RU2826735C2 - Nlrp3 inflammasome inhibitors - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to a compound of a certain structure or a pharmaceutically acceptable salt thereof, to a pharmaceutical composition having inhibitory activity on the NLRP3 inflammasome signaling pathway, and to the use of said compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or disorder, wherein signal transmission mediated by NLRP3 promotes a pathological process and/or manifestation of symptoms and/or progression of said disease or disorder. Compound of formula (I)

(I),

or a pharmaceutically acceptable salt thereof, where R¹ is Cl, CH₃, -OCF₃ or CF₃, R² is H, halogen, C₁-C₄alkyl or halogen-C₁-C₄alkyl, R³, R⁴ are H, CN, C₁-C₄alkyl or halogen-C₁-C₄alkyl, Z is -O- or -NH-(CH₂)_n-, where n equals 0, 1 or 2, R⁵ is selected from the following structures:

,

where R^5a is independently selected from C₁-C₄alkyl, hydroxy-C₁-C₄alkyl and H, and R^5b is independently selected from -OH, C₁-C₄alkyl, hydroxy-C₁-C₄alkyl, H, halogen, oxo, halogen-C₁-C₄alkyl and -CO₂H, and m is 0 or 1, or R⁵ is selected from the following structures:

,

where R^5d is independently selected from H, halogen, halogen-C₁-C₄alkyl and C₁-C₄alkyl. Pharmaceutical composition having inhibitory activity on the inflammasome signaling pathway based on NOD-like receptor protein 3 (NLRP3), containing a therapeutically effective amount of the above compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers. Use of said compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or disorder, wherein signal transmission mediated by NLRP3 promotes a pathological process and/or manifestation of symptoms and/or progression of said disease or disorder.

EFFECT: said group of inventions can be used to inhibit the NLRP3 inflammasome signaling pathway, treat or prevent diseases and/or disorders associated with NLRP3.

9 cl, 104 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to novel pyridazin-3-ylphenol compounds that are useful as inhibitors of the NOD-like receptor protein 3 (NLRP3) inflammasome signaling pathway. The present invention also relates to methods for preparing said compounds, pharmaceutical compositions containing said compounds, methods for using said compounds in the treatment of various diseases and disorders, and medicinal products containing them, and their use in diseases and disorders mediated by NLRP3.

BACKGROUND OF THE INVENTION

NOD-like receptor protein 3 (NLRP3) is a gene encoding a protein: the protein belongs to the nucleotide-binding 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 aseptic inflammatory danger signals, NLRP3 interacts with the adaptor protein apoptosis-associated speck-like regulatory protein (ASC) and procaspase-1 to form the NLRP3 inflammasome. Activation of the NLRP3 inflammasome then leads to the release of proinflammatory cytokines IL-1β (interleukin-1β) and IL-18 (interleukin-18) and, if dysregulated, can cause the pathological process in a number of disease development situations.

Activation of the NLRP3 inflammasome typically requires two steps. The first step involves a priming signal in which pathogen-activated molecular patterns (PAMPs) or danger-activated molecular patterns (DAMPs) are recognized by Toll-like receptors, leading to activation of nuclear factor kappa B (NF-κB)-mediated signaling, which in turn activates transcription of inflammasome-associated components, including inactive NLRP3 and pro-IL-1β (prointerleukin-1β) (Bauernfeindet al. J. Immunol.2009, 183, 787-791; Franchiet al Nat. Immunol.2012, 13, 325-332, Franchiet al J. Immunol.2014, 193, 4214–4222). The second step is the oligomerization of NLRP3 and the subsequent assembly of NLRP3, ASC, and procaspase-1 into the inflammasome complex. This triggers the conversion of procaspase-1 to caspase-1 and the production and secretion of mature IL-1β and IL-18 (Kimet al. J. Inflamm.2015, 12, 41; Ozakiet al J. Inflamm. Res. 2015, 8, 15-27; Rabeonyet al. Eur. J. Immunol.2015, 45, 2847-2857).

Activation of the NLRP3 inflammasome has been found to be associated with various inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases, such as autoinflammatory febrile syndrome such as cryopyrin-associated periodic syndrome (CAPS) (Mortimeret 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, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease (Petraseket al. J. Clin. Invest. 2012, 122, 3476-89; Petrasek et al. Nat. Rev. Gastroenterol. Hepatol.2015, 12, 387-400; Mridhaet al. J. Hepatol.2017, 66, 1037-46); disorders associated with inflammatory arthritis, such as gout, pseudogout (chondrocalcinosis), osteoarthritis (Ridkeret al N. Engl. J. Med.2017, 377, 1119-31) and rheumatoid arthritis (Mathewset al Ann. Rheum. Dis.2014, 73, 1202-10), acute or chronic arthropathy; kidney-related diseases such as hyperoxaluria (Knaufet al. Kidney Int. 2013, 84, 895-901), lupus nephritis, hypertensive nephropathy (Krishnan et alBr. J. Pharmacol. 2016, 173, 752-65), hemodialysis-associated inflammation, and diabetic nephropathy, which is a kidney-related complication of diabetes mellitus (type 1 and type 2 diabetes), also called diabetic kidney disease (Shahzadet al Kidney Int.2015, 87, 74-84). Emerging studies have suggested that the involvement of increased IL-1β and IL-18 production by the NLRP3 inflammasome may contribute to the onset and progression of various diseases, such as disorders associated with neuroinflammation, e.g., brain infection, acute injury, multiple sclerosis, Alzheimer's disease and neurodegenerative diseases (Shaoet al. Front. Pharmacol. 2015, 6, 262); cardiovascular/metabolic disorders/diseases, e.g. cardiovascular risk reduction (CvRR), atherosclerosis, type I and type II diabetes mellitus and its associated complications (eg, nephropathy, retinopathy), peripheral arterial disease (PAD), acute heart failure and hypertension (Ridker et alN. Engl. J. Med. 2017, 377, 1119-31; Vandanmasgar et al Nat. Med.2011, 17, 179-88; Huet al. Proc. Natl. Acad. Sci.. 2015, 112, 11318-23; Antonopoulos et al Curr. Opin. Pharmacol.2017, 39, 1-8; Toldo Set al Nat. Rev. Cardiol. 2018, 15, 203-214); wound healing and scar formation; inflammatory skin diseases, such as acne, hidradenitis suppurativa (Sweeneyet al Br. J. Dermatol. 2015, 173, 1361), asthma, sarcoidosis, age-related macular degeneration; cancer-related diseases/disorders, such as myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis, lung cancer, colon cancer (Ridkeret al Lancet 2017, 390, 1833-42; Derangere et al Cell. Death Differ.2014, 21, 1914-24, Gelfoet al Oncotarget2016, 7, 72167-83, Baixorcaet al Blood2016, 128, 2960-75; Careyet al Cell. Rep.2017, 18, 3204-18). Those diseases/disorders that have an immune or inflammatory nature are usually difficult to diagnose or treat effectively. Most treatments involve treating symptoms, slowing the progression of the disease/disorder, lifestyle changes, and surgery as a last resort (e.g., open-heart surgery for advanced atherosclerosis). Recent studies have linked mitochondrial dysfunction and NLRP3 activation in diseases associated with neuroinflammation, such as Parkinson's disease (Sarkaret al npj parkinson's disease2017, 3:30; Zhouet al Nature, 2011, 469, 221). One of the main problems associated with mitochondrial modulators is their poor metabolic stability; therefore, there is a need for selective and stable inhibitors in neuroinflammation of this nature (Leeet al Eur J Org Chem. 2017, 141, 240).

Therefore, there is a need for inhibitors of the NLRP3 inflammasome signaling pathway to provide new and/or alternative treatments for these inflammasome-associated diseases/disorders and others such as autoinflammatory febrile syndrome, which is a cryopyrin-associated periodic syndrome (e.g., CAPS), sickle cell disease, chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, hyperoxaluria, pseudogout (chondrocalcinosis), type I/type II diabetes mellitus and its associated complications (eg, nephropathy, retinopathy), disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions based on them and combinations thereof, wherein these compounds inhibit the NLRP3 inflammasome signaling pathway. The present invention further provides methods for treating or preventing a disease and/or disorders associated with NLRP3, comprising administering to a subject in need thereof an effective amount of the compounds of the present invention or a pharmaceutically acceptable salt thereof.

Various embodiments of the present invention are described herein.

In certain aspects, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I),

Where

R ¹ is Cl, CH ₃ , -OCF ₃ or CF ₃ ;

R ² is H, halogen, C ₁ -C ₄ alkyl or halo-C ₁ -C ₄ alkyl;

R ³ , R ⁴ are H, CN, C ₁ -C ₄ alkyl or halo-C ₁ -C ₄ alkyl;

Z represents -O- or -NH-(CH ₂ ) _n -, where n is 0, 1, or 2;

R ⁵ is mono- or bicyclic heterocyclyl optionally substituted with 1-2 substituents independently selected from C ₁ -C ₄ alkyl, halo-C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl, -OH, halogen, oxo and -CO ₂ H; or

R ⁵ is aryl or heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, halo-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl and -SO ₂ NH ₂ ; or

R ⁵ is C ₃ -C ₆ cycloalkyl optionally substituted with 1-3 substituents independently selected from C ₁ -C ₄ alkyl, halogen, halo-C ₁ -C ₄ alkyl and -OH; or

R ⁵ is C ₂ -C ₆ alkyl substituted with 1 or more substituents independently selected from -OH, C ₁ -C ₄ alkoxy, halogen, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ .

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 subformulas disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is useful for treating diseases and/or disorders associated with NLRP3 activity.

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 subformulas disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents.

In another aspect, the present invention provides a combination, in particular a pharmaceutical combination, as disclosed herein, for use as a medicinal product.

In another aspect, the present invention provides a compound of formula (I) or its subformulas disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder in which NLRP3-mediated signaling contributes to the pathological process and/or the manifestation of symptoms and/or the progression of said disease or disorder.

In another aspect, the present invention provides a method of treating a disease or disorder in which NLRP3-mediated signaling contributes to the pathological process and/or the manifestation of symptoms and/or the progression of said disease or disorder, comprising administering a therapeutically effective amount of a compound of formula (I) or its subformulas disclosed herein, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method for inhibiting NLRP3 inflammasome activity. in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I) or its subformulas disclosed herein, or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to the use of a compound of formula (I) or its subformulas disclosed herein, or a pharmaceutically acceptable salt thereof, as a medicament.

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

In another aspect, the present invention also provides a compound of formula (I) or its subformulas disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases.

DETAILED DESCRIPTION OF THE INVENTION

Thus, the present invention provides a compound of formula (I),

(I),

Where

R ¹ is Cl, CH ₃ , -OCF ₃ or CF ₃ ;

R ² is H, halogen, C ₁ -C ₄ alkyl or halo-C ₁ -C ₄ alkyl;

R ³ , R ⁴ are H, CN, C ₁ -C ₄ alkyl or halo-C ₁ -C ₄ alkyl;

Z represents -O- or -NH-(CH ₂ ) _n -, where n is 0, 1, or 2;

R ⁵ is mono- or bicyclic heterocyclyl optionally substituted with 1-2 substituents independently selected from C ₁ -C ₄ alkyl, halo-C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl, -OH, halogen, oxo and -CO ₂ H; or

R ⁵ is aryl or heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, halo-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl and -SO ₂ NH ₂ ; or

R ⁵ is C ₃ -C ₆ cycloalkyl optionally substituted with 1-3 substituents independently selected from C ₁ -C ₄ alkyl, halogen, halo-C ₁ -C ₄ alkyl and -OH; or

R ⁵ is C ₂ -C ₆ alkyl substituted with 1 or more substituents independently selected from -OH, C ₁ -C ₄ alkoxy, halogen, -NH ₂ , -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ .

Definitions

For the purpose of interpreting this description, the following definitions shall apply unless otherwise stated and, where appropriate, terms used in the singular shall also include the plural and vice versa.

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

As used herein, the term "C ₂ -C ₆ alkyl" refers to a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing no unsaturation, containing from two to six carbon atoms, and which is attached to the rest of the molecule by a single bond. "C ₂ -C ₆ alkyl" as defined herein is optionally substituted with 1 or more substituents, preferably 1 to 13 substituents, more preferably 1 to 8 substituents. More preferably, no more than 7 substituents. The term "C ₁ -C ₄ alkyl" should be construed accordingly. Examples of C ₂ -C ₆ alkyl include, but are not limited to, ethyl, n- propyl, 1-methylethyl ( iso -propyl), n -butyl, n -pentyl, and 1,1-dimethylethyl ( tert -butyl).

As used herein, the term "halo- _C1 - _C4 alkyl" or "halo- _C1 - _C4 alkyl" refers to a _C1 - _C4 alkyl radical, as defined above, substituted with one or more halogen atom radicals, as defined above. Examples of halo- _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.

As used herein, the term "C ₁ -C ₄ alkoxy" refers to a radical of the formula -OR _a , wherein R _a is a C ₁ -C ₄ alkyl radical, as generally defined above. Examples of "C ₁ -C ₄ alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy.

As used herein, the term "hydroxy- _C1 - _C4 alkyl" refers to a C1 _{- C4} alkyl radical wherein one of the hydrogen atoms of the _C1 - _C4 alkyl radical is replaced with OH. Examples of hydroxy- _C1 - _C4 alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, and 4-hydroxybutyl.

As used herein, the term "halogen atom" or "halogen" refers to bromine, chlorine, fluorine or iodine.

