] mmol millimole

[0737] NASH Nonalcoholic steatohepatitis

[0738] NBD Nucleotide binding site domain

[0739] NLR NOD-like receptors

[0740] NMP 1-Methylpyrrolidin-2-one

[0741] NMR Nuclear Magnetic Resonance

[0742] PAD Peripheral Arterial Disease

[0743] PAMP pathogen activated molecular pattern

[0744] Pd / C Palladium Carbon

[0745] PMA Phorbol 12-myristate 13-acetate

[0746] ppm parts per million

[0747] RP Invert

[0748] RPMI Roswell Park Memorial Institute

[0749] RT Room temperature – in degrees Celsius

[0750] Rt retention time

[0751] SFC Supercritical Fluid Chromatography

[0752] SLE Systemic lupus erythematosus

[0753] TFA Trifluoroacetic acid

[0754] THF Tetrahydrofuran

[0755] TMEDA N,N,N',N'-Tetramethylethane-1,2-diamine

[0756] TMS Tetramethylsilane

[0757] TNF-α Tumor necrosis factor-α

[0758] UPLC Ultra-Performance Liquid Chromatography

[0759] XantPhos-Pd-G2Chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) Analysis details

[0760] NMR: In Bruker Ultrashield TM 400(400MHz) or Bruker Ascend TM (400MHz) or Bruker cryo system (600MHz) spectrometer, with or without tetramethylsilane (TMS) as internal standard. Chemical shifts (δ values) are reported in ppm downfield from TMS, and spectral splitting patterns are designated as single signal (s), double signal (d), triple signal (t), quadruple signal (q), quint signal (quint), septuple signal (sept), multiple signal, unresolved or overlapping signal (m), broad signal (br). Deuterated solvents are given in brackets and have the chemical shift of dimethyl sulfoxide (δ 2.50ppm), methanol (δ 3.31ppm), chloroform (δ 7.26ppm) or other solvents as indicated in the NMR spectral data.

[0761] LC-MS: System: Waters Acquity UPLC with Waters SQ detector.

[0762] Column: Acquity HSS T3 1.8 μm 2.1×50 mm, column temperature: 60°C.

[0763] Gradient: from 5% B to 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.

[0764] Mass spectrometry results are reported as mass-to-charge ratios.

[0765] Preparation method

[0766] Flash column chromatography system:

[0767] System: Teledyne ISCO, CombiFlash Rf.

[0768] Column: Prepacked RediSep Rf cartridge.

[0769] The sample is typically adsorbed onto Isolute.

[0770] Achiral reversed phase (RP) chromatography:

[0771] System: Gilson automated purification LC system

[0772] Sunfire C18 5um 30x100mm column.

[0773] Detection: Gilson UV / VIS155 detector

[0774] Column temperature: RT

[0775] Eluent A: Water + 0.1% TFA

[0776] Eluent B: Acetonitrile

[0777] Flow rate: 30mL / min

[0778] gradient:

[0779]

[0780] Chiral normal phase chromatography:

[0781] System: Gilson automated purification LC system

[0782] Detection: Gilson UV / VIS-155 detector

[0783] Column temperature: RT

[0784] Achiral Supercritical Fluid Chromatography (SFC):

[0785] System: Waters SFC-100SFC System

[0786] Detection: Waters 2998PDA Detector

[0787] Waters 3100 Mass Spectrometer

[0788] Eluent A: CO2

[0789] Eluent B: As described in the examples

[0790] Chiral Supercritical Liquid Chromatography (SFC):

[0791] System: Waters SFC-100SFC System

[0792] Detection: Waters 2998PDA Detector

[0793] Waters 3100 Mass Spectrometer

[0794] Eluent A: CO2

[0795] Eluent B: As described in the examples

[0796] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used in the synthesis of the compounds of the present invention are commercially available or can be prepared by organic synthesis methods known to those of ordinary skill in the art.

[0797] Synthesis of intermediates

[0798] Synthesis of borate intermediates

[0799] 3-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol and 5-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenol, Int B001

[0800]

[0801] (1) 3-Chloro-2-iodo-5-(trifluoromethyl)phenol and 5-chloro-2-iodo-3-(trifluoromethyl)phenol, IntB002

[0802]

[0803] A mixture of 3-chloro-5-(trifluoromethyl)phenol (10 g, 50.9 mmol) and sodium hydride (2.44 g, 102 mmol) in 150 mL of toluene was stirred at 0 ° C for 30 min. Iodine (12.9 g, 50.9 mmol) was then added and the solution was stirred at 0 ° C for 3 h. The reaction mixture was then acidified with concentrated HCl to give a final pH of 4-5. It was extracted with EtOAc and the organic layer was washed with water and brine, dried over Na2SO4, filtered and evaporated. The crude mixture of positional isomers was used as is in the next step. LC-MS: Rt = 1.10 and 1.12 min; MS m / z 320.9 [MH]-.

[0804] (2) 5-chloro-1-(ethoxymethoxy)-2-iodo-3-(trifluoromethyl)benzene and 1-chloro-3-(ethoxymethoxy)- 2-Iodo-5-(trifluoromethyl)

[0805] Benzene, Int B003

[0806]

[0807] (Chloromethoxy)ethane (7.25 mL, 62.5 mmol) was added to a suspension of Int B002 (16 g, 49.6 mmol) and Cs2CO3 (16.2 g, 49.6 mmol) in 70 mL DMF. The reaction mixture was stirred at room temperature for 18 h. More (chloromethoxy)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 produce the title compound as a mixture of positional isomers, which was used in the next step without further purification. LC-MS: Rt=1.37 and 1.38 min.

[0808] (3) 2-(2-chloro-6-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-difluorophenyl Oxaborane and 2-(4-chloro-2-(ethoxymethoxy)-6-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3, 2-Dioxaborolane, IntB004

[0809]

[0810] A solution of Int B003 (11.9 g, 31.3 mmol), 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (9.08 mL, 62.5 mmol) and NEt3 (13.08 mL, 94 mmol) in 60 mL 1,4-dioxane was purged with nitrogen. Pd(OAc)2 (0.35 g, 1.56 mmol) and biphenyl-2-yl-dicyclohexylphosphine (1.1 g, 3.13 mmol) were added and the resulting mixture was stirred at 80 °C for 3 h. More Pd(OAc)2 (0.35 g, 1.56 mmol) was added and heating was continued for 13 h. The reaction was cooled to room temperature and washed with saturated NH4Cl solution, water and brine to obtain an orange oil. The crude product was purified by column chromatography on silica gel using cyclohexane and EtOAc (from 0% to 100%) to give the title compound as a mixture of positional isomers. LC-MS: Rt = 1.43 min.

[0811] (4) 3-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol and 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenol, Int B001

[0812] A solution of Int B004 (8.5 g, 22.34 mmol) and TFA (25.8 mL, 670.2 mmol) in 25 mL of CH2Cl2 was purged with nitrogen and stirred at 0°C for 1 h. The mixture was washed with saturated NH4Cl solution, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give an orange oil. The crude product was purified by column chromatography on silica gel using cyclohexane and EtOAc (from 0% to 5%) to give the title compound as a mixture of positional isomers. LC-MS: Rt = 1.23 min and 1.28 min; MS m / z 321.1 [MH]-.

[0813] (2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid, IntB005

[0814]

[0815] (1) 3-Methyl-5-(trifluoromethyl)phenol, IntB006

[0816]

[0817] LiOH (26.5 g, 630.33 mmol), Pd2(dba)3 (3.85 g, 4.20 mmol) and BippyPhos (4.25 g, 8.40 mmol) were added to a solution of 1-bromo-3-methyl-5-(trifluoromethyl)benzene (50 g, 210.11 mmol) in 500 mL 1,4-dioxane and 50 mL H2O. The reaction mixture was purged with nitrogen and heated at 100°C for 16 h. The reaction mixture was cooled to room temperature and heated by The pad was filtered and washed with EtOAc. The filtrate was washed with 1.5 M HCl, dried over Na2SO4, filtered and evaporated. The crude material was purified by column chromatography on silica gel using petroleum ether and EtOAc (from 0% to 15%) to give the title compound as a yellow oil. 1 H NMR (400MHz, 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]-.

[0818] (2) 2-iodo-3-methyl-5-(trifluoromethyl)phenol, Int B007

[0819]

[0820] NaH (60% dispersion in mineral oil, 5.92 g, 148 mmol) was added to an ice-cold solution of Int B006 (13.03 g, 74 mmol) in 370 mL of toluene. The suspension was stirred at 0 ° C for 30 minutes, then iodine (18.77 g, 74 mmol) was slowly added in batches and stirring was continued for 3 h. The mixture was diluted with water, acidified to pH=5 with 2M HCl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The crude material was purified by column chromatography on silica gel (220 g) using cyclohexane and EtOAc (from 5% to 100%) to obtain the title compound as a yellow oil. 1 HNMR (400MHz, CDCl3) δ (ppm) 7.08–7.04 (m, 2H), 5.74 (s, 1H), 2.50 (s, 3H). LC-MS: Rt=1.11min; MS m / z 301.0[MH]-.

[0821] (3) 2-iodo-1-methoxy-3-methyl-5-(trifluoromethyl)benzene, IntB008

[0822]

[0823] A mixture of KCO (24 g, 172.22 mmol), methyl iodide (8.1 mL, 129.13 mmol) and Int B007 (26 g, 86.09 mmol) in 300 mL of anhydrous acetone was stirred at room temperature for 5 h. It was then filtered and the filtrate was evaporated. The residue was dissolved in CHCl, washed with water, dried over NaSO, filtered and evaporated to give the title compound as an off-white solid. 1H NMR (400MHz, CDCl3) δ (ppm) 7.15 (s, 1H), 6.84 (s, 1H), 3.93 (s, 3H), 2.54 (s, 3H).