As used herein, the term "heterocyclyl" or "heterocyclic" refers to a stable 5- or 6-membered non-aromatic monocyclic ring or bicyclic ring or polycyclic ring radical that contains 3-24, preferably 4-16, most preferably 5-10 ring atoms; wherein one or more, preferably one to four, in particular one or two ring atoms are a heteroatom selected from, for example, oxygen, sulfur and nitrogen (the remaining ring atoms are therefore carbon atoms). The term "heterocyclyl" excludes heteroaryl. A heterocyclic group may be attached to the rest of the molecule via a heteroatom selected from, for example, oxygen, sulfur, nitrogen or carbon. Heterocyclyl may include, for example, fused or bridged rings, as well as spirocyclic rings. For example, the term "heterocyclyl" may refer to a 5-7 membered monocyclic ring containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur. Examples of monoheterocyclyl include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolan, oxathianyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, piperazinyl, oxapinyl, oxaazepanyl, oxathianyl, thiepanyl, azepanyl, dioxepanyl and diazepanyl. Preferably, monoheterocyclyl is morpholino, pyrrolidine or piperidinyl. Examples of bicyclic heterocyclyl include, for example, azabicyclooctanyl or octahydroindolizinyl. According to the present invention, the term "heterocyclyl" substituted with a substituent "OH" also includes "heterocyclyl" wherein the heteroatom, for example N or S, is oxidized to give, for example, heterocyclyl N-oxide, heterocyclyl S-oxide or heterocyclyl S-dioxide. Examples of heterocyclyl N-oxide include piperidinyl N-oxide. 1-Methylpyrrolidine-1-oxide. Examples of heterocyclyl S-oxide or heterocyclyl S-dioxide include tetrahydro-2H-thiopyran-1-oxide, tetrahydro-2H-thiopyran-1,1-dioxide and tetrahydrothiophene-1-oxide.

As used herein, the term "heteroaryl" refers to a radical that is a 5- or 6-membered aromatic monocyclic ring that contains 1, 2, 3, or 4 heteroatoms individually selected from nitrogen, oxygen, and sulfur. The heteroaryl radical may be bonded via a carbon atom or a heteroatom. Examples of heteroaryl include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, or pyridyl.

As used herein, the term " _C3 - _C6 cycloalkyl" refers to a stable monocyclic, bicyclic, or tricyclic saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, containing from three to ten carbon atoms. The term "bicyclic cycloalkyl" also includes spirobicyclic cycloalkyl. Examples of monocyclic _C3 - _C6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic _C3 - _C10 cycloalkyl include, but are not limited to, bicyclo[1.1.1]pentane.

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

Unless otherwise specified, the term "compounds of the present invention" refers to compounds of formula (I) or subformulas thereof (such as a compound of formula (II), a compound of formula (III), or a compound of formula (III-A) as described herein) and their salts, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including those substituted with deuterium). The term "compounds of the (present) invention" or "a compound of the (present) invention" refers to a compound as defined in any of the embodiments specified below.

Various embodiments of the present invention are described herein, with the understanding that the features set forth in each embodiment can be combined with other features set forth to produce additional embodiments of the present invention.

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

In embodiment 2, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1, characterized by formula (II),

(II),

where R ¹ , R ² , R ³ , R ⁴ and R ⁵ are defined in embodiment 1.

In embodiment 3, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1, characterized by formula (III),

(III),

where n is 0, 1 or 2; and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are defined in embodiment 1.

In embodiment 3a and according to embodiment 3, the present invention provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, characterized by formula (III-A),

(III-A),

where R ¹ , R ² , R ³ , R ⁴ and R ⁵ are defined in embodiment 1.

In embodiment 4, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof according to embodiment 1, 2, 3 or 3a, wherein R ⁵ is mono- or bicyclic heterocyclyl optionally substituted with 1-2 substituents independently selected from C ₁ -C ₄ alkyl, halo-C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl, -OH, halogen, oxo and -CO ₂ H.

In embodiment 5, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof according to embodiment 4, wherein R ⁵ is selected from the following:

wherein R ^5a is independently selected from C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl and H; and R ^5b is independently selected from -OH, hydroxy-C ₁ -C ₄ alkyl, H, halogen, oxo, halo-C ₁ -C ₄ alkyl and -CO ₂ H; X is O or CH ₂ ; and m is 0 or 1.

In embodiment 5a and according to embodiment 5, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from the following:

,

wherein R ^5a is independently selected from C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl and H; and R ^5b is independently selected from -OH, C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl, H, halogen, oxo, halo-C ₁ -C ₄ alkyl and -CO ₂ H; X is O or CH ₂ ; and m is 0 or 1.

In embodiment 5b and according to embodiment 5 and 5b, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is as described herein above and the stereochemical configuration at the carbon atom labeled with "⃰" is (R) or (S). Preferably, if Z is -NH-(CH ₂ )n-, wherein n=1 or 2, the stereochemical configuration at the carbon atom labeled with "⃰" is (S). Preferably, Z is -O- or -NH-(CH ₂ )n-, wherein n=0, the stereochemical configuration at the carbon atom labeled with "⃰" is (R).

In embodiment 5c and according to embodiment 5, 5a and 5b, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is preferably selected from the following structures:

wherein R ^5a is independently selected from C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl and H; and R ^5b is independently selected from -OH, C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl, H, halogen, oxo, halo-C ₁ -C ₄ alkyl and -CO ₂ H; and m is 0 or 1.

In embodiment 5d and in accordance with embodiments 5, 5a, 5b and 5c, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is preferably selected from the following structures:

wherein R ^5a is independently selected from C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl and H; and R ^5b is independently selected from -OH, C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl, H, halogen, oxo, halo-C ₁ -C ₄ alkyl and -CO ₂ H; and m is 0 or 1.

In embodiment 5e and according to embodiments 5, 5a, 5b, 5c and 5d, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ preferably represents the following structure:

,

where R ^5a is independently selected from C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl and H.

In embodiment 6, the present invention provides a compound of any of formulae (I), (II), (III), and (III-A), or a pharmaceutically acceptable salt thereof according to embodiments 1, 2, 3, or 3a, wherein R ⁵ is aryl or heteroaryl optionally substituted with 1-2 substituents independently selected from halogen, halo-C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl, and -SO ₂ NH ₂ .

In embodiment 6a and according to embodiment 6, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is preferably selected from the following structures:

wherein R ^5c is independently selected from H, C ₁ -C ₄ alkyl and -SO ₂ NH ₂ ; and s is 0, 1 or 2.

In embodiment 6b and according to embodiment 6, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is preferably selected from the following structures:

where R ^5c is independently selected from H, C ₁ -C ₄ alkyl and -SO ₂ NH ₂ .

In embodiment 6c and according to embodiments 6 and 6b, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is preferably selected from the following structures:

where R ^5c is independently selected from H and C ₁ -C ₄ alkyl.

In embodiment 7, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof according to embodiment 1, 2, 3 or 3a, wherein R ⁵ is C ₃ -C ₆ cycloalkyl optionally substituted with 1-3 substituents independently selected from C ₁ -C ₄ alkyl, halogen, halo-C ₁ -C ₄ alkyl and -OH.

In embodiment 7a and according to embodiment 7, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted with 1-3 substituents independently selected from C ₁ -C ₄ alkyl, halogen, halo-C ₁ -C ₄ alkyl and -OH.

In embodiment 7b and according to embodiment 7 and 7a, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is preferably selected from the following structures:

,

where R ^5e , R ^5e ', R ^5d , R ^5d ' and R ^5f are independently selected from H, C ₁ -C ₄ alkyl, halogen, halo-C ₁ -C ₄ alkyl and -OH.

In embodiment 7c and according to embodiment 7, 7a and 7b, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is preferably selected from the following structures:

where R ^5d and R ^5d ' are independently selected from H, halogen, halo-C ₁ -C ₄ alkyl and C ₁ -C ₄ alkyl.

In embodiment 7d and in accordance with embodiment 7, 7a, 7b and 7c, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is preferably selected from the following structures:

where R ^5d and R ^5d ' are independently selected from H, halogen, halo-C ₁ -C ₄ alkyl and C ₁ -C ₄ alkyl.

In embodiment 8, the present invention provides a compound of any of formulae (I), (II), (III), and (III-A), or a pharmaceutically acceptable salt thereof according to embodiments 1, 2, or 3, wherein R ⁵ is C ₂ -C ₆ alkyl substituted with 1 or more substituents independently selected from -OH, C ₁ -C ₄ alkoxy, halogen, -NH ₂ , -NH(C ₁ -C ₄ alkyl), and -N(C ₁ -C ₄ alkyl) ₂ .

In embodiment 8a and according to embodiment 8, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is preferably selected from the following structures:

where R ^5h is selected from -NH ₂ , -OH, -NH(C ₁ -C ₄ alkyl) and -N(C ₁ -C ₄ alkyl) ₂ .

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

In embodiment 9a and according to embodiment 9, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ² is halogen, C ₁ -C ₄ alkyl or halo-C ₁ -C ₄ alkyl; and R ³ is H.

In embodiment 9b and according to embodiment 9, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ² is H; and R ³ is CN, C ₁ -C ₄ alkyl or halo-C ₁ -C ₄ alkyl.

In embodiment 10, the present invention provides a compound of any of formulas (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof according to embodiments 1-9, wherein R ¹ is -OCF ₃ or -CF ₃ .

In embodiment 10a and according to embodiment 10, the present invention provides a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, wherein R ¹ is CF ₃ .

In embodiment 11, the present invention provides a compound of any one of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof according to embodiment 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;

TFA salts of 5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

TFA salts of (S)-5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

TFA salts of (R)-5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

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;

TFA salts of 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

TFA salts of 2-(4,5-dimethyl-6-(((S)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

TFA salts of 2-(4,5-dimethyl-6-(((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

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;

TFA salts of 3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

TFA salts of (S)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

TFA salts of (R)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

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;

TFA salts of 2-(6-((1,3-dimethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

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-(trifluoro

methyl)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;

HCl salt of 3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

HCl salt of (R)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

HCl salt of (S)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

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-((octahydroindolyzin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

3-methyl-2-(6-(((8R,8aR)-octahydroindolyzin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

3-methyl-2-(6-(((8R,8aS)-octahydroindolyzin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

3-methyl-2-(6-(((8S,8aR)-octahydroindolyzin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

3-methyl-2-(6-(((8S,8aS)-octahydroindolyzin-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]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

2-(6-(((3R,6R)-6-(hydroxymethyl)-1-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;

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

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

TFA salts of 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide;

TFA salts of (3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide;

TFA salts of (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide

or a pharmaceutically acceptable salt thereof.

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

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

(R)-2-(4-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;

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

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

(S)-2-(6-(((1-ethylpyrrolidin-2-yl)methyl)amino)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;

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

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

(R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-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;

(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;

(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;

(R)-2-(6-(((4,4-difluoropyrrolidin-2-yl)methyl)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-((trans-3-hydroxycyclobutyl)amino)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;

(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;

TFA salts of (R)-5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

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

TFA salts of 2-(4,5-dimethyl-6-(((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

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

(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;

TFA salts of (R)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol;

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

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

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

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

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

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

TFA salts of 2-(6-((1,3-dimethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol;

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

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

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

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

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

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

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

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

(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;

(R)-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-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

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

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

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

5-chloro-2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)phenol;

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

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

(R)-5-chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)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;

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

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

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

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

HCl salt of (S)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

2-(6-((1-hydroxy-2-methylpropan-2-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-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-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-(((8R,8aR)-octahydroindolyzin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol;

3-methyl-2-(6-(((8S,8aS)-octahydroindolyzin-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;

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

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

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

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

2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-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,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;

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

(1S,2R,3S)-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;

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

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

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

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

2-(6-(((R)-1-((R)-2-hydroxypropyl)piperidin-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-(((3S,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-(((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-(((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;

(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;

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

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

(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;

TFA salts of (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide

or a pharmaceutically acceptable salt thereof.

In embodiment 11b, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1, 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.

In embodiment 11c, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1, 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.

In embodiment 11d, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1, 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.

In embodiment 11e, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1, 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.

In embodiment 11f, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1, 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.

In embodiment 11g, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1, 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.

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

In embodiment 13, the present invention relates to a combination comprising a therapeutically effective amount of a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof according to any of embodiments 1-11g and one or more therapeutic agents.

In embodiment 14, the present invention relates to a combination comprising a therapeutically effective amount of a compound of any one of formulae (I), (II), (III), and (III-A), or a pharmaceutically acceptable salt thereof, according to embodiment 13, wherein the one or more therapeutic agents are independently selected from farnesoid X receptor (FXR) agonists; anti-steatosis agents; anti-fibrotic agents; JAK inhibitors; immune checkpoint inhibitors, including PD1 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, or PDL1 inhibitors; chemotherapy, radiation therapy, and surgical procedures; urate lowering therapies; anabolic and cartilage regenerative agents; IL-17 blockade agents; complement inhibitors; Bruton tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors (TLR7/8 inhibitors); CAR T-cell therapies; antihypertensive agents; cholesterol-lowering agents; leukotriene A4 hydrolase (LTAH4) inhibitors; SGLT2 inhibitors; β2-agonists; anti-inflammatory agents; non-steroidal anti-inflammatory drugs ("NSAIDs"); acetylsalicylic acid (ASA)-based drugs, including aspirin; paracetamol; regenerative therapy treatments; treatments for cystic fibrosis; or treatments for atherosclerosis.

In one embodiment, the present invention provides 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) or a pharmaceutically acceptable salt thereof 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.

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

In embodiment 16, the present invention relates to a compound according to any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof according to any of embodiments 1-11g, for use in the treatment of a disease or disorder in which NLRP3-mediated signaling contributes to the pathological process and/or the manifestation of symptoms and/or the progression of said disease or disorder.

In embodiment 17, the present invention relates to a method of treating a disease or disorder in which NLRP3-mediated signaling contributes to the pathological process and/or the manifestation of symptoms and/or the progression of said disease or disorder, comprising administering a therapeutically effective amount of a compound according to any of formulas (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof according to any of embodiments 1-11g.

In embodiment 18, the present invention relates to a compound of any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, according to any of embodiments 1-11g, for use according to embodiment 16, or to a method of treatment according to embodiment 17, wherein the disease or disorder is selected from inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g. cryopyrin-associated periodic syndrome), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, for example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In a particular aspect of embodiment 16, the present invention relates to a compound of any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is preferably selected from forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

In one embodiment, the present invention relates to a compound of any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof according to any of embodiments 1-11g, for use in the treatment of a disease or disorder selected from inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g. cryopyrin-associated periodic syndrome), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, for example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In a particular aspect of embodiment 18, the present invention relates to a compound of any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is preferably selected from forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

In embodiment 19, the present invention relates to a method for inhibiting the activity of NLRP3 inflammasome in a subject in need thereof, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of any of formulas (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof according to any of embodiments 1-11g.

In one embodiment, the present invention provides 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 of Formulas (I), (II), (III), and (III-A), or a pharmaceutically acceptable salt thereof, 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.

In one embodiment, the present invention relates to a method of treating a disease or disorder selected from inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g., cryopyrin-associated periodic syndrome), sickle cell anemia, systemic lupus erythematosus (SLE), liver-related diseases/disorders (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), inflammatory arthritis-related disorders (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, acute or chronic arthropathy), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, diabetic nephropathy, hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (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 scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis), wherein the method comprises administering to a subject a therapeutically effective amount of a compound of any of the formulas (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof 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. In particular, the disease or disorder is preferably selected from forms of autoinflammatory febrile syndrome (e.g. CAPS), sickle cell anemia, type I/II diabetes mellitus and its associated complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (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 scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

Depending on the choice of starting materials and procedures, the compounds may be present in the form of one of the possible stereoisomers or as mixtures thereof, for example as pure optical isomers, or as a mixture of stereoisomers such as racemates and mixtures of diastereoisomers, depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, mixtures of diastereoisomers and optically pure forms. Optically active ( R )- and ( S )-stereoisomers can be prepared using chiral synthons or chiral reagents or separated using conventional techniques. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included. Also intended in the present invention is the inclusion of any pseudo-asymmetric carbon atoms, represented herein as (r)- and (s)-, which are invariant under mirror reflection but are converted to their opposite by exchanging any two entities (PAC 1996, 68, 2193, Basic terminology of stereochemistry IUPAC recommendations 1996 ).

As used herein, the terms "salt" or "salts" refer to an acid addition salt or a base addition salt of a compound of the present invention. "Salts" include, in particular, "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 that are generally not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acidic and/or basic salts due to the presence of amino and/or carboxyl groups or similar groups.

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

Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.

Organic acids from which salts can be obtained 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.

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

Inorganic bases from which salts can be derived include, for example, ammonium salts and salts of metals from groups I-XII of the periodic table of elements. 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.

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, and the like. Specific organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

In another aspect, the present invention provides compounds of any of formulae (I), (II), (III), and (III-A) in the form of a salt which is acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, mucinate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenate, trifluoroacetate or xinafoate.

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

Any formula provided herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures depicted by the formulae provided herein, except that one or more atoms are replaced by an atom characterized by a selected atomic mass or mass number. Isotopes that can be included in the compounds of the present invention include, for example, isotopes of hydrogen.

In addition, the inclusion of certain isotopes, in particular deuterium (i.e., ² H or D), may provide certain therapeutic advantages due to increased metabolic stability, such as increased half-life in vivo, or a reduction in the required dose, or an improvement in the therapeutic index or tolerability. It is understood that deuterium in this context is considered as a substituent of the compound of formula (I). The concentration of deuterium can be determined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the abundance of an isotope and the natural abundance of said isotope. When a substituent in a compound of the present invention is designated as deuterium, such compound is characterized by an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation for 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.

In another aspect, the present invention provides a compound of formula (I),

(I),

or a pharmaceutically acceptable salt thereof, as defined herein, wherein R ⁵ is selected from the following:

where R ^5a , R ^5b , X and m are defined in embodiments 5, 5a - 5e, and one or more hydrogen atoms present in R ^5a and/or R ^5b may be replaced by a deuterium atom (including R ^5a or R ^5b may be a deuterium atom). For example, without limitation, deuterium may be included as follows:

.

In another aspect, the present invention provides a compound of formula (I),

(I),

or a pharmaceutically acceptable salt thereof, as defined herein, wherein if R ² , R ³ , R ⁴ are selected from the following: H, C ₁ -C ₄ alkyl or halo-C ₁ -C ₄ alkyl, then one or more hydrogen atoms present in said groups may be replaced by a deuterium atom. For example, without limitation, deuterium may be included as follows:

.

Other examples of isotopes that can be included in 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, respectively. Therefore, it should be understood that the present invention includes compounds in which one or more of any of the above isotopes are incorporated, 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 are present. Such isotopically labeled compounds are useful in metabolic studies (using ¹⁴ C), reaction kinetic studies (e.g., using 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 in the treatment of patients with radioactive isotopes. In particular, ¹⁸ F or a labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) or a pharmaceutically acceptable salt 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 a suitable isotopically labeled reagent in place of the unlabeled reagent previously used.

PHARMACEUTICAL COMPOSITION

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

As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, fillers, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, coloring agents, and combinations thereof, which should be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22 ^nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

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 elicit a biological or medical response in a subject, such as reducing or inhibiting the activity of an enzyme or protein, or ameliorating symptoms, alleviating conditions, slowing or delaying the progression of a disease, or preventing a 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, is effective to (1) at least partially alleviate, inhibit, prevent, and/or ameliorate a condition or disorder or disease (i) mediated by NLRP3, or (ii) associated with NLRP3 activity, or (iii) characterized by NLRP3 activity (normal or abnormal); or (2) reduce or inhibit NLRP3 activity; or (3) reduce or inhibit NLRP3 expression. 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 environment, is effective to at least partially reduce or inhibit NLRP3 activity or at least partially reduce or inhibit NLRP3 expression.

As used in this document, 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 another embodiment, the subject is a human.

As used herein, the terms "inhibit," "inhibition," or "inhibitory" refer to reducing the intensity or suppression of a given condition, symptom, or disorder, or disease, or to significantly reduce the basal activity for a biological activity or process. In particular, inhibition of NLRP3 or inhibition of the NLRP3 inflammasome signaling pathway involves reducing the ability of NLRP3 or the NLRP3 inflammasome signaling pathway to induce the production of IL-1-beta and/or IL-18. This may be achieved through mechanisms including, but not limited to, inactivation, destabilization, and/or alteration of the distribution of NLRP3.

As used herein, the term "NLRP3" is intended to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense strands of polynucleotides, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, various compounds, and active fragments thereof.

As used herein, the term "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or halting the progression of the disease or at least one of its clinical symptoms) or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be perceptible to the patient.

As used herein, the term "prevent," "causing prevention," or "preventing" any disease or disorder refers to the prophylactic treatment of a disease or disorder or the provision of a delay in the onset or progression of a disease or disorder.

As used in this document, a subject "needs" or is "in need of" treatment if such treatment will provide biological, medical, or quality-of-life benefit to such subject.

All methods described in this document may be performed in any suitable order unless otherwise indicated in this document or otherwise clearly contradicted by context. The use of any and all examples or introductory words preceding examples (e.g., "such as") provided herein are intended only to better explain the present invention and do not limit the scope of the present invention otherwise claimed.

Any asymmetric atom (eg carbon or the like) of the compound(s) of the present invention may be present in racemic or enantiomerically enriched form, for example in (R)-, (S)- or (R, S) configurations. 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 (R)- or (S)-configurations.

Accordingly, as used herein, a compound of the present invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, such as substantially pure geometric ( cis or trans ) stereoisomers, diastereoisomers, optical isomers (antipodes), racemates, or mixtures thereof.

Any resulting mixtures of stereoisomers may be separated on the basis of physicochemical differences of their constituents into pure or essentially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of the compounds of the present invention or intermediates can be resolved into optical antipodes by known methods, for example by separating their diastereoisomeric salts derived from an optically active acid or base and isolating the optically active acidic or basic compound. In particular, the basic moiety can thus be used to resolve the compounds of the present invention into their optical antipodes, for example, by fractional crystallization of a salt formed with an optically active acid, for example, tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O, O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be separated by chiral chromatography, e.g. high performance liquid chromatography (HPLC) using a chiral adsorbent.

METHOD FOR SYNTHESISING COMPOUNDS ACCORDING TO THE PRESENT INVENTION

The compounds of the present invention may be prepared according to the definition of a compound of formula (I) or a pharmaceutically acceptable salt thereof by the routes described in the following schemes or examples. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or introductory words preceding examples (e.g., "such as") provided herein are intended only to better explain the present invention and do not impose a limitation on the scope of the present invention otherwise claimed. In the following general methods R¹, R², R³, R⁴, R⁵, halogen and Z are as previously defined in the above embodiments or are limited by the designations in the schemes. Unless otherwise indicated, the starting materials are commercially available or prepared by known methods.

Reaction scheme 1

The compounds of the present invention described herein can be prepared by the reaction sequence shown in Scheme 1 (below), whereby an appropriately substituted 3,6-dihalopyridazine (M1) is reacted with either a suitable amine (M2a) in the presence of a base, such as DIPEA, at elevated temperatures, typically 150°C to 180°C (optionally under microwave irradiation), to give the 6-halopyridazine-3-amine (M3a), or with a suitable alcohol (M2b) in the presence of a base, e.g. NaH, at low temperature, typically 0°C, to give 3-halo-6-alkoxypyridazine (M3b). Both intermediates, (M3a) or (M3b), are then subjected to a Suzuki cross-coupling reaction with a suitable boronate (M4) in the form of a boronic acid or boronic ester, e.g. 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, using a suitable palladium catalyst, such as Pd(PPh₃)₄, and an aqueous base, usually Na₂CO₃or NaHCO₃, in a miscible solvent such as DME or dioxane to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Scheme 1

Reaction scheme 2

Alternatively, the compounds of the present invention described herein can be prepared by the reaction sequence shown in Scheme 2 (below), whereby an appropriately substituted 3,6-dihalopyridazine (M1) is subjected to a Suzuki cross-coupling reaction with either a suitable boronate (M4) in the form of a boronic acid or a boronic ester, such as 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (path A), using a suitable palladium catalyst, such as Pd(PPh₃)₄or XantPhos-Pd-G2, and an aqueous base, usually Na₂CO₃or NaHCO₃, in a miscible solvent such as DME or dioxane to give 3-halopyridazine (M5), or similarly react with a boronate (M6) bearing a protecting group P on the phenol such as methyl or benzyl, (path B), to give a compound of formula 3-halopyridazine (M7). The intermediate (M5) is then reacted with a suitable amine (M2a) in the presence of a base, such as DIPEA, at elevated temperatures, typically from 150°C to 180°C (optionally under microwave irradiation), to yield a compound of formula (I) or a pharmaceutically acceptable salt thereof, whereby the intermediate (M7), treated in the same manner, yields the protected form (M8), which is then subjected to the action of typical cleavage agents such as BBr₃, or catalytic hydrogenation to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Scheme 2

Reaction scheme 3

Alternatively, the compounds of the present invention described herein can be prepared by the reaction sequence shown in Scheme 3 (below), whereby an appropriately substituted intermediate (M5) is subjected to a Buchwald amination reaction with an appropriate amine (M2a) in the presence of a suitable palladium catalyst, such as _PdCl2 (dppf), and a base, typically LiOtBu, in a non-protic solvent such as toluene, to yield a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Scheme 3

The methods can be extended to prepare a compound of any of the formulas (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, described herein. Depending on the starting materials and the route chosen, as indicated in Scheme 1, Scheme 2 or Scheme 3 above, one skilled in the art will understand how to prepare a compound of formula (I) or a pharmaceutically acceptable salt thereof. Certain variations or alternative methods are described herein below in the experimental section.

The present invention further includes any variant of the processes of the present invention in which an intermediate product obtained in any step thereof is used as a starting material and the remaining steps are carried out, or in which the starting materials are obtained in situ under the reaction conditions, or in which the components of the reaction mixture are used in the form of their salts or optically pure material. 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.

In another aspect, 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 a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition may be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration) and rectal administration. Topical administration may also refer to inhalation or intranasal use. The pharmaceutical compositions of the present invention may be prepared 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 compositions are tablets or gelatin capsules containing the active ingredient together with one or more of:

a) thinners, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, for example silicon dioxide, talc, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; also in the case of tablets

c) binding agents, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary

d) leavening agents, for example, types of starch, agar, alginic acid or its sodium salt or effervescent mixtures; and

e) absorbents, colorants, flavorings and sweeteners.

METHOD OF USE OF THE PRESENT INVENTION

There is evidence for a role for NLRP3-induced IL-1 and IL-18 in inflammatory responses that occur in association with or as a result of a variety of disorders (Menu et al, Clinical and Experimental Immunology , 2011, 166, 1-15; Strowig et al, Nature , 2012, 481, 278-286). Mutations in NLRP3 have been found to be responsible for 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 group of inherited diseases characterized by recurrent fever and inflammation and consists of three autoinflammatory disorders that form a clinical continuum. These diseases, in order of increasing severity, are familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurologic cutaneous articular syndrome (CINCA; also called neonatal multisystem inflammatory disease, NOMID), and have all been shown to be caused by gain-of-function mutations in the NLRP3 gene, leading to increased secretion of IL-1-beta. NLRP3 has also been implicated in a variety of autoinflammatory diseases, including pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), Sweet's syndrome, chronic nonbacterial osteomyelitis (CNO), and acne vulgaris (Cook et al, Eur. J. Immunol ., 2010, 40, 595-653).

NLRP3 has been shown to be involved in a variety of autoimmune diseases, including but not limited to multiple sclerosis, type 1 diabetes mellitus (T1D), psoriasis, rheumatoid arthritis (RA), Behçet's disease, Schnitzler 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 a number of lung diseases, including chronic obstructive pulmonary disease (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 has also been suggested to play a role in a variety of central nervous system conditions, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington's disease, cerebral malaria, brain injury due to 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 various metabolic diseases, including type 2 diabetes mellitus (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-1beta has also been suggested in 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).