[0824] (4) 2-(2-methoxy-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane Pentaborane, IntB009

[0825]

[0826] Pinacol borane (50.5 mL, 348.03 mmol), biphenyl-2-yl-dicyclohexylphosphine (2.44 g, 6.96 mmol), Pd(OAc)2 (1.55 g, 6.96 mmol) and NEt3 (48.5 mL, 348.03 mmol) were added to a solution of Int B008 (22 g, 69.61 mmol) in 300 mL of anhydrous 1,4-dioxane (300 mL). The mixture was purged with nitrogen and heated to 100 °C for 16 h. After cooling to room temperature, it was passed through A pad of Celite was filtered and washed with EtOAc. The filtrate was evaporated and the residue was purified by column chromatography on silica gel using petroleum ether and EtOAc (from 0% to 10%) to give the title compound as an off-white solid. 1 H NMR (400MHz, CDCl3) δ (ppm) 7.02 (s, 1H), 6.85 (s, 1H), 3.84 (s, 3H), 2.40 (s, 3H), 1.40 (s, 9H).

[0827] (5) (2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid, IntB005

[0828] At 0°C, BBr (1M in CH2Cl2, 95mL, 94.86mmol) was added to a solution of Int B009 (12g, 37.95mmol) in 150mL anhydrous CH2Cl2. The reaction mixture was stirred at 0°C for 30min, after which it was carefully poured into about 250mL 10% NaOH solution so that the pH remained at about 9. The resulting mixture was washed with CH2Cl2. The aqueous layer was separated and adjusted to pH 5 with 1.5M HCl. The filtered precipitated solid was washed with petroleum ether and dried under vacuum to obtain the title compound as an off-white solid. 1 H NMR (400MHz, CD3OD) δ (ppm) 6.94 (s, 1H), 6.82 (s, 1H), 2.29 (s, 3H). MS(ESI):m / z 219.8[MH]- 3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (Trifluoromethyl)phenol, IntB010

[0829]

[0830] (1) 1-(Ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl)benzene, Int B011

[0831]

[0832] (Chloromethoxy)ethane (3.35 g, 35.50 mmol) was added dropwise to a white suspension of Int B007 (8.50 g, 28.10 mmol) and Cs2CO3 (9.17 g, 28.10 mmol) in 30 mL of dry DMF. The reaction mixture was stirred at room temperature for 2 h and then evaporated to dryness. The crude was purified by column chromatography on silica gel using cyclohexane and EtOAc (from 0% to 5%) to obtain the title compound. LC-MS: Rt=1.39 min.

[0833] (2) 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2- Dioxaborolane, Int B012

[0834]

[0835] A solution of Int B011 (10 g, 27.80 mmol), 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (20.15 mL, 139 mmol) and NEt3 (28.6 mL, 205 mmol) in 60 mL 1,4-dioxane was purged with nitrogen. Pd(OAc)2 (0.81 g, 3.61 mmol) and biphenyl-2-yl-dicyclohexylphosphine (2.33 g, 6.66 mmol) were added and the mixture was stirred at 80 °C for 18 h. It was then cooled to room temperature, diluted with EtOAc and washed with saturated NH4Cl, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on silica gel using cyclohexane and CH2Cl2 (from 0% to 20%) to obtain the title compound. LC-MS: Rt=1.40 min.

[0836] (3) 3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzene Phenol, Int B010

[0837] At 0°C, TFA (44.9 mL, 583 mmol) was slowly added to a solution of Int B012. (7.00 g, 19.43 mmol) in 250 mL of CH2Cl2. The reaction mixture was stirred at 0°C for 20 min and then evaporated. The resulting oil was purified by column chromatography on silica gel using cyclohexane and CH2Cl2 (from 0% to 100%) to obtain the title compound. 1HNMR (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]- 3,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)phenol, Int B013

[0838]

[0839] (1) 2-Iodo-3,5-dimethylphenol, Int B014

[0840]

[0841] 3,5-dimethylphenol (1g, 8.2mmol) is dissolved in 40mL toluene and cooled to 0 DEG C.NaH (60% dispersion in mineral oil, 655mg, 16.4mmol) is added in batches and the mixture is stirred at 0 DEG C for 20min, then stirred at room temperature for 10min, and finally cooled to 0 DEG C again.Iodine (2.08g, 8.2mmol) is then added in batches and stirring is continued for 30min.The reaction mixture is quenched by adding 0.5M HCl and extracted with EtOAc.The combined organic extracts are washed with water and brine, dried over Na2SO4, filtered and evaporated.The crude product is purified by column chromatography on silica gel (100g) using n-heptane and EtOAc (from 0% to 20%), and then n-heptane and EtOAc (5%) are used to run the second (isocratic) purification, to obtain the title compound in the form of off-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; MS m / z 246.9[MH]-

[0842] (2) 1-(Ethoxymethoxy)-2-iodo-3,5-dimethylbenzene, IntB015

[0843]

[0844] To a solution of Int B014 (660 mg, 2.66 mmol) in 6 mL DMF was added CsCO (867 mg, 2.66 mmol), followed by (chloromethoxy)ethane (311 μL, 3.35 mmol). The reaction mixture was stirred at room temperature overnight, then quenched with water and extracted with EtOAc. The combined organic extracts were dried over NaSO, filtered and evaporated. The crude product was purified by column chromatography on silica gel (50 g) using n-heptane and EtOAc (from 0% to 10%) to obtain the title compound in the form of a yellow 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] +

[0845] (3) 2-(2-(ethoxymethoxy)-4,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane Pentaborane, IntB016

[0846]

[0847] To a solution of Int B015 (393 mg, 1.28 mmol) in 2.5 mL 1,4-dioxanes, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (373 μL, 2.57 mmol) and NEt3 (537 μL, 3.85 mmol) are added and the vial is purged with nitrogen. Pd(OAc)2 (14.4 mg, 64 μmol) and biphenyl-2-yl-dicyclohexylphosphine (45 mg, 0.128 mmol) are added, the vial is sealed and heated at 80 ° C overnight. The reaction mixture is cooled to room temperature, quenched by adding water and extracted with EtOAc. The combined organic extracts are dried over Na2SO4, filtered and evaporated. The crude product is purified by column chromatography on silica gel (50 g) using n-heptane and EtOAc (from 0% to 20%) to obtain the title compound as a colorless 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] +

[0848] (4) 3,5-Dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, Int B013

[0849] A solution of Int B016 (486 mg, 1.59 mmol) in 25 mL of CH2Cl2 was cooled to -30 °C and TFA (611 μL, 7.94 mmol) was slowly added. After 1 h, the reaction was quenched at -30 °C by adding water. The mixture was neutralized by adding 1 M NaHCO3 solution and extracted twice with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and evaporated to give the title compound as a yellow oil, which was 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=1.37min; MS m / z 249.2[M+H] +

[0850] (2-Methoxy-4,6-dimethylphenyl)boronic acid, IntB017

[0851]

[0852] 1-Methoxy-3,5-xylene (1.04mL, 7.34mmol) and TMEDA (2.44mL, 16.15mmol) were dissolved in 16mL Et2O and cooled to 0-5°C under nitrogen. n-BuLi (1.6M in hexane, 10.1mL, 16.15mmol) was added dropwise to the colorless solution, keeping the temperature below 10°C. The resulting yellow suspension was stirred at room temperature for 1h, and then cooled to -78°C. During a time period of about 4min, B(OMe)3 (1.15mL, 10.28mmol) was added, keeping the temperature below -70°C. Stirring was continued at -78°C for 20min, and then the reaction mixture was allowed to warm to room temperature overnight. It was quenched by adding water and acidified to pH 1 with 4MHCl. The mixture was extracted 3 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 to give the title compound as a yellow semisolid. LC-MS: Rt = 0.74 min; MS m / z 180.9 [M+H] +

[0853] (2,4-dichloro-6-hydroxyphenyl)boronic acid and 3,5-dichloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane Pentaborane-2-yl)phenol, Int B018

[0854]

[0855] (1) 3,5-Dichloro-2-iodophenol, IntB019

[0856]

[0857] NaH (60% dispersion in mineral oil, 1.472g, 36.8mmol) was added to a solution of 3,5-dichlorophenol (2.00g, 12.27mmol) in 30mL anhydrous toluene in batches at 0°C under nitrogen. The resulting mixture was allowed to warm to room temperature and stirred for 30min. The suspension was then cooled to 0°C and iodine (2.49g, 9.82mmol) was added very slowly. The reaction mixture was stirred at 0°C for 1.5h, then quenched by adding 1M HCl and extracted with CH2Cl2. The organic extract was washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on silica gel (50g) using n-heptane and EtOAc (from 0% to 50%) to obtain 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 / z287.0[MH]-

[0858] (2) 1,5-dichloro-3-(ethoxymethoxy)-2-iodobenzene, IntB020

[0859]

[0860] By (chloromethoxy) ethane (1.004g, 10.62mmol), Int B019 (2.8g, 8.43mmol) and CsCO (2.75g, 8.43mmol) in 25mL DMF suspension stirred at room temperature for 22h. By adding water quenching reaction mixture, and separate each layer. The aqueous layer is extracted with CHCl and the combined organic extracts are dried over NaSO, filtered and concentrated. The crude material is purified by column chromatography on silica gel (100g) using n-heptane and EtOAc (from 0% to 25%) to obtain the title compound as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.39 (d, 1H), 7.13 (d, 1H), 5.39 (s, 2H), 3.69 (q, 2H), 1.14 (t, 3H).

[0861] (3) 2-(2,4-dichloro-6-(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxolane Borane, IntB021

[0862]

[0863] By Int B020 (2.7g, 7.78mmol), 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1M in THF, 15.56mL, 15.56mmol) and NEt3 (3.25mL, 23.34mmol) in 15mL 1,4-dioxane solution was purged with nitrogen for 30min. Then, Pd (OAc) was added (87mg, 0.389mmol) and biphenyl-2-base-dicyclohexylphosphine (273mg, 0.778mmol) and the mixture was stirred at 80 DEG C for 20h. By adding saturated NH4Cl quenching reaction mixture, and separate each layer. The organic layer is washed with water and brine, then evaporated to obtain an orange oil. The crude was purified by column chromatography on silica gel (100 g) using n-heptane and EtOAc (from 0% to 20%) followed by a second chromatography on silica gel (50 g) using n-heptane and EtOAc (from 0% to 5%) to give the title compound as a light 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, 12H), 1.12 (t, 3H).