Other diseases in which NLRP3 has been shown to be involved include ocular diseases such as wet and dry forms of 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 ., 2017, 95(8), 803–8), noninfectious uveitis and optic nerve injury (Puyang et al. Sci. Rep . 2016, 6, 209–98); liver diseases including nonalcoholic steatohepatitis (NASH) and acute alcoholic hepatitis (Henao-Meija et al, Nature , 2012, 482, 179–185); inflammatory reactions in the lungs and skin (Primiano et al. J. Immunol . 2016, 197(6), 2421–33), including contact hypersensitivity (such as bullous pemphigoid (Fang et al. J Dermatol Sci . 2016, 83(2), 116–23)), atopic dermatitis (Niebuhr et al. Allergy, 2014, 69(8), 1058–67), hidradenitis suppurativa (Alikhan et al. J. Am. Acad. Dermatol ., 2009,60(4), 539–61), and sarcoidosis (Jager et al. Am. J. Respir. Crit. Care Med., 2015, 191, A5816); inflammatory reactions in joints (Braddock et al, Nat. Rev. Drug Disc , 2004, 3, 1-10); amyotrophic lateral sclerosis (Gugliandolo et al. Int. J. Mol. Sci ., 2018, 19(7), E1992); cystic fibrosis (Iannitti et al. Nat. Commun ., 2016, 7, 10791); stroke (Walsh et al, Nature Reviews , 2014, 15, 84-97); chronic kidney disease (Granata et al. PLoS One 2015, 10(3), eoi22272); and inflammatory bowel diseases, including ulcerative colitis and Crohn's disease (Braddock et al., Nat. Rev. Drug Disc , 2004, 3, 1-10; Neudecker et al. J. Exp. Med . 2017, 214(6), 1737-52; Lazaridis et al. Dig. Dis. Sci . 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).

Activation of the NLRP3 inflammasome has been shown to enhance some 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).

NLRP3 has also been implicated in the pathogenesis of many forms of cancer (Menu et al, Clinical and Experimental Immunology, 2011, 166, 1-15). For example, several previous studies have suggested a role for IL-1beta in cancer invasiveness, growth, and metastasis, and inhibition of IL-1beta with canakinumab has been shown to reduce lung cancer incidence and overall cancer mortality in a randomized, double-blind, placebo-controlled trial (Ridker et al. Lancet ., 2017, 390(10105), 1833-42). Inhibition of the NLRP3 inflammasome or IL-1-beta has also been shown to inhibit the proliferation and migration of lung cancer cells in vitro (Wang et al. Oncol Rep., 2016, 35(4), 2053-64). A role for the NLRP3 inflammasome has been suggested in myelodysplastic syndromes, 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 glioma (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 21(3), 144-51) and head and neck squamous cell carcinoma (Huang et al. J. Exp. Clin. Cancer Res ., 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 ., 2017, 36(1), 81), and activation of the NLRP3 inflammasome in peripheral nerves contributes to chemotherapy-induced neuropathic pain (Jia et al. Mol. Pain ., 2017, 13, 1-11). NLRP3 has also been shown to be required for the efficient control of viruses, bacteria, and fungi.

Activation of NLRP3 leads to cell pyroptosis, a feature that plays an important role in clinical disease manifestation (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). Thus, NLRP3 inhibitors are expected to block pyroptosis as well as the release of proinflammatory cytokines (e.g. IL-1-beta) from the cell.

Compounds of any of formulae (I), (II), (III) and (III-A), or a compound according to any of the previous embodiments, or a compound according to any of the illustrative examples (e.g., from example 001 to example 104 disclosed herein) in free form or in the form of a pharmaceutically acceptable salt exhibit valuable pharmacological properties, such as NRLP3 inhibitory properties in the NLRP3 signaling pathway, such as indicated by the in vitro tests given in the next section and are therefore indicated for therapy or for use as research chemicals, e.g. as pharmacologically active compounds.

The compounds of the present invention may be useful in the treatment of an indication selected from inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as diseases, disorders or conditions in which NLRP3-mediated signaling contributes to the pathological process and/or the manifestation of symptoms and/or progression and which may be susceptible to NLRP3 inhibition and which can be treated or prevented according to any of embodiments 1-19 or with a compound according to any of the illustrative examples (e.g., from example 001 to example 104 disclosed herein) of the present invention, including the following.

I. Inflammation, including inflammation resulting from an inflammatory disorder, such as an autoinflammatory disorder, inflammation that occurs as a symptom of a noninflammatory disorder, inflammation that occurs as a result of an infection, or inflammation due to trauma, injury, or an autoimmune reaction. Examples of inflammation that can be treated or prevented include inflammatory responses that occur in association with or as a result of the following:

(a) a skin condition 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 forms or alopecia;

(b) a joint condition such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, microcrystalline arthropathy (eg, pseudogout, gout) or seronegative spondyloarthropathy (eg, ankylosing spondylitis, psoriatic arthritis or Reiter's disease);

(c) a muscle condition such as polymyositis or myasthenia gravis;

(d) a gastrointestinal condition 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 allergy that may have effects away from the gut (e.g. migraine, rhinitis or eczema);

(e) a respiratory system condition such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, extrinsic or dust-induced asthma and in particular chronic or inveterate asthma such as late-onset asthma and airways hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, chronic caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, rhinitis sicca, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis such as 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;

(f) a vascular condition such as atherosclerosis, Behcet's disease, vasculitis, or Wegener's granulomatosis;

(g) an immunopathological condition, such as an autoimmune condition such as systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type 1 diabetes mellitus, idiopathic thrombocytopenic purpura, or Graves' disease;

(h) an ocular condition such as uveitis, allergic conjunctivitis, or vernal conjunctivitis;

(i) a nervous condition such as multiple sclerosis or encephalomyelitis;

(j) an infectious 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 haemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis infection, Mycobacterium avium-intracellulare complex infection, Pneumocystis carinii pneumonia, orchitis/epididymitis, legionellosis, Lyme disease, influenza A virus infection, Epstein-Barr virus infection, viral encephalitis/aseptic meningitis, or pelvic inflammatory disease;

(k) a renal condition such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, uremia, or nephritic syndrome;

(l) a lymphatic condition such as Castleman's disease;

(m) a condition of the immune system or a condition in which the immune system is involved, such as hyper-IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease;

(n) a liver condition such as chronic active hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), or primary biliary cirrhosis;

(o) cancer, including the forms of cancer listed below in this document;

(p) burn, wound, trauma, hemorrhage or stroke;

(q) exposure to radiation; and/or

(r) obesity; and/or

(s) pain such as inflammatory hyperalgesia.

II. An inflammatory disease, including inflammation resulting from an inflammatory disorder, such as an autoinflammatory disease such as forms of cryopyrin-associated periodic syndrome (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean fever (FMF), neonatal multisystem inflammatory disease (NOMID), Majid syndrome, pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), adult-onset Still's disease (AOSD), haploinsufficiency of A20 (HA20), childhood granulomatous arthritis (PGA), PLCG2-associated antibody deficiency with immune dysregulation (PLAID), autoinflammation and PLCG2-associated antibody deficiency with immune dysregulation (APLAID), or sideroblastic anemia with B-cell immunodeficiency, periodic fever episodes, and developmental delay (SIFD).

III. Immune diseases, such as autoimmune diseases such as acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), antisynthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular deficiency, autoimmune thyroiditis, celiac disease, Crohn's disease, type 1 diabetes mellitus (T1D), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki disease, lupus erythematosus 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), severe myasthenia, opsomeclonal syndrome (OMS), optic neuritis, atrophic form of autoimmune thyroiditis, pemphigus, pernicious anemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, refractory gouty arthritis, Reiter's syndrome, Sjogren's syndrome, systemic sclerosis as a systemic connective tissue disorder, Takayasu's arteritis, temporal arteritis, autoimmune hemolytic anemia with warm antibodies, Wegener's granulomatosis, general alopecia, Behcet's 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;

IV. Cancer including lung cancer, renal cell carcinoma, non-small cell lung carcinoma (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 cell 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, cancer esophagus, Ewing sarcoma family tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, glioma, Hodgkin's disease, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, carcinoid tumor of the lung, lymphoma including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, cancer of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cavity and oropharynx cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer glands, skin cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymus cancer, thyroid cancer including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor;

V. Infections, including viral infections (such as those caused by influenza virus, human immunodeficiency virus (HIV), alphavirus (such as chikungunya virus and Ross River fever virus), flaviviruses (such as dengue virus and Zika virus), herpes viruses (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 type 5), or human papillomavirus), bacterial infections (such as those caused by Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordetella pertussis, Burkholderia pseudomallei, Corynebacterium diphtheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Haemophilus influenzae, Pasteurella multocida, 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), fungal infections (e.g., Candida or Aspergillus species), protozoal infections (e.g., Plasmodium, Babesia, Giardia, Entamoeba, Leishmania, or Trypanosoma species), helminthic infections (eg, those caused by schistosomes, roundworms, tapeworms, or flukes), and prion infections;

VI. Central nervous system diseases such as Parkinson's disease, Alzheimer's disease, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain damage due to pneumococcal meningitis, intracranial aneurysms, traumatic brain injury, multiple sclerosis and amyotrophic lateral sclerosis;

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

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, aneurysms including abdominal aortic aneurysm, cardiovascular risk reduction (CvRR), and pericarditis including Dressler syndrome;

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

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

XI. Kidney diseases, including acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis and diabetic nephropathy;

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

XIII. Skin diseases including dermatitis such as contact dermatitis and atopic dermatitis, contact hypersensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other skin diseases causing cyst formation, and acne nodularis;

XIV. Lymphatic conditions such as lymphangitis and Castleman's disease;

XV. Mental disorders such as depression and psychological stress;

XVI. Graft-versus-host disease;

XVII. Bone diseases, including osteoporosis, osteopetrosis;

XVIII. Blood disease, including sickle cell anemia;

XIX. Allodynia, including mechanical allodynia; and

XX. Any disorder in which the individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.

More particularly, the compounds of the present invention may be useful in the treatment of an indication selected from inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g. cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, for example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In particular, this applies to forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

In particular, the compounds of the present invention or a pharmaceutically acceptable salt thereof may be useful in the treatment of a disease or disorder, preferably selected from the forms of autoinflammatory febrile syndrome (e.g. CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

Thus, as a further aspect, the present invention provides the use of a compound of any of formulae (I), (II), (III) and (III-A), or a compound according to any of the previous embodiments (i.e. according to any of embodiments 1-11g), or a compound according to any of the illustrative examples (e.g. from example 001 to example 104 disclosed herein), or a pharmaceutically acceptable salt thereof, in therapy. In a further embodiment, the therapy is selected from the therapy of a disease that can be treated by inhibiting the NLRP3 inflammasome signaling pathway. In another embodiment, the disease is selected from the above list, preferably inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g. cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, for example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In particular, this applies to forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

Thus, as a further aspect, the present invention provides a compound of any of Formulae (I), (II), (III) and (III-A), or a compound according to any of the previous embodiments (i.e. according to any of Embodiments 1-11g), or a compound according to any of the Illustrative Examples (e.g., from Ex 001 to Ex 104 disclosed herein), or a pharmaceutically acceptable salt thereof, for use in therapy. In a further embodiment, the therapy is selected from the therapy of a disease that can be treated by inhibiting the NLRP3 inflammasome signaling pathway. In another embodiment, the disease is selected from the above list, preferably inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, for example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In particular, this applies to forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

In another aspect, the present invention provides a method of treating a disease, the treatment of which is accomplished by inhibiting NLRP3, comprising administering a therapeutically effective amount of a compound of any of formulae (I), (II), (III) and (III-A), or a compound according to any of the previous embodiments (i.e., according to any of embodiments 1-11g), or a compound according to any of the illustrative examples (e.g., from example 001 to example 104 disclosed herein), or a pharmaceutically acceptable salt thereof. In a further embodiment, the disease is selected from the above list, preferably inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, eg acute, chronic), kidney-related diseases (eg hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In particular, this applies to forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

In a further aspect, the present invention provides a compound of any of Formulae (I), (II), (III), and (III-A), or a compound according to any of the previous embodiments (i.e., according to any of Embodiments 1-11g), or a compound according to any of the illustrative examples (e.g., from Example 001 to Example 104 disclosed herein), or a pharmaceutically acceptable salt thereof, useful in the treatment of a disease, disorder, or condition substantially or entirely mediated by the activity of the NLRP3 inflammasome as disclosed herein and/or NLRP3-induced IL-1beta and/or NLRP3-induced IL-18. Some of the diseases, disorders, or conditions referred to herein arise from mutations in NLRP3, in particular arise from increased NLRP3 activity.

Thus, as a further aspect, the present invention provides the use of a compound of any of formulae (I), (II), (III) and (III-A), or a compound according to any of the previous embodiments (i.e. according to any of embodiments 1-11g), or a compound according to any of the illustrative examples (e.g. from example 001 to example 104 disclosed herein), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament. In a further embodiment, the medicament is for the treatment of a disease that is treated by inhibiting the NLRP3 inflammasome signaling pathway. In another embodiment, the disease is selected from the above list, preferably inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g. cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, for example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In particular, this applies to forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

In another embodiment, the present invention provides 3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In another embodiment, the present invention provides (S)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In a preferred embodiment of the present invention there is provided (R)-3-methyl-2-(5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder that is treated by inhibiting the NLRP3 signaling pathway. For example, the disease or disorder is selected from the above list, preferably inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g. cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, For example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In particular, the compounds of the present invention may be useful in the treatment of forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

In one embodiment, the present invention provides 2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In another embodiment, the present invention provides (S)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In a preferred embodiment of the present invention there is provided (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder that is treated by inhibiting the NLRP3 signaling pathway. For example, the disease or disorder is selected from the above list, preferably inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g. cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, For example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In particular, the compounds of the present invention may be useful in the treatment of forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

In another embodiment, the present invention provides 2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In another embodiment, the present invention provides (S)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In a preferred embodiment of the present invention there is provided (R)-2-(6-((1-ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder that is treated by inhibiting the NLRP3 signaling pathway. For example, the disease or disorder is selected from the above list, preferably inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g. cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, For example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In particular, the compounds of the present invention may be useful in the treatment of forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

In another embodiment, the present invention provides 2-(6-((3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In another embodiment, the present invention provides 2-(6-(((trans)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In a preferred embodiment of the present invention, there is provided 2-(6-(((cis)-3-hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder that is treated by inhibiting the NLRP3 signaling pathway. For example, the disease or disorder is selected from the above list, preferably inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g. cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, For example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In particular, the compounds of the present invention may be useful in the treatment of forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

In another embodiment, the present invention provides 2-(6-((3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In another embodiment, the present invention provides 2-(6-(((1S,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In another embodiment, the present invention provides 2-(6-(((1R,3R)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In another embodiment, the present invention provides 2-(6-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In a preferred embodiment of the present invention, there is provided 2-(6-(((1R,3S)-3-hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder that is treated by inhibiting the NLRP3 signaling pathway. For example, the disease or disorder is selected from the above list, preferably inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g. cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, for example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In particular, the compounds of the present invention may be useful in the treatment of forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

In another embodiment, the present invention provides 5-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In another embodiment, the present invention provides (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 for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In another embodiment, the present invention provides (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 for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In another embodiment, the present invention provides (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 for use in the treatment of a disease or disorder treated by inhibiting the NLRP3 signaling pathway. In a preferred embodiment of the present invention there is provided (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 for use in the treatment of a disease or disorder, the treatment of which is accomplished by inhibiting the NLRP3 signaling pathway. For example, the disease or disorder is selected from the above list, preferably inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g. cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, for example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis). In particular, the compounds of the present invention may be useful in the treatment of forms of autoinflammatory febrile syndrome (e.g., CAPS), sickle cell disease, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathies), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, disorders associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (eg, cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).

The pharmaceutical composition or combination of the present invention can be provided in a single dosage of about 1-1000 mg of the active ingredient(s) for a subject weighing about 50-70 kg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 1-100 mg, or about 1-50 mg of the active ingredients. The therapeutically effective dosage of the compound, pharmaceutical composition or combinations thereof depends on the type of subject, body weight, age and the individual condition, disorder or disease being treated or its severity. An attending physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat or inhibit the progression of a disorder or disease.

The above mentioned dosage parameters are evident in the tests.in vitroAnd in vivousing mainly mammals, such as mice, rats, dogs, non-human primates, or isolated organs, tissues and preparations thereof. The compounds of the present invention can be usedin vitroin the form of solutions, for example, aqueous solutions, andin vivoenterally or parenterally, preferably intravenously, for example, in the form of a suspension or aqueous solution. Dosagein vitrocan be in the concentration range of approximately 10^-3mol/l up to 10^-9mol/l. Therapeutically effective amountin vivodepending on the route of administration, it can be in the range of approximately 0.1-500 mg/kg or approximately 1-100 mg/kg.

COMBINATION PRODUCT AND COMBINATION THERAPY ACCORDING TO THE PRESENT INVENTION

"Combination" refers to a fixed combination in a single unit dosage form or to a combined administration wherein a compound of the present invention and a combination partner (e.g., another medicinal product, as explained below, also referred to as "the therapeutic agent" or "the co-administered agent") may be administered independently at the same time or separately at intervals, particularly if the intervals allow the combination partners to exhibit cooperative, e.g. synergistic effect. Individual components may be packaged in a kit or provided separately. One or both components (e.g. powders or liquids) may be reconstituted or diluted to the required dose prior to administration. The terms "co-administration" or "combination administration" or similar terms as used herein are intended to cover the administration of the selected combination partner to a single subject in need thereof (e.g., to the patient) and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining more than one therapeutic agent, which includes both fixed and non-fixed combinations of therapeutic agents. The term "pharmaceutical combination" as used herein refers to a fixed combination in a single dosage unit or a non-fixed combination or kit of parts for combined administration, wherein two or more therapeutic agents may be administered independently at the same time or separately at intervals, particularly where such intervals allow the combination partners to exhibit cooperative, e.g. synergistic effect. The term "fixed combination" means that both therapeutic agents, e.g. the compound of the present invention and the combination partner are administered to the patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" means that both therapeutic agents, for example, a compound of the present invention and a combination partner are administered to a patient as separate entities simultaneously, in parallel or sequentially without specific time limits, whereby such administration provides therapeutically effective levels of the two compounds in the patient's body. The latter is also applicable to "cocktail therapy", for example, when administering three or more therapeutic agents.

The term "combination therapy" refers to the administration of two or more therapeutic agents for the treatment of a therapeutic condition or disorder described herein. Such administration encompasses co-administration of these therapeutic agents substantially simultaneously, such as in a single capsule having a fixed ratio of the active ingredients. Alternatively, such administration encompasses co-administration in multiple or separate containers (e.g., tablets, capsules, powders and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to the required dose prior to administration. In addition, such administration also encompasses the use of each type of therapeutic agent sequentially at approximately the same time or at different times. In any event, the treatment regimen will provide the beneficial effects of the combination of medicinal products in the treatment of the conditions or disorders described herein.

The compound of the present invention can be administered simultaneously with one or more other therapeutic agents, or before or after them. The compound of the present invention can be administered separately from the other agents by the same or a different route of administration, or together with them in a single pharmaceutical composition. The therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with the compound of the present invention.

In one embodiment, the present invention provides a product comprising a compound of any of formulas (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 the treatment of a disease or condition mediated by NLRP3. Products provided as a combination preparation include a composition comprising a compound of any of formulas (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof and the other therapeutic agent(s) together in the same pharmaceutical composition, or a compound of any of formulas (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof and the other therapeutic agent(s) in separate form, such as in the form of a kit.

In one embodiment, the present invention provides a pharmaceutical combination comprising a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any of the previous embodiments (i.e., according to any of embodiments 1-11g) or a pharmaceutically acceptable salt thereof, and other therapeutic agent(s). The pharmaceutical combination may optionally comprise a pharmaceutically acceptable carrier as described above.

In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any of the previous embodiments (i.e., according to any of embodiments 1-11g) or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises means for separately containing said compositions, such as a container, a compartmental bottle or a compartmental foil pouch. An example of such a kit is a blister pack, typically used for packaging tablets, capsules, etc.

The kit of the present invention can be used to administer different dosage forms, such as oral and parenteral administration, to administer separate compositions at different dosing intervals, or to titrate separate compositions relative to each other. To promote compliance, the kit of the present invention typically includes instructions for administration.

In the combination therapies of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Furthermore, the compound of the present invention and the other therapeutic agent may be combined into a combination therapy: (i) prior to dispensing the combination product to physicians (e.g., in the case of a kit containing a compound of the present invention and another therapeutic agent); (ii) by the physicians themselves (or under the guidance of a physician) shortly before administration; (iii) by the patients themselves, for example, during sequential administration of a compound of the present invention and another therapeutic agent.

Accordingly, the present invention provides the use of a compound of any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition mediated by NLRP3, wherein the medicament is prepared for administration with another therapeutic agent. The present invention also provides the use of another therapeutic agent for the treatment of a disease or condition mediated by NLRP3, wherein the medicament is administered with a compound of any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, or a compound according to any of the previous embodiments (i.e., according to any of embodiments 1-11g) or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound of any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, or a compound according to any of the previous embodiments (i.e. according to any of embodiments 1-11g), or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition mediated by NLRP3, wherein the compound of any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, or a compound according to any of the previous embodiments (i.e. according to any of embodiments 1-11g), or a pharmaceutically acceptable salt thereof, is formulated 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 formulated for administration with a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any of the previous embodiments (i.e. according to any of embodiments 1-11g) or a pharmaceutically acceptable salt thereof. The present invention also provides a compound of any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, or a compound according to any of the previous embodiments (i.e. according to any of embodiments 1-11g), or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition mediated by NLRP3, wherein the compound of any of formulae (I), (II), (III) and (III-A), or a pharmaceutically acceptable salt thereof, or a compound according to any of the previous embodiments (i.e. according to any of embodiments 1-11g), or a pharmaceutically acceptable salt thereof, is administered 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 administered with a compound of any of formulae (I), (II), (III) and (III-A) or a pharmaceutically acceptable salt thereof, or a compound according to any of the previous embodiments (i.e., according to any of embodiments 1-11g) or a pharmaceutically acceptable salt thereof.

The present invention also provides the use of a compound of any of Formulae (I), (II), (III), and (III-A), or a pharmaceutically acceptable salt thereof, or a compound of any of the previous embodiments (i.e., any of Embodiments 1-11g), or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition mediated by NLRP3, wherein the patient has previously (e.g., up to 24 hours previously) been treated with another therapeutic agent. The present invention also provides the use of another therapeutic agent for the treatment of a disease or condition mediated by the NLRP3 inflammasome signaling pathway, wherein the patient has previously (e.g., up to 24 hours previously) been treated with a compound of any of Formulae (I), (II), (III), and (III-A), or a pharmaceutically acceptable salt thereof, or a compound of any of the previous embodiments (i.e., any of Embodiments 1-11g), or a pharmaceutically acceptable salt thereof.

In one embodiment, the other therapeutic agent is a therapeutic agent useful in the treatment of inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases as disclosed herein.

In one embodiment, the other therapeutic agent useful in the combination therapy is selected from farnesoid X receptor (FXR) agonists; anti-steatosis agents; anti-fibrotic agents; JAK inhibitors; immune checkpoint inhibitors; chemotherapy, radiation therapy, and surgical procedures; urate lowering therapies; anabolic and cartilage regenerative agents; IL-17 blockade agents; complement inhibitors; Bruton tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors (TLR7/8 inhibitors); CAR T cell therapies; antihypertensive agents; cholesterol lowering agents; leukotriene A4 hydrolase (LTAH4) inhibitors; SGLT2 inhibitors; β2 agonists; anti-inflammatory agents; non-steroidal anti-inflammatory drugs ("NSAIDs"); medicines based on acetylsalicylic acid (ASA), including aspirin; paracetamol; treatments using the regenerative therapy method; treatments for cystic fibrosis and treatments for atherosclerosis.

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

Suitable sodium glucose transporter 2 (SGLT2) inhibitors for use in combination include, but are not limited to, the compounds disclosed in US 8,163,704 (Attorney File No. PAT053854-WO-PCT), WO2011/048112, WO2011/048148, or WO2010/128152.

Suitable β2-agonists for use in combination include, but are not limited to, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, dopexamine, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, nolomirole, orciprenaline, pirbuterol, procaterol, reproterol, ritodrine, rimiterol, salbutamol, salmefamol, salmeterol, sibenadet, soterot, 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-[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-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-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 mixtures thereof and also optionally in the form of a pharmacologically compatible acid addition salt.

Suitable cartilage regenerative therapy agents for use in combination include, but are not limited to, the ANGPTL3 peptidomimetics disclosed in WO2014/138687 (Attorney File Number PAT055625-WO-PCT) or the chondrogenesis activator disclosed in WO2015/175487 (Attorney File Number PAT055940-WO-PCT).

Suitable immune checkpoint inhibitors for use in combination include, but are not limited to, PD1 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, PDL1 inhibitors. Suitable PD1 inhibitors include, but are not limited to, the antibody molecule disclosed in WO2015/112900. Suitable LAG-3 inhibitors include, but are not limited to, the antibody molecule disclosed in WO2015/138920. Suitable TIM-3 inhibitors include, but are not limited to, the antibody molecule disclosed in WO2015/117002. Suitable TIM-3 inhibitors include, but are not limited to, the antibody molecule disclosed in WO2015/117002. Suitable PDL1 inhibitors include, but are not limited to, the antibody molecule disclosed in WO/2016/061142.

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

Suitable FXR agonists for use in combination include, but are not limited to, obeticholic acid (also called OCA, Intercept), GS9674, elafibranor (GFT505), GW4064, UPF987, FXR-450, fexaramine, methylfolate, methyldeoxycholate, 5β-cholanic acid, 7α,12α-diol derivative of 5β-cholanic acid, NIHS700, marchantin A, marchantin E, MFA-1, INT767 (also called 6α-ethyl-CDCA, disclosed in WO2014/085474), 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]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid (also known as tropifexor) or a pharmaceutically acceptable salt thereof, or a compound disclosed in WO 2012/087519, or a compound disclosed in WO 2015/069666.

Suitable JAK inhibitors for use in combination include, but are not limited to, ruxolitinib.

Suitable NSAIDs for use in combination include, but are not limited to, aceclofenac, acemetacin, acetylsalicylic acid, alclofenac, alminoprofen, amfenac, ampiroxicam, amtolmetin guacil, anirolac, antrafenine, azapropazone, benorilate, bermoprofen, bindarit, bromfenac, bucloxic acid, bucolome, bufexamac, bumadizone, butibufen, butixirate, carbasalate calcium, carprofen, choline magnesium trisalicylate, celecoxib, cinmetacin, cinnoxicam, clidanac, clobuzarit, deboxamet, dexibuprofen, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, enfenaminsaur, ethersalate, etodolac, etofenamate, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, fenoprofen, fentiazac, fepradinol, feprazone, flobufen, floctafenin, flufenamic acid, flufenisal, flunoxaprofen, flurbiprofen, flurbiprofenaxetil, furofenac, furprofen, glucamethacin, phenac, ibuprofen, indobufen, indomethacin, indomethacinfarnesil, indoprofen, isoxepak, isoxicam, ketoprofen, ketorolac, lobenzarit, lonazolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, meclofen, mefenamic acid, meloxicam, mesalazine, miroprofen, mofezolac, nabumetone, naproxen, niflumic acid, olsalazine, oxaprozin, oxypinac, oxyphenbutazone, parecoxib, phenylbutazone, pelubiprofen, pimeprofen, pyrazolac, piroxicam, pirprofen, pranoprofen, prifelon, prinomod, proglumetacin, proquazone, protizininzaur, rofecoxib, romazarit, salicylamide, salicylic acid, salmistein, salnacedin, salsalate, sulindac, sudoxicam, suprofen, talniflumate, tenidap, tenosal, tenoxicam, tepoxalin, tiaprofenic acid, taramide, tilnoprofen arbamel, thymegadine, tinoridine, thiopenac, tolfenamic acid, tolmetin, ufenamate, valdecoxib, ximoprofen, zaltoprofen, zoliprofen and their combinations.