[0864] (4) (2,4-dichloro-6-hydroxyphenyl)boronic acid and 3,5-dichloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxazoline Cyclopentaborane-2-yl)phenol, IntB018

[0865] A solution of Int B021 (880 mg, 2.54 mmol) in 10 mL of CH2Cl2 was cooled to 0°C. TFA (3.91 mL, 50.7 mmol) was added and the reaction mixture was stirred at 0°C for 1 h. The mixture was quenched by the addition of saturated NH4Cl. The layers were separated and the organic extracts were washed with water and brine. The solvent was evaporated to give the title compound as a mixture, which was used without purification. LC-MS: Rt = 0.76 min and 1.32 min; MS m / z 205.0 [MH]- and 289.0 [M+H] +

[0866] 3-Chloro-5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and 5-chloro-3- Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, IntB022

[0867]

[0868] A mixture of positional isomers was synthesized starting from 3-chloro-5-fluorophenol analogously to Int B018 as described above. LC-MS: Rt = 1.25 min.

[0869] (2-Hydroxy-4,6-bis(trifluoromethyl)phenyl)boronic acid, IntB023

[0870]

[0871] To a solution of (2-methoxy-4,6-bis(trifluoromethyl)phenyl)boronic acid (500 mg, 1.736 mmol) in 10 mL of CHCl was added BBr (1 M in CHCl, 8.68 mL, 8.68 mmol) dropwise at 0°C under nitrogen. The resulting light orange solution was allowed to warm to room temperature and stirred for 17 h. The reaction mixture was poured into ice-water (about 30 mL) and the pH was adjusted to 10 by the addition of 2M NaOH. The aqueous layer was separated, acidified to pH 1 by the addition of 2M HCl and extracted with CHCl followed by EtOAc. The combined organic extracts were dried over NaSO, filtered and evaporated. The crude was purified by column chromatography on silica gel (25 g) using CHCl and MeOH (from 0% to 5%) to give the title compound as a beige solid. LC-MS: Rt=0.81 min; MSm / z 273.1 [MH]- Synthesis of 6-halogeno-pyridazine-3-amine intermediates (R)-6-chloro-N-(1-ethylpiperidin-3-yl)pyridazine- 3-Amine, IntP024

[0872]

[0873] To a solution of 3,6-dichloropyridazine (3 g, 20.13 mmol) and (R)-1-ethylpiperidin-3-amine (5.24 g, 22.15 mmol) in 80 mL of NMP was added DIPEA (17.59 mL, 101 mmol) and the reaction mixture was stirred at 150 °C for 48 h. It was then cooled to room temperature, poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The crude was purified by column chromatography on silica gel using CH2Cl2 and MeOH (from 0% to 10%) to provide the title compound. LC-MS: Rt = 0.42 min; MS m / z 241.2 [M+H] +

[0874] (R)-6-Chloro-N-(1-methylpiperidin-3-yl)pyridazin-3-amine, Int P025

[0875]

[0876] A mixture of 3,6-dichloropyridazine (500 mg, 3.26 mmol), (R)-1-methylpiperidin-3-amine (379 mg, 3.32 mmol) and DIPEA (505 mg, 3.91 mmol) in 4 mL NMP was heated at 150 °C for 4 h. The reaction was cooled to room temperature and evaporated to dryness. The residue was dissolved in EtOAc and washed with saturated Na2CO3 solution. The aqueous layer was extracted 3 times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and evaporated to give a dark orange oil, which was purified by column chromatography on silica gel (50 g) using CH2Cl2 and MeOH containing 5% NH4OH (from 0% to 10%) to obtain the title compound. 1 H NMR (600 MHz, DMSO-d6) δ (ppm) 7.34 (d, 1H), 7.00 (d, 1H), 6.92 (d, 1H), 4.03–3.93 (m, 1H), 2.90–2.70 (m, 1H), 2.58–2.51 (m, 1H) overlapped with DMSO signal, 2.19 (s, 3H), 2.12–1.87 (m, 2H), 1.84–1.75 (m, 1H), 1.74–1.64 (m, 1H), 1.57–1.47 (m, 1H), 1.37–1.23 (m, 1H). LC-MS: Rt = 0.34 min; MS m / z 227.2 [M+H] +

[0877] (R)-6-chloro-N-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)pyridazin-3-amine, IntP026 and (R)-6-chloro- N-(1-methylpiperidin-3-yl)-5-(trifluoromethyl)pyridazin-3-amine, IntP027

[0878]

[0879] A solution of 3,6-dichloro-4-(trifluoromethyl)pyridazine (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) in 5 mL 1-butanol was heated at 110 °C for 20 h. The reaction mixture was evaporated and the crude material was purified and separated by column chromatography on silica gel (220 g) using CH2Cl2 and MeOH (from 0% to 10%). The fractions containing Int P026 (first elution) or Int P027 (second elution) were separated, combined and evaporated. The two products were then individually distributed between CH2Cl2 and 1M NaOH. The organic extract was dried over Na2SO4, filtered and evaporated to give the title compounds Int P026 (brown oil) and Int P027 (light yellow solid), respectively.

[0880] Int P026 (first elution):1 H-NMR (400MHz, DMSO-d6) δ (ppm) 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, overlapped with m, 2H), 1.71-1.58 (m, 3H), 1.56-1.43 (m, 1H). LC-MS: Rt = 0.52 min; MS m / z 295.1 [M+H] +

[0881] Int P027 (second elution): 1 H NMR (400 MHz, 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, overlapped with m, 1H), 2.08-1.98 (m, 1H), 1.81-1.63 (m, 2H), 1.58-1.46 (m, 1H), 1.43-1.30 (m, 1H). LC-MS: Rt = 0.59 min; MS m / z 295.1 [M+H] +

[0882] cis-3-((6-chloro-4-(trifluoromethyl)pyridazin-3-yl)amino)-1-methylcyclobutan-1-ol, IntP028 and cis Formula -3-((6-chloro-5-(trifluoromethyl)pyridazin-3-yl)amino)-1-methylcyclobutan-1-ol, IntP029

[0883]

[0884] A solution of 3,6-dichloro-4-(trifluoromethyl)pyridazine (1 g, 4.61 mmol), cis-3-amino-1-methylcyclobutane-1-ol hydrochloride (0.698 g, 5.07 mmol) and DIPEA (2.415 mL, 13.83 mmol) in 5 mL 1-butanol was heated at 180 ° C in a microwave apparatus for 1 h. The reaction mixture was distributed between EtOAc and 10% NaHCO3 solution. The organic extract was washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified and separated by column chromatography on silica gel (40 g) using CH2Cl2 and MeOH (from 0% to 10%). The fractions containing the product were separately combined and evaporated to give the title compounds Int P028 (first elution) (brown oil) and Int P029 (second elution) (light yellow solid), respectively.

[0885] Int P028 (first elution): 1H-NMR (400MHz, DMSO-d6) δ (ppm) 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 282.1[M+H] +

[0886] Int P029 (second elution): 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.83 (d, 1H), 7.24 (s, 1H), 5.06 (s, 1H), 4.02–3.87 (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] +

[0887] (R)-6-chloro-4-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine, IntP030 and (R)-6-chloro-5-methyl N-(1-methylpiperidin-3-yl)pyridazin-3-amine, IntP031

[0888]

[0889] A solution of 3,6-dichloro-4-methylpyridazine (1.02 g, 6.26 mmol), (R)-1-methylpiperidin-3-amine (0.986 mL, 7.51 mmol) and DIPEA (3.28 mL, 18.77 mmol) in 5 mL NMP was heated at 180 ° C under microwave irradiation for 2 h. The reaction mixture was mostly evaporated and the residue was partitioned between CH2Cl2 and 1M NaOH. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The crude was purified by column chromatography on silica gel (40 g) using CH2Cl2 and MeOH (from 0% to 20%) to give the title compound as an approximately 1:3 mixture of positional isomers. The mixture was further purified and separated by chiral SFC (column: ChiralPak AY, 250×30 mm, 5 μm; at 38° C., eluent B: 35% EtOH+0.1% NH 4 OH, flow rate: 50 mL / min, pressure: 100 bar, cycle time: 8 min.) to provide the title compounds Int P030 (first elution) (as an orange oil) and Int P031 (second elution) (as a brown solid), respectively.