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 a compound described in WO2015/079417, WO2015/083008, WO2015/110923, WO2014/173289, WO2012/021444, WO2013/081016, WO2013/067274, WO2012/170976, WO2011/162515, US2017/119766, WO2016/065226, US 9688676, WO2016/201280, WO2017/059702, US9630968, US2014/0256734, WO2017118277, WO2014/039899, WO/16/105531, WO2018/005849, WO2013/185082 or in J. Med. Chem., 2016, 59(19), 9173-9200. Of particular interest are BTK inhibitors comprising the compound of Example 31 described in WO2014/039899, wherein the compound is characterized by the following structure:

and is described as compound 14f in Journal of Medicinal Chemistry , 2016, 59(19), 9173-9200; the compound of example 2 described in US2017/119766, the compound of example 223 described in WO2016/065226, which is

or compound 1 described in WO2016/201280, compound 1 described in WO2017/059702, or compound 1 described in WO2017/118277; or a pharmaceutically acceptable salt thereof.

Also of particular interest are BTK inhibitors comprising a compound as described in WO2015/079417, for example a compound selected from 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-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)propoxy)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.

EXAMPLES

EXPLANATION OF THE INVENTION WITH EXAMPLES

The present invention is further illustrated by the following examples and synthesis schemes, which should not be construed as limiting the scope or spirit of the present invention to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and that this does not impose any limitations on the scope of the present invention. In addition, it should be understood that various other embodiments, modifications and equivalents thereof can be resorted to, which may be suggested by those skilled in the art, without departing from the spirit of the present invention and/or the scope of the appended claims.

The compounds of the present invention can be prepared using methods known in the art of organic synthesis. It is understood that in all methods, protecting groups for unstable or reactive groups can be used, if necessary, in accordance with the general principles of chemistry. The handling of protecting groups is carried out in accordance with standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons). These groups are removed at an appropriate stage in the synthesis of the compound using methods obvious to those skilled in the art.

Unless otherwise stated, reagents and solvents were used as received from private suppliers.

Chemical names were generated using ChemBioDraw Ultra v14 from CambridgeSoft.

Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations were carried out under reduced pressure, typically from about 15 mmHg to 100 mmHg (= 20-133 mbar). The structure of the final products, intermediates and starting materials was confirmed by standard analytical methods, e.g. microanalysis and determination of spectroscopic characteristics, for example, by MS, IR, NMR. The abbreviations used are standard abbreviations used in the given technical field.

ABBREVIATIONS

AcOH Acetic acid ASC Speck-like apoptosis-associated regulatory protein BINAP (2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl) BippyPhos 5-(Di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-1,4-bipyrazole Boc tert-Butyloxycarbonyl CAPS Forms of cryopyrin-associated periodic syndrome DAMP Molecular structures activated by danger signals DIAD Diisopropyl azodicarboxylate DIPEA N- diisopropylethylamine DME 1,2-Dimethoxyethane DMF N,N -dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-Bis(diphenylphosphino)ferrocene EtOAc Ethyl acetate EtOH Ethanol h. Hour(hours) HCl Hydrogen chloride HTRF Homogeneous time-resolved fluorescence Hz/MHz Hertz/Megahertz IC ₅₀ Half-maximal inhibitory concentration IL-1β Interleukin 1-beta IR Infrared LC-MS Liquid chromatography with mass spectrometry LPS Lipopolysaccharides from Escherichia coli O111:B4 LRR Leucine Rich Repeat M Mol/l mCPBA 3-Chloroperoxybenzoic acid MEK Methyl ethyl ketone; butan-2-one MeOH Methanol min. Minute ml/l Milliliter/liter mmol Millimole NASH Non-alcoholic steatohepatitis NBD Nucleotide-binding site domain NLR NOD-like receptors NMP 1-Methylpyrrolidin-2-one NMR Nuclear magnetic resonance PAD Peripheral arterial disease PAMP Molecular structures activated by pathogens Pd/C Palladium on carbon PMA Phorbol-12-myristate-13-acetate ppm Parts per million RP Reversed phase RPMI Roswell Park Memorial Institute k.t. Room temperature - in degrees Celsius Rt Retention time SFC Supercritical fluid chromatography SLE Systemic lupus erythematosus TFA Trifluoroacetic acid THF Tetrahydrofuran TMEDA N, N, N',N'-Tetramethylethane-1,2-diamine TMS Tetramethylsilane TNF-α Tumor necrosis factor-α UPLC High performance liquid chromatography XantPhos-Pd-G2 Chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II)

ANALYSIS DETAILS

• NMR. Measurements were performed on a Bruker Ultrashield ^TM 400 (400 MHz), or Bruker Ascend ^TM (400 MHz), or Bruker cryo system (600 MHz) spectrometer with or without tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are given in ppm downfield from TMS, the spectral separation pattern is designated as singlet ( s ), doublet ( d ), triplet ( t ), quartet ( q ), quintet ( quint ), septet ( sept ), multiplet, unseparated or overlapping signals ( m ), broad signal ( br ). Deuterated solvents are given in parentheses and are characterized by chemical shifts relative to dimethyl sulfoxide (δ 2.50 ppm), methanol (δ 3.31 ppm), chloroform (δ 7.26 ppm), or other solvents as indicated in the NMR data.

• LC-MS. System: Waters Acquity UPLC with Waters SQ detector.

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

Gradient: 5 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.

Mass spectrometry results are presented as mass-to-charge ratios.

PREPARATION METHODS

• Flash Column Chromatography System

System: Teledyne ISCO, CombiFlash Rf.

Columns: Pre-packaged RediSep Rf cartridges.

Samples were typically adsorbed onto Isolute.

• Achiral reversed phase (RP) chromatography

System: Gilson LC Auto-Cleaning System,

Sunfire C18 5 µm column, 30×100 mm.

Detection: Gilson UV/VIS 155 Detector

Column temperature: r.t.

Eluent A: water+0.1% TFA

Eluent B: acetonitrile

Flow rate: 30 ml/min

Gradient

Time [min.] % A (eluent A) % B (eluent B) 0,0 95 5 2.0 95 5 17 5 95 18 0 100 20 0 100

• Chiral normal phase chromatography

System: Gilson LC Auto-Cleaning System

Detection: Gilson UV/VIS-155 Detector

Column temperature: r.t.

• Achiral supercritical fluid chromatography (SFC)

System: Waters SFC-100 SFC system

Detection: PDA detector Waters 2998,

Waters 3100 mass detector

Eluent A: _CO2

Eluent B: described in the examples

• Chiral supercritical fluid chromatography (SFC)

System: Waters SFC-100 SFC system

Detection: PDA detector Waters 2998,

Waters 3100 mass detector

Eluent A: _CO2

Eluent B: described in the examples

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

SYNTHESIS OF INTERMEDIATE COMPOUNDS

Synthesis of intermediate compounds with a boronate group

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, industrial compound B001,

And .

(1) 3-Chloro-2-iodo-5-(trifluoromethyl)phenol and 5-chloro-2-iodo-3-(trifluoromethyl)phenol, ind. conn. B002,

And .

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. Then iodine (12.9 g, 50.9 mmol) was 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 Na ₂ SO ₄ , filtered and evaporated. The crude mixture of regioisomers was used as such in the next step. LC-MS: Rt = 1.10 and 1.12 min; MS m/z 320.9 [MH]-.

(2) 5-Chloro-1-(ethoxymethoxy)-2-iodo-3-(trifluoromethyl)benzene and 1-chloro-3-(ethoxymethoxy)-2-iodo-5-(trifluoromethyl)benzene, ind. conn. B003,

And .

(Chloromethoxy)ethane (7.25 mL, 62.5 mmol) was added to a suspension of ind. B002 (16 g, 49.6 mmol) and _Cs2CO3 (16.2 g, 49.6 mmol) in 70 _mL DMF. The reaction mixture was stirred at rt for 18 h. Additional (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 give the title compound as a mixture of regioisomers, which was used without further purification in the next step. LC-MS: Rt = 1.37 and 1.38 min.

(3) 2-(2-Chloro-6-(ethoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-(4-chloro-2-(ethoxymethoxy)-6-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, industrial compound B004,

And .

A solution of industrial compound 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 of 1,4-dioxane was purged with nitrogen. Pd(OAc) ₂ (0.35 g, 1.56 mmol) and biphenyl-2-yl-dicyclohexylphosphane (1.1 g, 3.13 mmol) were added and the resulting mixture was stirred at 80 °C for 3 h. Additional Pd(OAc) ₂ (0.35 g, 1.56 mmol) was added and heating was continued for 13 h. The reaction mixture was cooled to rt, washed with saturated _NH4Cl solution, water and brine to give an orange oil. The crude product was purified by column chromatography on silica gel using cyclohexane and EtOAc (0% to 100%) to give the title compound as a mixture of regioisomers. LC-MS: Rt=1.43 min.

(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, ind. comp. B001

A solution of ind. 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 (0% to 5%) to give the title compound as a mixture of regioisomers. LC-MS: Rt=1.23 min and 1.28 min; MS m/z 321.1 [MH]-.

(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid, ind. comp. B005

(1) 3-Methyl-5-(trifluoromethyl)phenol, industrial compound B006

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 of 1,4-dioxane and 50 mL of _H2O . The reaction mixture was purged with nitrogen and heated at 100 °C for 16 h. The reaction mixture was cooled to rt, filtered through a pad _of Celite® 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 (0% to 15%) to give the title compound as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) 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=0.95 min; MS m/z 175.0 [MH]-.

(2) 2-Iodo-3-methyl-5-(trifluoromethyl)phenol, industrial compound B007

NaH (60% dispersion in mineral oil, 5.92 g, 148 mmol) was added to an ice-cold solution of industrial compound B006 (13.03 g, 74 mmol) in 370 mL of toluene. The suspension was stirred at 0 °C for 30 min, then iodine (18.77 g, 74 mmol) was slowly added in portions and stirring was continued for 3 h. The mixture was diluted with water, acidified with 2 M HCl to pH = 5 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by column chromatography on silica gel (220 g) using cyclohexane and EtOAc (5% to 100%) to give the title compound as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.08-7.04 (m, 2H), 5.74 (s, 1H), 2.50 (s, 3H). LC-MS: Rt = 1.11 min; MS m/z 301.0 [MH]-.

(3) 2-Iodo-1-methoxy-3-methyl-5-(trifluoromethyl)benzene, industrial compound B008

A mixture _{of K2CO3} (24 g, 172.22 mmol), methyl iodide (8.1 mL, 129.13 mmol) and ind. B007 (26 g, 86.09 mmol) in 300 _{mL anhydrous} acetone was stirred at rt for 5 h. Then it was filtered and the filtrate was evaporated. The residue was dissolved in _CH2Cl2 , washed with water, dried over _Na2SO4 , filtered and evaporated to give the title compound as an off-white solid. ^1H NMR (400 MHz, _CDCl3 ) δ (ppm) 7.15 (s, 1H), 6.84 (s, 1H), 3.93 (s, 3H), 2.54 (s, 3H).

(4) 2-(2-Methoxy-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, industrial compound B009

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

(5) (2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid, ind. comp. B005

BBr₃(1 M in CH₂Cl₂, 95 ml, 94.86 mmol) was added to the solutionprom. conn. B009 (12 g, 37.95 mmol) in 150 ml anhydrous CH₂Cl₂at 0°C. The reaction mixture was stirred at 0°C for 30 min, after which it was carefully poured into ~250 ml of 10% NaOH solution such that the pH was maintained at ~9. The resulting mixture was washed with CH₂Cl₂The aqueous layer was separated and the pH was adjusted to 5 with 1.5 M HCl. The precipitated solid was filtered, washed with petroleum ether and dried under vacuum to give the title compound as an off-white solid.¹H NMR (400 MHz, CD3OD) δ (ppm) 6.94 (s, 1H), 6.82 (s, 1H), 2.29 (s, 3H). MS (ESI): mass/charge 219.8 [M-H]-

3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol, ind. comp. B010

(1) 1-(Ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl)benzene, industrial compound B011

(Chloromethoxy)ethane (3.35 g, 35.50 mmol) was added dropwise to a white suspension of ind. compound 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 rt for 2 h, then evaporated to dryness. The crude material was purified by column chromatography _on silica gel using cyclohexane and EtOAc (0% to 5%) to give the title compound. LC-MS: Rt=1.39 min.

(2) 2-(2-(Ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, industrial compound B012

A solution of ind. comp. 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 of 1,4-dioxane was purged with nitrogen. Pd(OAc) ₂ (0.81 g, 3.61 mmol) and biphenyl-2-yl-dicyclohexylphosphane (2.33 g, 6.66 mmol) were added and the mixture was stirred at 80 °C for 18 h. Then it was cooled to rt, 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} (0% to 20%) to give the title compound. LC-MS: Rt=1.40 min.