[0890] Int P030 (first elution): 1H-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)overlapping with 2.13(s,3H),1.89-1.77(m,1H),1.74-1.67(m,1H),1.61-1.51(m,2H).LC-MS:Rt=0.40min;MS m / z241.1[M+H] +

[0891] Int P031 (second elution): 1 H NMR (400MHz, CDCl3) δ (ppm) 6.52 (s, 1H), 5.13 (br s, 1H), 4.08-3.97 (m, 1H), 2.65-2.33 (m, 3H), 2.32-2.24 (m, 1H) overlapped with 2.26 (s, 3H) and 2.25 (s, 3H), 1.75-1.69 (m, 1H), 1.69-1.52 (m, 3H). LC-MS: Rt = 0.43 min; MS m / z 241.1 [M+H] +

[0892] Alternatively, the substituted pyridazine intermediate Int P030 was prepared using the regioselective route described below:

[0893] (R)-6-Chloro-4-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine, IntP030

[0894]

[0895] (1) 6-chloro-2-(4-methoxybenzyl)-5-methylpyridazin-3(2H)-one, IntP032

[0896]

[0897] 6-Chloro-4-methylpyridazin-3(2H)-one (25 g, 173 mmol), 1-(bromomethyl)-4-methoxybenzene (36.5 g, 182 mmol), K2CO3 (47.8 g, 346 mmol) and Bu4NBr (2.79 g, 8.65 mmol) were dissolved in 300 mL of acetonitrile. The mixture was heated to 90°C and stirred for 2.25 h. The mixture was cooled to room temperature and The filtrate was evaporated to dryness under reduced pressure to give the title compound as a brown oil, which was used in the next step without further purification. LC-MS: Rt = 0.98 min; MS m / z 265.1 [M+H] +

[0898] (2) (R)-2-(4-methoxybenzyl)-5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazine-3(2H)- Ketone, Int P033

[0899]

[0900] A mixture of IntPO32 (30.5 g, 115.3 mmol), (R)-1-methylpiperidin-3-amine (15 g, 131 mmol) and CsCO (75 g, 231 mmol) in 300 mL of anhydrous toluene was purged with nitrogen for 5 min. Then, Pd(OAc) (1.3 g, 5.79 mmol) and BINAP (8 g, 12.85 mmol) were added successively and the reaction mixture was stirred at reflux for 3 h. It was then cooled to room temperature and heated to room temperature. The filter cake was washed with toluene. The filtrate was evaporated to dryness under reduced pressure to give the title compound as a brown oil, which was used without further purification. LC-MS: Rt = 0.51 min; MS m / z 343.5 [M+H] +

[0901] (3) (R)-5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3(2H)-one, Int P034

[0902]

[0903] Int P033 (39.4 g, 115 mmol) was dissolved in 250 mL TFA. The dark brown mixture was stirred at reflux for 2 days. The reaction mixture was evaporated to dryness. The residue was dissolved in 200 mL acetonitrile and 5 mL water and evaporated to dryness again. The resulting black oil was triturated with Et2O. The supernatant was removed and the remaining brown oil was dried under high vacuum to give the title compound, which was used without further purification. LC-MS: Rt = 0.19 / 0.25 min (injection peak); MS m / z 223.2 [M+H] +

[0904] (4) (R)-6-Chloro-4-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine, Int P030

[0905]

[0906] POCl3 (250 mL) was added to a solution of Int P034 (38.7 g, 115 mmol) in 250 mL of dry acetonitrile and the mixture was heated at reflux for 2.5 days. The reaction mixture was cooled to room temperature and evaporated to dryness. The black oily residue was dissolved in 200 mL of acetonitrile. The solution was added dropwise (strongly exothermic) to an ice-cold saturated solution of Na2CO3. The pH was adjusted to>12 by adding 30% NaOH. The black mixture was evaporated to dryness and then treated with a 1:1 mixture of CH2Cl2 and MeOH. The black suspension was stirred at room temperature for 30 min. It was then passed through Filter through a pad of Cetyl acetate and wash the filter cake with more 1:1 mixture of CH2Cl2 and MeOH (about 500 mL). The filtrate was evaporated to dryness to give the title compound as a black solid, which was used without further purification. LC-MS: Rt = 0.43 min; MS m / z 241.1 [M+H] +

[0907] cis-3-((6-chloro-4-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol, Int P035 and cis-3- ((6-chloro-5-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol, Int P036

[0908]

[0909] By cis-3-amino-1-methylcyclobutane-1-ol (309mg, 2.392mmol), 3,6-dichloro-4-methylpyridazine (300mg, 1.840mmol) and DIPEA (1.3mL, 7.36mmol) in 1.9mL 1-butanol solution was heated at 180 ° C in a microwave apparatus for 90 minutes. The reaction mixture was evaporated and the crude orange oil was distributed between EtOAc and 2M Na2CO3 solution. The organic extract was washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified and separated by column chromatography on silica gel (40g) using CH2Cl2 and MeOH (from 0% to 5%). The fractions containing the product were merged separately and evaporated to give the title compound Int P035 (first elution) (as beige solid) and Int P036 (second elution) (as white solid) respectively.

[0910] Int P035 (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=0.58min; MS m / z 228.1[M+H]+

[0911] Int P036 (second elution): 1 H NMR(400MHz, CDCl3)δ(ppm)6.52–6.47(m,1H),5.81–5.69(m,1H),3.91–3.76(m,1 H),2.76(s,1H),2.72–2.63(m,2H),2.29(d,3H),2.18–2.08(m,2H),1.43(s,3H). LC-MS: Rt=0.58min; MS m / z 228.1[M+H] +

[0912] cis-3-((6-chloropyridazin-3-yl)amino)-1-methylcyclobutan-1-ol, Int P037

[0913]

[0914] A solution of 3,6-dichloropyridazine (1 g, 6.71 mmol), cis-3-amino-1-methylcyclobutane-1-ol (0.970 g, 7.05 mmol) and DIPEA (4.1 mL, 23.49 mmol) in 8 mL of 1-butanol was heated at 180 ° C under microwave irradiation for 1 h. The reaction mixture was poured into water and extracted 3 times with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude was triturated with acetonitrile for 20 min, filtered out and washed with acetonitrile once more to give the title compound as a beige solid. 1 H-NMR (400MHz, DMSO-d6) 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] +

[0915] (1S,3R)-3-((6-chloropyridazin-3-yl)amino)cyclohexan-1-ol, IntP038

[0916]

[0917] A solution of 3,6-dichloropyridazine (100 mg, 0.671 mmol), (1S,3R)-3-aminocyclohexan-1-ol (102 mg, 0.671 mmol) and DIPEA (0.352 mL, 2.014 mmol) was heated at 180 °C in a microwave apparatus for 1 hour. The residue was dissolved in EtOAc and washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel (12 g) using CH2Cl2 and MeOH (from 0% to 10%) provided the title compound as a sticky solid. LC-MS: Rt = 0.55 min; MS m / z 228.1 [M+H] +

[0918] (R)-3-Chloro-6-((1-methylpiperidin-3-yl)oxy)pyridazine, Int P039

[0919]

[0920] To the ice-cold mixture of 3,6-dichloropyridazine (150mg, 1.0mmol) and (R)-3-hydroxy-1-methylpiperidine (128mg, 1.1mmol) in 1mL1,4-dioxane, NaH (60% in mineral oil, 161mg, 4.0mmol) is slowly added, and the suspension is stirred at 0°C for 1h. It is then quenched by careful addition of water and acidified with 1M HCl. The aqueous layer is separated and washed with EtOAc, then alkalized by adding saturated NaCO solution and extracted with EtOAc. The organic extract is evaporated and the crude is purified by column chromatography on silica gel (25g) using CHCl and MeOH (from 0% to 20%) to obtain 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) overlapped 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] +

[0921] The following pyridazine intermediates (IntP) were prepared analogously to the above procedure using the corresponding 3,6-dihalopyridazines and appropriate amines, optionally followed by a deprotection step:

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930] Further modification of piperazine intermediates: 1-((R)-3-((6-chloropyridazin-3-yl)amino)piperidin-1-yl)propan-2- Alcohol, Int P105

[0931]

[0932] Int P100 (200 mg, 0.621 mmol) was dissolved in 2 mL DMF, then K2CO3 (429 mg, 3.11 mmol) and 1-cyclopropan-2-ol (0.23 mL, 1.86 mmol) were added. The yellow suspension was stirred at 100 ° C for 4.5 hours, and then at 120 ° C for 1.5 hours. The mixture was cooled to room temperature, diluted with a small amount of water and purified by non-chiral reverse phase HPLC to give the title compound as a light yellow solid. LC-MS: Rt = 0.40 min; MS m / z 271.2 [M + H] + (R)-1-(3-((6-chloropyridazin-3-yl)amino)piperidin-1-yl)-2-methylpropan-2-ol, Int P106

[0933]

[0934] The title compound was synthesized using Int P100 and 1-chloro-2-methylpropan-2-ol in analogy to the procedure described above for Int P105. LC-MS: Rt = 0.47 min; MS m / z 285.3 [M+H] +

[0935] Synthesis of selected amines for the above intermediates (R)-2-(3-aminopiperidin-1-yl)ethan-1-ol dihydrochloride, Int A107

[0936]

[0937] (1) (R)-tert-butyl (1-(2-hydroxyethyl)piperidin-3-yl)carbamate, IntA108

[0938]

[0939] A suspension of tert-butyl (R)-piperidin-3-ylcarbamate (10 g, 49.9 mmol), 2-bromoeth-1-ol (6.24 g, 49.9 mmol) and Na2CO3 (10.58 g, 100 mmol) in 100 mL of acetonitrile was stirred at room temperature for 2 days. The suspension was filtered and the solid was washed several times with acetonitrile. The combined filtrate was evaporated. The residue was purified by column chromatography on silica gel using CH2Cl2 and MeOH (from 0% to 10%) to give the title compound. LC-MS: Rt = 0.40 min; MS m / z 245.1 [M+H] +

[0940] (2) (R)-2-(3-aminopiperidin-1-yl)ethan-1-ol dihydrochloride, IntA107

[0941] A solution of Int A108 (10.0 g, 40.9 mmol) in 20 mL of CH2Cl2 was treated with 4 M HCl in 1,4-dioxane (40.9 mL, 164 mmol). The mixture was stirred at room temperature for 3 h. The precipitate was filtered off, washed several times with 1,4-dioxane and dried under high vacuum at 60 °C overnight to provide the title compound. LC-MS: Rt = 0.15 min; MS m / z 145.2 [M+H] + 1-(tert-Butyl) 2-methyl 5-aminopiperidin-1,2-dicarboxylate, IntA109

[0942]

[0943] (1) 1-(tert-Butyl) 2-methyl 5-hydroxypiperidin-1,2-dicarboxylate, IntA110

[0944]

[0945] 1-tert-Butyl-2-methyl 5-oxopiperidin-1,2-dicarboxylate (500 mg, 1.943 mmol) was dissolved in 15 mL MeOH and cooled to 0 ° C. NaBH4 (73.5 mg, 19.43 mmol) was added in batches. After stirring for 3 h, half of the MeOH was removed under reduced pressure. The residue was diluted with EtOAc and then washed with 0.5 M HCl, 0.5 M NaOH and brine. The organic extract was dried over Na2SO4, filtered and evaporated to give the title compound as a colorless oil. The mixture of diastereomers was used without further purification. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 4.95 (d, 1H), 4.70–4.54 (m, 1H), 3.97–3.84 (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 (diastereomer), 9H), 1.04–0.94 (m, 1H).