(3) 3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenol, ind. comp. B010

TFA (44.9 mL, 583 mmol) was slowly added to a solution of intermediate B012 (7.00 g, 19.43 mmol) in 250 mL _{of CH2Cl2} at 0 °C. 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} (0% to 100%) to give the title compound. ¹ H NMR (400 MHz, 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= 1.38 min; MS mass/charge 301.1 [MH]-

3,5-Dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, industrial compound B013

(1) 2-Iodo-3,5-dimethylphenol, industrial compound B014

3,5-Dimethylphenol (1 g, 8.2 mmol) was dissolved in 40 mL toluene and cooled to 0 °C. NaH (60% dispersion in mineral oil, 655 mg, 16.4 mmol) was added portionwise and the mixture was stirred at 0 °C for 20 min, then at rt for 10 min and finally cooled again to 0 °C. Iodine (2.08 g, 8.2 mmol) was then added portionwise and stirring was continued for 30 min. The reaction mixture was quenched by addition of 0.5 M HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by column chromatography on silica gel (100 g) using n-heptane and EtOAc (0% to 20%) followed by a second (isocratic) cycle using n-heptane and EtOAc (5%) to afford the title compound as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 = 1.03 min; MS m/z 246.9 [MH]-

(2) 1-(Ethoxymethoxy)-2-iodo-3,5-dimethylbenzene, industrial compound B015

To a solution of ind. B014 (660 mg, 2.66 mmol) in 6 mL DMF was _{added Cs2CO3} (867 mg, 2.66 mmol) followed by (chloromethoxy)ethane (311 µL, 3.35 mmol). The reaction mixture was stirred at rt overnight, then quenched by addition _of water and extracted with EtOAc. The combined organic extracts were dried over _Na2SO4 , filtered and evaporated. The crude material was purified by column chromatography on silica gel (50 g) using n-heptane and EtOAc (0% to 10%) to give the title compound as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=1.36 min; MS m/z 307.2 [M+H] ⁺

(3) 2-(2-(Ethoxymethoxy)-4,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, industrial compound B016

To a solution of ind. B015 (393 mg, 1.28 mmol) in 2.5 mL of 1,4-dioxane were added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (373 µL, 2.57 mmol) and _NEt3 (537 µL, 3.85 mmol) and the vial was purged with nitrogen. Pd(OAc) ₂ (14.4 mg, 64 µmol) and biphenyl-2-yl-dicyclohexylphosphane (45 mg, 0.128 mmol) were added, the vial was sealed and heated at 80 °C overnight. The reaction mixture was cooled to rt, quenched by addition of water and extracted with EtOAc. _The combined organic extracts were dried over _Na2SO4 , filtered and evaporated. The crude material was purified by column chromatography on silica gel (50 g) using n-heptane and EtOAc (0% to 20%) to give the title compound as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 = 1.36 min; MS m/z 307.2 [M+H] ⁺

(4) 3,5-Dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, ind. comp. B013

A solution of ind. B016 (486 mg, 1.59 mmol) in 25 mL _{of CH2Cl2} was cooled to -30 °C and TFA (611 μL, 7.94 mmol) was added slowly. After 1 h, the reaction mixture 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 (400 MHz, DMSO-d ₆ ) δ (ppm) 8.72 (s, 1H), 6.43 (s, 1H), 6.38 (s, 1H), 2.24 (s, 3H), 2.16 (s, 3H), 1.30 (s, 12H). LC-MS: Rt=1.37 min; MS m/z 249.2 [M+H] ⁺

(2-Methoxy-4,6-dimethylphenyl)boronic acid, industrial compound B017

1-Methoxy-3,5-dimethylbenzene (1.04 mL, 7.34 mmol) and TMEDA (2.44 mL, 16.15 mmol) were dissolved in 16 mL of _Et2O and cooled to 0-5 °C under nitrogen atmosphere. n-BuLi (1.6 M in hexane, 10.1 mL, 16.15 mmol) was added dropwise to the colorless solution while maintaining the temperature below 10 °C. The resulting yellow suspension was stirred at rt for 1 h, then it was cooled to -78 °C. B(OMe) ₃ (1.15 mL, 10.28 mmol) was added over a period of approximately 4 min while maintaining the temperature below -70 °C. Stirring was continued at -78 °C for 20 min, then the reaction mixture was allowed to warm to rt overnight. It was quenched by addition of water and acidified with 4 M HCl to pH 1. The mixture was extracted 3 times with CH ₂ Cl ₂ 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 semi-solid. LC-MS: Rt = 0.74 min; MS m/z 180.9 [M+H] ⁺

(2,4-Dichloro-6-hydroxyphenyl)boronic acid and 3,5-dichloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, industrial compound B018,

And .

(1) 3,5-Dichloro-2-iodophenol, industrial compound B019

NaH (60% dispersion in mineral oil, 1.472 g, 36.8 mmol) was added portionwise to a solution of 3,5-dichlorophenol (2.00 g, 12.27 mmol) in 30 mL of dry toluene at 0 °C under nitrogen. The resulting mixture was allowed to warm to rt and stirred for 30 min. The suspension was then cooled to 0 °C and iodine (2.49 g, 9.82 mmol) was added very slowly. The reaction mixture was stirred for 1.5 h at 0 °C, then quenched by adding 1 M HCl and extracted with CH ₂ Cl ₂ . The organic extract was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by column chromatography on silica gel (50 g) using n-heptane and EtOAc (0% to 50%) to give the title compound as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 11.32 (s, 1H), 7.14 (d, 1H), 6.81 (d, 1H). LC-MS: Rt = 1.09 min; MS m/z 287.0 [MH]-

(2) 1,5-Dichloro-3-(ethoxymethoxy)-2-iodobenzene, industrial compound B020

A suspension of (chloromethoxy)ethane (1.004 g, 10.62 mmol), ind. compound B019 (2.8 g, 8.43 mmol) and _Cs2CO3 (2.75 g, 8.43 mmol) in 25 mL of _DMF was stirred at rt for 22 h. The reaction mixture was quenched by addition of water and the layers were separated. The aqueous layer was extracted with _CH2Cl2 and _the combined organic extracts were dried _{over Na2SO4} , filtered and evaporated. The crude material was purified by column chromatography on silica gel (100 g) using n-heptane and EtOAc (0% to 25%) to give the title compound as a brown solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ (ppm) 7.39 (d, 1H), 7.13 (d, 1H), 5.39 (s, 2H), 3.69 (q, 2H), 1.14 (t, 3H).

(3) 2-(2,4-Dichloro-6-(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, industrial compound B021

A solution of ind. comp. B020 (2.7 g, 7.78 mmol), 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 M in THF, 15.56 mL, 15.56 mmol), and NEt ₃ (3.25 mL, 23.34 mmol) in 15 mL of 1,4-dioxane was purged with nitrogen for 30 min. Pd(OAc) ₂ (87 mg, 0.389 mmol) and biphenyl-2-yl-dicyclohexylphosphane (273 mg, 0.778 mmol) were then added and the mixture was stirred at 80 °C for 20 h. The reaction mixture was quenched by adding saturated NH ₄ Cl and the layers were separated. The organic layer was washed with water and brine, then evaporated to give an orange oil. The crude material was purified by column chromatography on silica gel (100 g) using n-heptane and EtOAc (0% to 20%) followed by a second round of chromatography on silica gel (50 g) using n-heptane and EtOAc (0% to 5%) to give the title compound as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

(4) (2,4-Dichloro-6-hydroxyphenyl)boronic acid and 3,5-dichloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, ind. comp. B018

A solution of ind. 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 adding saturated _NH4Cl . The layers were separated and the organic extract was washed with water and brine. The solvent was evaporated to give the title compounds 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] ⁺

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, industrial compound B022,

And .

The mixture of regioisomers was synthesized analogously to industrial compound B018 as described above, starting from 3-chloro-5-fluorophenol. LC-MS: Rt=1.25 min.

(2-Hydroxy-4,6-bis(trifluoromethyl)phenyl)boronic acid, ind. comp. B023

To a solution of (2-methoxy-4,6 _- bis(trifluoromethyl)phenyl)boronic acid (500 mg, 1.736 mmol) in 10 mL _{of CH2Cl2} was added _BBr3 (1 M in _CH2Cl2 , 8.68 mL, 8.68 mmol) dropwise at 0 °C under nitrogen. The resulting pale orange solution was warmed to rt and stirred for 17 h. The reaction mixture was poured into ice water (~30 mL) and the pH was adjusted to 10 by adding 2 M NaOH. The aqueous layer was separated, acidified to pH 1 by adding 2 M HCl and extracted with _CH2Cl2 then EtOAc. _{The combined organic extracts were dried over Na2SO4 , filtered} and evaporated. The crude material was purified by column chromatography on silica gel (25 g) using CH ₂ Cl ₂ and MeOH (0% to 5%) to give the title compound as a beige solid. LC-MS: Rt=0.81 min; MS m/z 273.1 [MH]-

Synthesis of 6-halo-pyridazine-3-amine intermediates

(R)-6-Chloro-N-(1-ethylpiperidin-3-yl)pyridazin-3-amine, ind. comp. P024

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. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by column chromatography on silica gel using CH ₂ Cl ₂ and MeOH (0% to 10%) to give the title compound. LC-MS: Rt = 0.42 min; MS mass/charge 241.2 [M+H] ⁺

(R)-6-Chloro-N-(1-methylpiperidin-3-yl)pyridazin-3-amine, ind. comp. P025

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 of NMP was heated at 150 °C for 4 h. The reaction mixture was cooled to rt and evaporated to dryness. The residue was dissolved in EtOAc and washed with saturated Na ₂ CO ₃ solution. The aqueous layer was extracted 3 more 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 (0% to 10%) to give the title compound. ¹ H NMR (600 MHz, DMSO-d ₆ ) 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) overlapping 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 mass/charge 227.2 [M+H] ⁺

(R)-6-Chloro-N-(1-methylpiperidin-3-yl)-4-(trifluoromethyl)pyridazin-3-amine, ind. comp. P026 and (R)-6-chloro-N-(1-methylpiperidin-3-yl)-5-(trifluoromethyl)pyridazin-3-amine, ind. comp. P027,

And .

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 of 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 CH ₂ Cl ₂ and MeOH (0% to 10%). Fractions containing ind. P026 (first elution) or ind. P027 (second elution) were combined separately and evaporated. Both products were then separately partitioned between _CH2Cl2 and 1 M NaOH. _The organic extracts were dried over _Na2SO4 , filtered and evaporated to give the title compounds, prom. P026 as a brown oil and prom. P027 as _a pale yellow solid, respectively.

Ind. comp. P026 (first elution): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, overlap 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] ⁺

Infr. P027 (second elution): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, overlap 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] ⁺

cis-3-((6-Chloro-4-(trifluoromethyl)pyridazin-3-yl)amino)-1-methylcyclobutan-1-ol, prom. comp. P028, and cis-3-((6-chloro-5-(trifluoromethyl)pyridazin-3-yl)amino)-1-methylcyclobutan-1-ol, prom. comp. P029,

And .

A solution of 3,6-dichloro-4-(trifluoromethyl)pyridazine (1 g, 4.61 mmol), cis -3-amino-1-methylcyclobutan-1-ol hydrochloride (0.698 g, 5.07 mmol) and DIPEA (2.415 mL, 13.83 mmol) in 5 mL of 1-butanol was heated at 180 °C for 1 h in a microwave oven. The reaction mixture was partitioned between EtOAc and 10% NaHCO ₃ solution. The organic extract was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified and separated by column chromatography on silica gel (40 g) using CH ₂ Cl ₂ and MeOH (0% to 10%). The product containing fractions were combined separately and evaporated to give the title compounds, i.e., P028 (first elution) as a brownish oil and P029 (second elution) as a pale yellow solid, respectively.

Ind. comp. P028 (first elution): ¹ H-NMR (400 MHz, DMSO-d ₆ ) 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=0.82 min; MS m/z 282.1 [M+H] ⁺

Infr. comp. P029 (second elution): ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=0.82 min; MS m/z 282.1 [M+H] ⁺

(R)-6-Chloro-4-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine, ind. comp. P030, and (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine, ind. comp. P031,

And .

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 of NMP was heated at 180 °C for 2 h under microwave irradiation. The reaction mixture was mostly evaporated and the residue was partitioned between CH ₂ Cl ₂ and 1 M NaOH. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, and evaporated. The crude material was purified by column chromatography on silica gel (40 g) using CH ₂ Cl ₂ and MeOH (0% to 20%) to afford the title compounds as a ~1:3 mixture of regioisomers. This mixture was further purified and separated by chiral SFC (column: ChiralPak AY, 250 x 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 afford the title compounds, which are ind. P030 (first elution) as an orange oil and ind. P031 (second elution) as a brown solid, respectively.

Infr. comp. P030 (first elution): ¹ H NMR (400 MHz, CDCl ₃ ) 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=0.40 min; MS m/z 241.1 [M+H] ⁺

Infr. P031 (second elution): ¹ H NMR (400 MHz, CDCl ₃ ) 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) overlapping 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] ⁺

Alternatively, a substituted pyridazine intermediate, representing intermediate compound P030 , was prepared using the regioselective route described below.

(R)-6-Chloro-4-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine, ind. comp. P030

(1) 6-Chloro-2-(4-methoxybenzyl)-5-methylpyridazin-3(2H)-one, ind. comp. P032

6-Chloro-4-methylpyridazin-3(2H)-one (25 g, 173 mmol), 1-(bromomethyl)-4-methoxybenzene (36.5 g, 182 mmol), K ₂ CO ₃ (47.8 g, 346 mmol) and Bu ₄ NBr (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 rt and filtered through a pad of Celite®. The filtrate was evaporated to dryness under reduced pressure to give the title compound as a brown oil, which was used in the next step without further purification. LC-MS: Rt = 0.98 min; MS m/z 265.1 [M+H] ⁺

(2) (R)-2-(4-Methoxybenzyl)-5-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3(2H)-one, prom. comp. P033

A mixture of prom. P032 (30.5 g, 115.3 mmol), (R)-1-methylpiperidin-3-amine (15 g, 131 mmol) _{and Cs2CO3} (75 g, 231 mmol) in 300 mL of dry toluene was purged with nitrogen for 5 min. Pd(OAc) ₂ (1.3 g, 5.79 mmol) and BINAP (8 g, 12.85 mmol) were then added successively and the reaction mixture was stirred at reflux for 3 h. It was then cooled to rt and filtered through a pad of Celite®. 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 mass/charge 343.5 [M+H] ⁺

(3) (R)-5-Methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3(2H)-one, prom. comp. P034

Prom. comp. 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 again evaporated to dryness. The resulting black oil was triturated with Et ₂ O. 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 peaks); MS m/z 223.2 [M+H] ⁺

(4) (R)-6-Chloro-4-methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine, ind. comp. P030

POCl ₃ (250 mL) was added to a solution of ind. compound P034 (38.7 g, 115 mmol) in 250 mL dry acetonitrile and the mixture was heated under reflux for 2.5 days. The reaction mixture was cooled to rt and evaporated to dryness. The black oily residue was dissolved in 200 mL acetonitrile. This solution was added dropwise (highly exothermic reaction) to ice-cold saturated Na ₂ CO ₃ solution. The pH was adjusted to >12 by adding 30% NaOH. The black mixture was evaporated to dryness then treated with a 1:1 mixture of CH ₂ Cl ₂ and MeOH. This black suspension was stirred for 30 min at rt. It was then filtered through a pad of Celite® and _the filter cake was washed with additional 1:1 _CH2Cl2 :MeOH (~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] ⁺

cis-3-((6-Chloro-4-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol, prom. comp. P035, and cis-3-((6-chloro-5-methylpyridazin-3-yl)amino)-1-methylcyclobutan-1-ol, prom. comp. P036,

.