[0946] (2) 1-(tert-Butyl) 2-methyl 5-azidopiperidin-1,2-dicarboxylate, IntA111

[0947]

[0948] Int A110 (526 mg, 1.927 mmol) was dissolved in 10 mL of toluene and treated with PPh (1.064 g, 4.06 mmol) and Zn (N) (468 mg, 1.521 mmol) at room temperature. DIAD (0.789 mL, 4.06 mmol) was then added dropwise to the mixture. After stirring at room temperature for 4 h, the reaction mixture was filtered through Hyflo and washed with EtOAc. The filtrate was evaporated and the crude product was purified by column chromatography on silica gel (50 g) using n-heptane and EtOAc (from 10% to 80%) to obtain the title compound as a mixture of diastereomers. 1 H-NMR (400 MHz, 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).

[0949] (3) 1-(tert-Butyl) 2-methyl 5-aminopiperidin-1,2-dicarboxylate, IntA109

[0950] To a suspension of Pd / C (159 mg, 0.15 mmol, 10% Pd content) in 10 mL MeOH was added a solution of Int A111 (426 mg, 1.498 mmol) in 30 mL MeOH. The mixture was hydrogenated at room temperature under atmospheric pressure for 1 h. The mixture was passed through The filtrate was filtered through a pad of Celite® and washed with EtOAc. The filtrate was evaporated to give the title compound as a mixture of diastereomers and used without further purification. 1H-NMR (400 MHz, 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), 1.82–1.71 (m, 1H), 1.49–1.40 (m, 2H) overlapped with 1.38 (s, 9H).

[0951] Synthesis of Examples

[0952] Example Ex 001

[0953] (R)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0954]

[0955] Int P024 (770mg, 1.663mmol) and Int B010 (754mg, 2.495mmol) are dissolved in 8mL 1,4-dioxane and 2M NaCO (0.25mL, 0.499mmol) is added. Then, Pd (Ph P) (96mg, 0.083mmol) is added and the reaction mixture is purged with nitrogen for 5min and then stirred for 1h at 120°C under microwave radiation. The reaction mixture is poured into water and extracted twice with EtOAc. The combined organic extracts are evaporated and the residue is purified by column chromatography on silica gel using CH Cl and MeOH (from 0% to 10%) to provide the title compound. 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.14(s,1H),7.22(d,1H),7.10(d,1H),7.04(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] +

[0956] Example Ex 002

[0957] 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl) phenol

[0958]

[0959] A mixture of Int P037 (50 mg, 0.145 mmol), Int B005 (35.1 mg, 0.160 mmol) and 2M NaCO (0.218 mL, 0.435 mmol) in 1 mL DME and 1 mL water was purged with argon for 3 min. Then, Pd (PPh) (8.38 mg, 7.25 μmol) was added and the mixture was heated at 140 ° C for 30 min under microwave irradiation. The reaction mixture was evaporated and purified by column chromatography on silica gel (4 g) using CHCl and MeOH (from 0% to 4%) to provide the title compound as a light yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ(ppm)10.13(s,1H),7.22(d,1H),7.13(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] +

[0960] Example Ex 003

[0961] 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[0962]

[0963] A mixture of Int P038 (50 mg, 0.220 mmol), Int B010 (73.0 mg, 0.242 mmol) and 2M Na2CO3 (0.329 mL, 0.659 mmol) in 5 mL 1,4-dioxane was purged with argon for 3 min. Then, Pd(PPh3)4 (7.61 mg, 6.59 μmol) was added and the mixture was stirred at 120 ° C for 6 h. Another batch of Int B010 (50.0 mg, 0.166 mmol) and more Pd(PPh3)4 (5 mg, 4.33 μmol) were added together and continued to heat for 24 h. The reaction mixture was allowed to cool to room temperature. It was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and evaporated. The crude was purified by SFC (column: Waters TORUS2-PIC 130A, 250x30 mm, 5 μm; 35°C, eluent B: 17%-25% MeOH in 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),2.02–1.92(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=0.78min; MS m / z 368.2[M+H] +

[0964] Example Ex 004

[0965] (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0966]

[0967] A mixture of Int P031 (438 mg, 1.819 mmol), commercially available (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (CAS 1072951-50-8, 412 mg, 2.001 mmol), Pd(PPh3)4 (63.1 mg, 0.055 mmol) and 1.2 M NaHCO3 (4.55 mL, 5.46 mmol) in 9 mL 1,4-dioxane was heated at 105 ° C overnight. For complete conversion, another batch of (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (187 mg, 0.909 mmol) was added and the mixture was heated at 180 ° C for 30 min under microwave irradiation. The reaction mixture was diluted with water and extracted twice with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and evaporated. The crude was purified by column chromatography on silica gel (40 g) using CH2Cl2 and MeOH (from 0% to 20%). The fractions containing the product were evaporated and triturated with CH2Cl2 to give the title compound as a white 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, overlapped with m, 1H), 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 = 0.67 min; MS m / z 367.3 [M+H] +

[0968] Example Ex 005

[0969] (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl) phenol

[0970]

[0971] Amine Int P030 (76 mg, 0.316 mmol), borate Int B010 (124 mg, 0.410 mmol) and 2M Na2CO3 aqueous solution (0.474 mL, 0.947 mmol) in 2 mL 1,4-dioxane were purged with argon for 3 min. Then, Pd (Ph3P)4 (10.9 mg, 9.4 μmol) was added and the mixture was heated at 120 ° C for 2 hours. Another batch of Int B010 (50 mg, 0.166 mmol) and Pd (Ph3P)4 (10.9 mg, 9.4 μmol) were added and heating was continued overnight. The reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered and evaporated. The crude was purified by SFC (column: Waters Viridis 2-EP 130A, 250x30 mm, 5 μm; 35°C, eluent B: 16%-24% MeOH in 10 min., flow rate: 100 mL / min, pressure: 120 bar) to afford 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),5.80(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+3H),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,1H). LC-MS: Rt=0.74min; MS m / z 381.3[M+H] +

[0972] Analogously to the above procedures, the following examples were synthesized using appropriate halo-pyridazine intermediates (Int P) and corresponding boronic acid or boronate intermediates (Int B) or commercially available boronic acids (BCA), respectively, optionally followed by a deprotection step:

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993] The following examples Ex 083 (A / B) to Ex 096 (A / B) were prepared following an analogous procedure as in example Ex 001 using the corresponding amine and boronate as defined herein as racemates followed by a chiral chromatography step.

[0994] Examples Ex 083A and Ex 083B

[0995] 3-Methyl-2-(6-(((8R,8aR)-octahydroindolizin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol and 3-Methyl-2-(6-(((8S,8aS)-octahydroindolizin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0996] The racemate (rac)-3-methyl-2-(6-(((8r,8ar)-octahydroindolizin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (prepared as described in Example Ex 001 starting from Int P041 and Int B010) was separated by chiral normal phase chromatography (column: Chiralpak AD, 250 x 30 mm, 5 μm; room temperature, eluent: n-heptane:EtOH=90:10+0.05% DEA; flow rate: 20 mL / min; cycle time: 15 min) to provide two enantiomers Ex 083A (first elution, room temperature=25 min) and Ex 083B (second elution, room temperature=31 min), respectively.

[0997] Ex 083A 1 H NMR (400MHz, DMSO-d6) δ10.14(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 393.2[M+H]+

[0998] Ex 083B 1 H NMR(600MHz,DMSO-d6)δ10.19(s,1H),7.23(d,1H),7.11(s,1H),7.06(s,1H),6.96–6.76(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),2.03–1.87(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]+

[0999] Examples Ex 084A and Ex 084B

[1000] (R)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)piperidin-2-yl)methyl)amino)pyridazin-3-yl)- Methyl)phenol and (S)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5- (Trifluoromethyl)phenol

[1001] The racemic 2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described in Example Ex 001 starting from Int P044 and Int B010) was separated by chiral normal phase chromatography (column: Chiralpak AD, 250 x 30 mm, 5 μm; room temperature, eluent: n-heptane:EtOH=80:20+0.05% DEA; flow rate: 20 mL / min; cycle time: 30 min) to provide two enantiomers Ex 084A (first elution, room temperature=15 min) and Ex 084B (second elution, room temperature=23.5 min), respectively.

[1002] Ex 084A 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.15(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]+

[1003] Ex 084B 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.15(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]+

[1004] Examples Ex 085A and Ex 085B 3-methyl-2-(6-(((1S,2S,5S)-8-methyl-8-azabicyclo[3.2.1] (oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (Ex 085A) and

[1005] 3-Methyl-2-(6-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazine-3- 5-(Trifluoromethyl)phenol (Ex 085B)

[1006]

[1007] The racemic product (prepared as described in Example Ex 001 starting from Int P048 and Int B010) was separated by chiral normal phase chromatography (column: Chiralpak IG, 250 x 30 mm, 5 μm; 40° C., eluent: n-heptane: i-PrOH=70:30+0.1% ammonia; flow rate: 80 mL / min; pressure: 120 bar, cycle time: 20 min) to provide two enantiomers Ex 085A (first elution, Rt=7 min) and Ex 085B (second elution, Rt=11.9 min), respectively. The stereochemistry was assigned by X-ray crystallography.

[1008] Ex 085A 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.16(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,3 H),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]+

[1009] Ex 085B 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.21(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,3 H),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]+

[1010] Examples Ex 086A and Ex 086B 2-(6-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1] (oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (Ex 086B) and

[1011] 2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazine-3- methyl)-3-methyl-5-(trifluoromethyl)

[1012] phenol (Ex 086A)

[1013]

[1014] The racemate 2-(6-((-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described in Example Ex 001 starting from Int P050 and Int B010) was separated by chiral SFC (column: Chiralpak IG, 250 x 30 mm, 5 μm, 40° C., eluent B: i-PrOH 35% + 0.1% ammonia; flow rate: 70 mL / min; pressure: 110 bar, cycle time: 6 min) to provide two enantiomers Ex 086A (first elution, Rt=5.2 min) and Ex 086B (second elution, Rt=6.5 min), respectively. The stereochemistry was assigned by ROESY NMR.

[1015] Ex 086A 1 H NMR(600MHz,DMSO-d6)δ10.17(s,1H),7.21(d,1H),7.11(s,1H),7.05(s,1H),6.83(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,1H),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 423.3[M+H]+

[1016] Ex 086B 1H NMR(600MHz,DMSO-d6)δ10.17(s,1H),7.21(d,1H),7.11(s,1H),7.05(s,1H),6.83(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,1H),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 423.3[M+H]+

[1017] Examples Ex 087A and Ex 087B

[1018] 2-(6-(((3R,6R)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5- (Trifluoromethyl)phenol and 2-(6-(((3S,6S)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)- 3-Methyl-5-(trifluoromethyl)phenol

[1019] The racemate 2-(6-((-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described in Example Ex 001 starting from Int P052 and Int B010) was separated by chiral SFC (column: Chiralpak IG-LL, 250 x 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) to provide two diastereomers Ex 087A (first elution, Rt=8.2 min) and Ex 087B (second elution, Rt=11.3 min), respectively.

[1020] Ex 087A 11H NMR (600 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.22 (d, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 7.02 (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, 1H), 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 = 0.71 min; MS m / z 423.3 [M+H]+

[1021] Ex 087B 1 1H NMR (600 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.22 (d, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 7.02 (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, 1H), 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 = 0.71 min; MS m / z 423.3 [M+H]+

[1022] Examples Ex 088A and Ex 088B

[1023] (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)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 Alkane-1,2-diol

[1024] The racemate 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol (prepared as described in Example Ex 001 starting from Int P053 and Int B010) was separated by chiral SFC (column: Chiralpak IG, 250 x 30 mm, 5 μm, 40°C, eluent B: MeOH 25% + 0.1% ammonia; flow rate: 80 mL / min; pressure: 120 bar, cycle time: 20 min) to provide two enantiomers Ex 088A (first elution, Rt = 8.7 min) and Ex 088B (second elution, Rt = 13.8 min), respectively.

[1025] Ex 088A 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.19(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; MSm / z 358.1[M+H]+

[1026] Ex 088B 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.17(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; MSm / z 358.1[M+H]+

[1027] Examples Ex 089A and Ex 089B

[1028] (1S,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane Alkane-1,2-diol and (1R,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino) Cyclopentane-1,2-diol

[1029] The racemic 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol (prepared as described in Example Ex 001 starting from Int P054 and Int B010) was separated by chiral SFC (column: i-LuxCel (IC), 250 x 30 mm, 5 μm; eluent B: MeOH 15% + 0.1% ammonia; flow rate: 80 mL / min; cycle time: 30 min) to provide two diastereomers Ex 089A (first elution, Rt = 14.3 min) and Ex 089B (second elution, Rt = 22.2 min), respectively.

[1030] Ex 089A 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.18(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),3.74–3.66(m,1H),2.29–2.19(m,1H) ,2.13(s,3H),1.95–1.83(m,1H),1.63–1.52(m,1H),1.42–1.32(m,1H). LC-MS: Rt=0.7min; MS m / z 370.3[M+H]+

[1031] Ex 089B 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.19(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]+

[1032] Examples Ex 090A and Ex 090B

[1033] (S)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol and (R)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[1034] The racemate 2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described in Example Ex 001 starting from Int P056 and Int B010) was separated by chiral SFC (column: Chiralpak IB-N, 250x30 mm, 5 μm, 40°C, eluent B: i-PrOH 23% + 0.1% ammonia; flow rate: 80 mL / min; pressure: 120 bar, cycle time: 20 min) to provide two enantiomers Ex 090A (first elution, Rt = 9.6 min) and Ex 090B (second elution, Rt = 13 min), respectively.

[1035] Ex 090A 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.18(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]+

[1036] Ex 090B 1 H NMR(600MHz,DMSO-d6)δ(ppm)10.17(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]+

[1037] Examples Ex 091A and Ex 091B

[1038] 3-Methyl-2-(6-(((2S,3S)-2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)benzene phenol and 3-Methyl-2-(6-(((2R,3R)-2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[1039] The racemic 3-methyl-2-(6-((2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (prepared as described in Example Ex 001 starting from Int P099 and Int B010) was separated by chiral SFC (column: Lux i-Cellulose 5, 250×30 mm, 5 μm, 40° C., eluent B: MeOH 23%+0.1% NH 3, flow rate: 80 mL / min, pressure: 120 bar, cycle time: 20 min) to provide the title compounds Ex 091A (first elution, Rt=9.17 min) and Ex 091B (second elution, Rt=12.01 min), respectively.

[1040] Ex 091A 1 H NMR(400MHz,CD3OD)δ(ppm)7.34(d,1H),7.08(s,1H),7.01-7.03(m,2H),4.27-4.22(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,1H),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] +

[1041] Ex 091B 1 H NMR(400MHz,CD3OD)δ(ppm)7.35(d,1H),7.07(s,1H),7.05-7.01(m,2H),4.27-4.21(m,1H),3.18-3.12(m,1H),3.11-3.02(m,1 H),2.81-2.72(m,1H),2.21(s,3H),2.10-1.99(m,1H),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] +

[1042] Examples Ex 092A and Ex 092B 2-(6-(((R)-1-((S)-2-hydroxypropyl)piperidin-3-yl)amino)pyridazine-3- 3-Methyl-5-(trifluoromethyl)phenol and 2-(6-(((R)-1-((R)-2-hydroxypropyl)piperidin-3-yl)amino)pyridazine- 3-Methyl-5-(trifluoromethyl)phenol

[1043] A mixture of diastereoisomers of 2-(6-(((3R)-1-(2-hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described in Example Ex 001 starting from Int P105 and Int B010) was separated by chiral SFC (column: ChiralPak AD, 250×30 mm, 5 μm, 40° C., eluent B: EtOH 25%+0.1% NH 3, flow rate: 80 mL / min, pressure: 120 bar, cycle time: 20 min) to provide the title compounds Ex 092A (first elution, Rt=8.7 min) and Ex 092B (second elution, Rt=12.0 min), respectively.

[1044] Ex 092A 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.14(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,1 H),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] +

[1045] Ex 092B 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.14(s,1H),7.22(d,1H),7.10(s,1H),7.05(s,1H),6.8 8(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] +

[1046] Examples Ex 093A and Ex 093B

[1047] 2-(6-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol and 2-(6-(((3R,5R)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[1048] A mixture of diastereoisomers of 2-(6-((5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described in Example Ex 003 starting from Int P102 and Int B005) 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) to provide the title compounds Ex 093A (first elution, Rt=6.9 min) and Ex 093B (second elution, Rt=11.5 min), respectively.

[1049] Ex 093A 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.17(s,1H),7.23(d,1H),7.10(s,1H),7.0 4(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] +

[1050] Ex 093B 1H NMR(400MHz,DMSO-d6)δ(ppm)10.14(s,1H),7.24(d,1H),7.10(s,1H),7.0 5(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] +

[1051] Examples Ex 094A and Ex 094B

[1052] 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl) 4-(4-(2-aminophenyl)phenol and 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl) 4-(4-(2-aminophenyl)phenol

[1053] A mixture of diastereoisomers of 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol was prepared as follows: rac-Ex 093A / B (40 mg, 0.10 mmol) was dissolved in THF and formaldehyde (0.038 mL, 0.51 mmol, 37% in water) was added. NaBH(OAc)3 (43 mg, 0.205 mmol) was added and the resulting mixture was stirred at RT for 1 h. Formaldehyde (0.038 mL, 0.51 mmol, 37% in water), NaBH(OAc)3 (43 mg, 0.205 mmol) and AcOH (1 drop) were further added. After stirring for an additional 2 hours, the reaction was quenched by the addition of NaHCO3 solution and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by achiral RP chromatography. The fractions containing the purified product were combined and adjusted to pH 8-9 using saturated NaHCO3 solution, then extracted twice with EtOAc. The organics were dried over Na2SO4, filtered and concentrated in vacuo. The diastereomeric products were separated by chiral SFC (column: Lux i-Cellulose-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) to provide the title compounds Ex 094A (first elution, Rt=3.99 min) and Ex 094B (second elution, Rt=4.52 min), respectively.

[1054] Ex 094A 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.18 (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 = 0.86 min; MS m / z 385.2 [M+H] +

[1055] Ex 094B 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 10.19 (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 = 0.86 min; MS m / z 385.2 [M+H] +

[1056] Examples Ex 095A and Ex 095B

[1057] 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)- 4-(4-(2-aminophenyl)phenol and 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl) 4-(4-(2-aminophenyl)phenol

[1058] A mixture of diastereoisomers of 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described in Example Ex 001 starting from Int P103 and Int B005) was separated by chiral SFC (column: Lux Amylose-1, 250×30 mm, 5 μm, 40° C., eluent B: 17% [iPrOH+0.1% NH 3 ], flow rate: 80 mL / min, pressure: 120 bar, cycle time: 20 min) to provide the title compounds Ex 095A (first elution, Rt=13.58 min) and Ex 095B (second elution, Rt=15.01 min), respectively.

[1059] Ex 095A 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.16(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),2.10–2.04(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] +

[1060] Ex 095B 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.17(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),2.10–2.04(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] +

[1061] Examples Ex 096A and Ex 096B

[1062] 2-(6-(((3S,5R)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol and 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[1063] A mixture of diastereoisomers of 2-(6-((5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described in Example Ex 001 starting from Int P104 and Int B005) was separated by chiral SFC (column: Lux Amylose-1, 250×30 mm, 5 μm, 40° C., eluent B: 40% [MeOH+0.1% NH 3 ], flow rate: 80 mL / min, pressure: 120 bar, cycle time: 20 min) to provide the title compounds Ex 096A (first elution, Rt=4.79 min) and Ex 096B (second elution, Rt=9.34 min), respectively.

[1064] Ex 096A 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.16(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).

[1065] LC-MS: Rt=0.82min; MS m / z 371.2[M+H] +

[1066] Ex 096B 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.17(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).

[1067] LC-MS: Rt=0.82min; MS m / z 371.2[M+H] +

[1068] Example Ex 097

[1069] (3S,5R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methyl Piperidin-3-ol

[1070]

[1071] A solution of crude tert-butyl (3S,5R)-3-hydroxy-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (660 mg, 1.409 mmol) prepared similarly to Example Ex 002 using intermediate Int P043 and boronic acid Int B005 in 3 mL of CH2Cl2 was treated with 4M HCl in 1,4-dioxane (4,23 mL, 16.91 mmol) at room temperature for 2 h. The reaction mixture was evaporated. The resulting solid was dissolved in a mixture of 2 mL of DMSO and 2 mL of CH2Cl2 and treated with paraformaldehyde (76 mg, 2.52 mmol). After 1 h, NaBH(OAc)3 (534 mg, 2.52 mmol) was added and stirring was continued at room temperature for 18 h. The reaction mixture was evaporated and the crude was purified by column chromatography on silica gel using CH 2 Cl 2 and MeOH containing 5% ammonia (from 0% to 30%) to afford the title compound as an off-white solid. 1 H NMR(600MHz,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-MS: Rt=0.61min; MS m / z 383.2[M+H] + .

[1072] Example Ex 098

[1073] 2-(6-(((1-Hydroxycyclopentyl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[1074]

[1075] (1) 2-(6-chloropyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, IntX109

[1076]

[1077] The mixture of Int B010 (150mg, 0.497mmol), 3,6-dichloropyridazine (89mg, 0.596mmol), Pd(Ph3P)4 (28.7mg, 0.025mmol) and 2M Na2CO3 (0.75mL, 1.5mmol) in 3.9mL 1,4-dioxane was purged with nitrogen. The vial was sealed and heated at 120°C for 1h under microwave radiation. The reaction mixture was diluted with saline and extracted 3 times with AcOEt. The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude material was purified by column chromatography on silica gel (25g) using cyclohexane and EtOAc (from 0% to 50%) to provide the title compound. 1 H NMR (600MHz, 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] +

[1078] (2) 2-(6-(((1-hydroxycyclopentyl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

[1079] A mixture of Int X109 (95 mg, 0.214 mmol), 1-(aminomethyl)cyclopentanol (73.9 mg, 0.642 mmol) and DIPEA (0.112 mL, 0.642 mmol) in 5 mL NMP was heated at 150° C. for 18 h. The reaction mixture was evaporated and purified by SFC (column: Reprospher PEI 100A, 250×30 mm, 5 μm, 40° C., eluent B: 25%-35% MeOH in 10 min, flow rate: 100 mL / min, pressure: 120 bar) to provide the title compound. 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.37(s,1H),7.22(d,1H),7.09(s,1H),7.05(s,1H),7.0 1(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 / z368.2[M+H] +

[1080] ExampleEx 099

[1081] 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin Pyridine-2-one

[1082]

[1083] (1) 2-(6-chloro-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, IntX110

[1084]

[1085] A mixture of 3,6-dichloro-4-methylpyridazine (1.60 g, 9.52 mmol), (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boric acid (2.09 g, 9.52 mmol) and 2M NaCO (14.28 mL, 28.6 mmol) in 95 mL of 1,4-dioxane was purged with argon for 5 min. Then, Pd(PPh) (0.66 g, 0.57 mmol) was added, and the mixture was stirred at 120 ° C for 1 h under an argon atmosphere. The reaction mixture was quenched with water and brine (50 mL each) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were dried over NaSO, filtered and evaporated. The crude product was ground overnight with 5 mL of CHCl. ​​The resulting solid was collected by filtration, washed and dried with a small amount of CHCl to provide the title compound as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.36(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]+

[1086] (2) 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methyl 2-Hydroxypiperidin-2-one

[1087] LiOtBu (167 mg, 1.982 mmol) and PdCl (dppf) (12.09 mg, 0.017 mmol) are added to a suspension of Int X110 (100 mg, 0.330 mmol) and 5-amino-1-methylpiperidin-2-one (63.5 mg, 0.496 mmol) in 2 mL of toluene. The vial is closed and heated overnight at 105 ° C. After cooling to room temperature, the reaction mixture is poured into water (30 mL) and extracted with EtOAc (3x 50 mL). The combined organic extracts are dried over Na2SO4, filtered and evaporated. The crude product is first purified by column chromatography on silica gel (25 g) using n-heptane and EtOAc (from 0% to 100%), then using CH2Cl2 and MeOH (from 0% to 30%) to obtain the title compound as a brown solid. 1H NMR(400MHz,DMSO-d6)δ10.14(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]+

[1088] Example Ex 100

[1089] (R)-3-Methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[1090]

[1091] The compound was synthesized analogously to the procedure described for Example Ex 099 using tert-butyl (R)-3-aminopiperidine-1-carboxylate in step (2) followed by TFA-mediated Boc-cleavage and extraction by NaHCO 3 to afford 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,1H),1.70-1.43(m,3H),1.27–1.20(m,2H). LC-MS: Rt=0.86min; MS m / z 367.1[M+H] + .

[1092] Example Ex 101

[1093] (R)-2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl) 4-( ...phenyl)-phenol)

[1094]

[1095] The compound was synthesized similarly to the procedure described in Example Ex 099 using (R)-1-ethylpiperidin-3-amine in step (2) to afford the title compound as an off-white solid. 1H NMR(400MHz,MeOH-d4)δ(ppm)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),2.88-2.66(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] +

[1096] Example Ex 102

[1097] (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methyl 2-Hydroxypiperidin-2-one

[1098]

[1099] The compound was synthesized similarly to the procedure described in Example Ex 099 using (R)-3-amino-1-methylpiperidin-2-one hydrochloride in step (2) to afford the title compound as an off-white solid. 1 H NMR(400MHz,DMSO-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),1.88-1.78(m,1H). LC-MS: Rt=0.87min; MS m / z 395.2[M+H] +

[1100] Example Ex 103

[1101] 4-(2-((6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl)amino)ethyl)benzenesulfonamide

[1102]

[1103] (1) 4-(2-((6-(2-methoxy-4,6-dimethylphenyl)pyridazin-3-yl)amino)ethyl), IntX111

[1104]

[1105] Int P101 (400 mg, 1.279 mmol), Int B017 (493 mg, 1.918 mmol) and Pd(Ph3P)4 (148 mg, 0.128 mmol) were dissolved in 10 mL of DME. 2M Na2CO3 (1.92 mL, 3.84 mmol) was added and the reaction mixture was stirred at 90 °C for 22 h. The reaction mixture was poured into water and extracted 3 times with EtOAc. The combined organic extracts were washed with brine and evaporated to dryness. The crude was purified by column chromatography on silica gel (12 g) using CH2Cl2 and MeOH (from 0% to 10%). The fractions containing the product were evaporated to dryness and triturated with MeOH to provide the title compound as an off-white solid. LC-MS: Rt=0.80 min; MS m / z 413.2 [M+H] +

[1106] (2) 4-(2-((6-(2-hydroxy-4,6-dimethylphenyl)pyridazin-3-yl)amino)ethyl)benzenesulfonamide

[1107] Int X111 (65 mg, 0.137 mmol) was suspended in 5 mL of CH2Cl2, and then BBr3 (1 M in CH2Cl2, 0.206 mL, 0.206 mmol) was added. The resulting orange suspension was stirred at room temperature for 3 h. The reaction mixture was evaporated to dryness, and the residue was purified by non-chiral RP chromatography. The fractions containing the purified product were combined and adjusted to pH 8-9 using saturated NaHCO3 solution, and then extracted twice with CH2Cl2. The combined organic extracts were evaporated to obtain the title compound as a beige solid. 1 H NMR(400MHz,DMSO-d6)δ(ppm)9.46(s,1H),7.78(d,2H),7.49(d,2H),7.31(s,2H),7.20(d,1H),6.96-6.9 1(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] +

[1108] Example Ex 104

[1109] (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1- Methylpiperidine 1-oxide TFA-salt

[1110]

[1111] A solution of Example Ex 005 (27 mg, 0.071 mmol) in 1 mL of CH2Cl2 was treated with mCPBA (13.6 mg, 0.079 mmol) and stirred at room temperature for 90 min. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. The crude was purified by achiral RP chromatography to provide the title compound as a white solid. 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=0.86min; MS m / z 397.2[M+H]+

[1112] Biological assays and data

[1113] The activity of the compounds according to the invention can be evaluated by the following in vitro methods. The compounds of formula (I), or pharmaceutically acceptable salts thereof, exhibit valuable pharmacological properties, such as the property of being susceptible to inhibiting NLRP3 activity (e.g. as indicated in the tests provided in the following sections), and are therefore indicated for use in therapies associated with NLRP3 inflammasome activity.

[1114] IL-1β secretion assay:

[1115] Monocytic THP-1 cells (ATCC: TIB-202) were maintained in RPMI medium (RPMI / Hepes + 10% fetal bovine serum + sodium pyruvate + 0.05 mM β-mercaptoethanol (1000x stock) + penicillin-streptomycin) according to the supplier's instructions. Cells were batch differentiated with 0.5 μM phorbol 12-myristate 13-acetate (PMA; Sigma #P8139) for 3 hours, the medium was changed, and the cells were plated at 50,000 cells / well in 384-well flat-bottom cell culture plates (Greiner, #781986) and allowed to differentiate overnight. A 1:3.16 serial dilution series of compounds in DMSO was added to the cells at 1:100 and incubated for 1 hour. The NLRP3 inflammasome was activated by adding 15 μM (final concentration) nigericin (Enzo Life Sciences, #BML-CA421-0005), and the cells were incubated for 3 hours. 10 μL of supernatant was removed and IL-1β levels were monitored using HTRF assay (CisBio, #62IL1PEC) according to the manufacturer's instructions. Viability and cell pyroptosis were monitored by adding PrestoBlue cell viability reagent (Life Technologies, #A13261) directly to the cell culture plates.

[1116] TNF-α secretion assay :

[1117] The monocytic THP-1 cells are maintained in RPMI culture medium as described above according to the instructions of the provider. Undifferentiated cells are planted in 384-well flat-bottomed cell plates (Gelaina Company, #781986) with 50,000 cells / well, and are allowed to stand overnight. Experimental compounds are prepared and added as described above. According to the experiment, TNF-α secretion is triggered by adding 1 μg / mL PPS (Sigma Company, #L4391) or 100ng / mL Pam3CSK4 (Invivogen Company, #tlrl-pms), and cells are incubated for 3 hours. 10 μL supernatant is removed, and HTRF is used to measure (CisBio Company, #62TNFPEC) to monitor TNF-α levels according to the instructions of the manufacturer. Viability is monitored as described above.

[1118] Data explanation:

[1119] IC was calculated by logistic fitting from a plot of percent inhibition versus inhibitor concentration according to the following formula: 50 value:

[1120] y=A2+(A1–A2) / (1+(x / IC 50 )^p)

[1121] Where y is the % inhibition at inhibitor concentration x, A1 is the minimum inhibition value, i.e. 0%, and A2 is the maximum inhibition value, i.e. 100%. The exponent p is the Hill coefficient. Curve fitting was performed using an in-house developed software suite.

[1122] NLRP3-dependent IL-1β secretion was stimulated in PMA-differentiated THP-1 cells by addition of nigericin, and cytokines were measured in serum 3 hours later. As discussed above, activation of the NLRP3 inflammasome requires both the NF-kB-dependent priming step and the addition of NLRP3 activating factors. To ensure that inhibitors did not interfere with the priming step, Pam3CSK4-stimulated NF-kB-dependent TNF-α secretion was monitored as a counter-screen. The inhibitory effects (IC 50 ) data are given in the table below.

[1123]

[1124]

[1125]

[1126]

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in the treatment of the following diseases or disorders, wherein: NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression of the disease or disorder, in R 1 is Cl, CH3, -OCF3 or CF3; R 2 is H, halo, C1-C4 alkyl or halo-C1-C4 alkyl; R 3 , R 4 is H, CN, C1-C4 alkyl or halogenated C1-C4 alkyl; Z is –O- or -NH-(CH2) n -, where n is 0, 1 or 2; R 5 Selected from the following structures: Where R 5a are independently selected from C1-C4 alkyl, hydroxy C1-C4 alkyl and H; and R 5b is independently selected from -OH, C1-C4 alkyl, hydroxy C1-C4 alkyl, H, halo, oxo, halo C1-C4 alkyl and -CO2H; and m is 0 or 1; or R 5 Select from the following structures: Where R 5d and R 5d’ Independently selected from H, halo, haloC1-C4 alkyl and C1-C4 alkyl.

2. The use according to claim 1, wherein the compound has formula (II): Where R 1 , R 2 , R 3 , R 4 and R 5 As defined in claim 1.

3. The use according to claim 1, wherein the compound has formula (III): wherein n is 0, 1 or 2; and R 1 , R 2 , R 3 , R 4 and R 5 As defined in claim 1.

4. The use according to any one of claims 1 to 3, wherein R 2 and R 3 At least one of them is H.

5. The use according to any one of claims 1 to 3, wherein R 1 Yes – OCF3 or CF3.

6. The use according to claim 4, wherein R 1 Yes – OCF3 or CF3.

7. The use according to claim 1, wherein the compound is selected from: 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)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-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)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin-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)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5,5-difluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)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)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methylpyridazin-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)phenol; (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 3-methyl-2-(6-((pyrrolidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((pyrrolidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((pyrrolidin-2-ylmethyl)amino)pyridazin-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)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(2-hydroxy-2-methylpropoxy)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazin-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)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; 2-(6-((2-hydroxycyclopentyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (cis)-2-(6-((2-hydroxycyclopentyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (trans)-2-(6-((2-hydroxycyclopentyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 3,5-Dichloro-2-(6-((2-hydroxyethyl)amino)pyridazin-3-yl)phenol; 2-(6-((2-hydroxyethyl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 3,5-Dichloro-2-(6-((2,2,2-trifluoroethyl)amino)pyridazin-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)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((cis-3-hydroxycyclobutyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Chloro-2-(6-((3-hydroxycyclobutyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol 3-Chloro-2-(6-((trans-3-hydroxycyclobutyl)amino)pyridazin-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)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 5-chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridazin-3-yl)-3-(trifluoromethyl)phenol; 3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-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)-3,5-bis(trifluoromethyl)phenol; (R)-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3,5-bis(trifluoromethyl)phenol; 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-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)pyridazin-3-yl)-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)pyridazin-3-yl)amino)piperidine-2-carboxylic acid; 3-methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridazin-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)phenol; 3,5-Dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-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)pyridazin-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)pyridazin-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)pyridazin-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)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 5-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)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)pyridazin-3-yl)-3-(trifluoromethyl)phenol; (S)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-(trifluoromethyl)phenol; (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-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-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (R)-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-5-methylpyridazin-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-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-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-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)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)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-2-one; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-2-one; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-2-one; 2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((2-fluoro-3-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidin-2-one; (S)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidin-2-one; (R)-5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)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)piperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-(trifluoromethyl)cyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-(trifluoromethyl)cyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 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)amino)-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)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol; 5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)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)pyridazin-3-yl)phenol; (S)-5-chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol; (R)-5-chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol; 2-(6-((2-hydroxy-2-methylpropyl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((2-hydroxy-2-methylpropyl)amino)-4-methylpyridazin-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)pyridazin-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)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (R)-3-methyl-2-(6-(((4-methylmorpholin-3-yl)methyl)amino)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-methylpropyl)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)phenol; (R)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol HCl-salt (R)-3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol HCl-salt (S)-3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol HCl-salt; 2-(6-((1-hydroxy-2-methylpropan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-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-methylpyridazin-3-yl)-5-(trifluoromethoxy)phenol; 2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenol; (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenol; (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenol; 3-methyl-2-(6-((octahydroindolizin-8-yl)amino)pyridazin-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; 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; 3-methyl-2-(6-((8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1S,2S,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1S,2R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1S,2R,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1S,2S,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1R,2S,5S)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1R,2S,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,2S,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,2R,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,2S,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,2R,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]oct-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-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,6R)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,6S)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,6S)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol; (R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol; 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol; (1S,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol; (1S,2R,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol; (1S,2S,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol; (1S,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol; (1R,2R,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol; (1R,2S,3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol; (1R,2R,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol; (1R,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol; (S)-2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazin-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)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 3-Methyl-2-(6-((2-methylpiperidin-3-yl)amino)pyridazin-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)pyridazin-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; 2-(6-(((S)-1-((R)-2-hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((S)-1-((S)-2-hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((R)-1-((R)-2-hydroxypropyl)piperidin-3-yl)amino)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,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)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)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3S,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5R)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-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)-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)pyridazin-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-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)-phenol; (S)-2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)-phenol; (R)-2-(6-((1-ethylpiperidin-3-yl)amino)-5-methylpyridazin-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)pyridazin-3-yl)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)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide; (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide; 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)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide TFA salt; (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide TFA salt; or a pharmaceutically acceptable salt thereof.

8. The use according to claim 7, wherein the compound is selected from: 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; and (S)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol.

9. The use according to claim 7, wherein the compound is selected from: 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; and 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol.

10. The use according to claim 7, wherein the compound is selected from: 2-(6-((3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; and 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol.

11. The use according to claim 7, wherein the compound is selected from: 2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; (R)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; and (S)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol.

12. The use according to claim 7, wherein the compound is selected from: 2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; and (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol.

13. The use according to any one of claims 1 to 12, wherein the medicament is administered in combination with one or more therapeutic agents.

14. The use according to claim 13, wherein the one or more therapeutic agents are independently selected from farnesoid X receptor agonists; anti-steatosis agents; anti-fibrotic agents; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiotherapy and surgery; urate-lowering therapy; anabolic agents and cartilage regeneration therapy; blockers of IL-17; complement inhibitors; Bruton's tyrosine kinase inhibitors; Toll-like receptor inhibitors; CAR-T therapy; antihypertensive agents; cholesterol-lowering agents; leukotriene A4 hydrolase inhibitors; SGLT2 inhibitors; β2-agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs; acetylsalicylic acid drugs; regenerative therapy treatments; cystic fibrosis treatments; and atherosclerosis treatments.

15. The use according to any one of claims 1 to 14, wherein the disease or disorder is selected from: an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease.

16. The use according to any one of claims 1 to 14, wherein the disease or disorder is selected from: autoinflammatory febrile syndrome, liver-related diseases / disorders, inflammatory arthritis-related disorders, kidney-related diseases, neuroinflammation-related diseases, cardiovascular / metabolic diseases / disorders, inflammatory skin diseases, wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases / disorders.

17. The use according to claim 16, wherein the disease or disorder is selected from the group consisting of cryptopyrin-associated periodic syndromes, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis, alcoholic liver disease, gout, pseudogout, osteoarthritis, rheumatoid arthritis, acute joint disease, chronic joint disease, hyperoxaluria, lupus nephritis, type I / type II diabetes and related complications, hypertensive nephropathy, hemodialysis-related inflammation, multiple sclerosis, brain infection, acute injury, neurodegenerative disease, Alzheimer's disease, cardiovascular risk reduction, hypertension, atherosclerosis, type I and type II diabetes and related complications, peripheral arterial disease, acute heart failure, hidradenitis suppurativa, acne, colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis.

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