A solution of cis -3-amino-1-methylcyclobutan-1-ol (309 mg, 2.392 mmol), 3,6-dichloro-4-methylpyridazine (300 mg, 1.840 mmol) and DIPEA (1.3 mL, 7.36 mmol) in 1.9 mL of 1-butanol was heated at 180 °C for 90 min in a microwave oven. The reaction mixture was evaporated and the crude orange oil was partitioned between EtOAc and 2 M _Na2CO3 solution. The organic extract was washed with brine, dried _{over Na2SO4} , filtered and evaporated. The crude material was purified and separated by column chromatography on silica gel (40 g) using _CH2Cl2 and _MeOH (0% _to 5%). The product containing fractions were combined separately and evaporated to give the title compounds, i.e., P035 (first elution) as a beige solid and P036 (second elution) as a white solid, respectively.

Ind. comp. P035 (first elution): ¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm) 7.02 (s, 1H), 4.38 (br s, 1H), 4.32-4.20 (m, 1H), 2.77-2.63 (m, 2H), 2.11 (s, 3H), 2.09-2.00 (m, 2H), 1.96 (s, 1H), 1.45 (s, 3H). LC-MS: Rt=0.58 min; MS m/z 228.1 [M+H] ⁺

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

cis-3-((6-Chloropyridazin-3-yl)amino)-1-methylcyclobutan-1-ol, prom. comp. P037

A solution of 3,6-dichloropyridazine (1 g, 6.71 mmol), cis -3-amino-1-methylcyclobutan-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 for 1 h under microwave irradiation. The reaction mixture was poured into water and extracted 3 times with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was triturated with acetonitrile for 20 min, filtered and washed once with additional acetonitrile to give the title compound as a beige solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 7.33 (overlap of 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] ⁺

(1S,3R)-3-((6-Chloropyridazin-3-yl)amino)cyclohexan-1-ol, prom. comp. P038

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 for 1 h. The residue was dissolved in EtOAc and washed with saturated NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and evaporated. Column chromatography on silica gel (12 g) using CH ₂ Cl ₂ and MeOH (0% to 10%) afforded the title compound as a sticky solid. LC-MS: Rt = 0.55 min; MS m/z 228.1 [M+H] ⁺

(R)-3-Chloro-6-((1-methylpiperidin-3-yl)oxy)pyridazine, ind. comp. P039

To an ice-cold mixture of 3,6-dichloropyridazine (150 mg, 1.0 mmol) and (R)-3-hydroxy-1-methylpiperidine (128 mg, 1.1 mmol) in 1 mL of 1,4-dioxane was slowly added NaH (60% in mineral oil, 161 mg, 4.0 mmol) and the suspension was stirred at 0 °C for 1 h. It was then quenched by careful addition of water and acidified with 1 M HCl. The aqueous layer was separated and washed with EtOAc, then made basic by adding saturated Na ₂ CO ₃ solution and extracted with EtOAc. The organic extract was evaporated and the crude material was purified by column chromatography on silica gel (25 g) using _CH2Cl2 and _MeOH (0% to 20%) to give the title compound as a colourless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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) overlap 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=0.36 min; MS m/z 228.2 [M+H] ⁺

The following pyridazine intermediates ( IntP ) were prepared analogously to the above procedures using the corresponding 3,6-dihalopyridazines and suitable amines, optionally followed by a deprotection step.

Industrial connection no. Structure Name LC-MS
(min; mass/charge) Industrial connection P040 (S)-2-(3-((6-Chloropyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol Rt=0.32;
257.2 [M+H]+ Prom. conn. P041 (rac)-(8r,8ar)-N-(6-Chloropyridazin-3-yl)octahydroindolyzin-8-amine Rt=0.38;
253.2 [M+H]+ Prom. conn. P042 (rac)-6-Chloro-N-(1-isopropylpiperidin-3-yl)pyridazin-3-amine Rt=0.35;
255.3 [M+H]+ Prom. conn. P043 tert-Butyl-(3R,5S)-3-((6-chloropyridazin-3-yl)amino)-5-hydroxypiperidine-1-carboxylate Rt=0.78;
329.2 [M+H]+ Prom. conn. P044 (rac)-2-(2-(((6-Chloropyridazin-3-yl)amino)methyl)piperidin-1-yl)ethan-1-ol) Rt=0.34;
271.2 [M+H]+ Prom. conn. P045 (S)-6-Chloro-N-((1-ethylpyrrolidin-2-yl)methyl)pyridazin-3-amine Rt=0.38;
241.2 [M+H]+ Prom. conn. P046 (rac)-tert-Butyl-5-((6-chloropyridazin-3-yl)amino)-3,3-difluoropiperidine-1-carboxylate Rt=0.98;
349.2 [M+H]+ Prom. conn. P047 2-(((6-Chloropyridazin-3-yl)amino)methyl)-1,1,1,3,3,3-hexafluoropropan-2-ol Rt=0.92;
310.1 [M+H]+ Prom. conn. P048 (rac)-(1s,2s,5s)-N-(6-Chloropyridazin-3-yl)-8-methyl-8-azabicyclo[3.2.1]octan-2-amine Rt=0.37;
253.2 [M+H]+ Prom. conn. P049 (R)-6-Chloro-3-((1-ethylpiperidin-3-yl)amino)pyridazine-4-carbonitrile Rt=0.44;
266.3 [M+H]+ Industrial connection P050 (rac)-2-((1s,2s,5s)-2-((6-Chloropyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-ol Rt=0.39;
284.2 [M+H]+ Prom. conn. P051 (R)-2-(3-((6-Chloro-4-methylpyridazin-3-yl)amino)piperidin-1-yl)ethan-1-ol Rt=0.42;
271.3 [M+H]+ Prom. conn. P052 (rac)-((cis)-5-((6-Chloropyridazin-3-yl)amino)-1-methylpiperidin-2-yl)methanol Rt=0.34;
257.2 [M+H]+ Prom. conn. P053 (rac)-3-((6-Chloropyridazin-3-yl)amino)-2-methylpropan-1,2-diol Rt=0.39;
218.1 [M+H]+ Prom. conn. P054 (rac)-(1s,2r,3s)-3-((6-Chloropyridazin-3-yl)amino)cyclopentane-1,2-diol Rt=0.43;
230.1 [M+H]+ Prom. conn. P055 (R)-6-Chloro-N-(pyrrolidin-2-ylmethyl)pyridazin-3-amine Rt=0.33;
213.2 [M+H]+ Prom. conn. P056 (rac)-1-((6-Chloropyridazin-3-yl)amino)-3-methylbutan-2-ol Rt=0.62;
216.2 [M+H]+ Prom. conn. P057 1-((6-Chloropyridazin-3-yl)amino)-2-methylpropan-2-ol Rt=0.49;
202.1 [M+H]+ Prom. conn. P058 N1-(6-Chloropyridazin-3-yl)-N2,N2,2-trimethylpropane-1,2-diamine Rt=0.36;
229.2 [M+H]+ Prom. conn. P059 (R)-6-Chloro-N-(1-methylpyrrolidin-3-yl)pyridazin-3-amine Rt=0.32;
213.1 [M+H]+ Industrial connection P060 1-((6-Chloropyridazin-3-yl)oxy)-2-methylpropan-2-ol Rt=0.58;
203.1 [M+H]+ Prom. conn. P061 (R)-6-Chloro-N-(piperidin-2-ylmethyl)pyridazin-3-amine Rt=0.37;
227.1 [M+H]+ Prom. conn. P062 (S)-6-Chloro-N-(piperidin-2-ylmethyl)pyridazin-3-amine Rt=0.37;
227.1 [M+H]+ Prom. conn. P063 (S)-6-Chloro-N-((4,4-difluoropyrrolidin-2-yl)methyl)pyridazin-3-amine Rt=0.37;
249.1 [M+H]+ Prom. conn. P064 (R)-6-Chloro-N-((4,4-difluoropyrrolidin-2-yl)methyl)pyridazin-3-amine Rt=0.37;
249.1 [M+H]+ Industrial connection P065 (rac)-trans-2-((6-Chloropyridazin-3-yl)amino)cyclopentanol Rt=0.55;
214.2 [M+H]+ Prom. conn. P066 2-((6-Chloropyridazin-3-yl)amino)ethanol Rt=0.36;
174.0 [M+H]+ Prom. conn. P067 2-((6-Chloro-4-(trifluoromethyl)pyridazin-3-yl)amino)ethanol Rt=0.65;
242.1 [M+H]+ Prom. conn. P068 6-Chloro-N-(2,2,2-trifluoroethyl)pyridazin-3-amine Rt=0.33;
212.1 [M+H]+ Prom. conn. P069 6-Chloro-N-(pyridin-2-ylmethyl)pyridazin-3-amine Rt=0.45;
221.1 [M+H]+ Prom. conn. P070 N1-(6-Chloropyridazin-3-yl)-2-methylpropan-1,2-diamine Rt=0.33;
201.1 [M+H]+ Prom. conn. P071 (S)-3-Methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; Rt=0.68;
353.2 [M+H]+ Prom. conn. P072 cis-3-((6-Chloropyridazin-3-yl)amino)cyclobutan-1-ol Rt=0.41;
200.1 [M+H]+ Prom. conn. P073 trans-3-((6-Chloropyridazin-3-yl)amino)cyclobutan-1-ol Rt=0.43;
200.1 [M+H]+ Prom. conn. P074 (S)-6-Chloro-N-(piperidin-3-yl)pyridazin-3-amine Rt=0.35;
213.2 [M+H]+ Prom. conn. P075 6-Chloro-N-((2-methylpyridin-3-yl)methyl)pyridazin-3-amine Rt=0.37;
235.1 [M+H]+ Prom. conn. P076 (S)-6-Chloro-N-(1-methylpiperidin-3-yl)pyridazin-3-amine Rt=0.33;
227.2 [M+H]+ Prom. conn. P077 (1R,3R)-3-((6-Chloropyridazin-3-yl)amino)cyclohexan-1-ol Rt=0.57;
228.1 [M+H]+ Prom. conn. P078 (1S,3S)-3-((6-Iodopyridazin-3-yl)amino)cyclohexan-1-ol Rt=0.61;
320.1 [M+H]+ Prom. conn. P079 (R)-3-((6-Iodopyridazin-3-yl)amino)-1-methylpiperidin-2-one Rt=0.59;
333.0 [M+H]+ Prom. conn. P080 (R)-5-((6-Chloropyridazin-3-yl)amino)piperidin-2-one Rt=0.45;
227.1 [M+H]+ Prom. conn. P081 (R)-3-Fluoro-4-((6-iodopyridazin-3-yl)amino)-2-methylbutan-2-ol Rt=0.63;
326.0 [M+H]+ Prom. conn. P082 6-Iodo-N-(6-(trifluoromethyl)piperidin-3-yl)pyridazin-3-amine Rt=0.68;
373.1 [M+H]+ Prom. conn. P083 (R)-6-Chloro-N-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)pyridazin-3-amine Rt=0.91;
295.1 [M+H]+ Prom. conn. P084 cis-3-((6-Chloropyridazin-3-yl)amino)-1-(trifluoromethyl)cyclobutan-1-ol Rt=0.68;
268.0 [M+H]+ Prom. conn. P085 1-((6-Chloro-4-methylpyridazin-3-yl)amino)-2-methylpropan-2-ol Rt=0.59;
216.1 [M+H]+ Prom. conn. P086 1-((6-Chloro-5-methylpyridazin-3-yl)amino)-2-methylpropan-2-ol Rt=0.57;
216.1 [M+H]+ Prom. conn. P087 (R)-6-Chloro-4,5-dimethyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine Rt=0.51
255.3 [M+H]+ Prom. conn. P088 1-(tert-Butyl)-2-methyl-5-((6-chloropyridazin-3-yl)amino)piperidine-1,2-dicarboxylate Rt=0.95
371.4 [M+H]+ Prom. conn. P089 6-Chloro-N-(pyrimidin-5-yl)pyridazin-3-amine Rt=0.51
208.1 [M+H]+ Prom. conn. P090 6-Chloro-N-cyclopropylpyridazine-3-amine Rt=0.53
170.1 [M+H]+ Prom. conn. P091 6-Chloro-N-(pyridin-3-yl)pyridazin-3-amine Rt=0.44
207.1 [M+H]+ Prom. conn. P092 (rac)-6-Chloro-N-(1,3-dimethylpiperidin-3-yl)pyridazin-3-amine Rt=0.43
241.1 [M+H]+ Prom. conn. P093 tert-Butyl-(R)-3-((6-chloropyridazin-3-yl)amino)piperidine-1-carboxylate Rt=0.98;
313.3 [M+H]+ Prom. conn. P094 tert-Butyl (2S,4S)-2-(((6-chloropyridazin-3-yl)amino)methyl)-4-fluoropyrrolidine-1-carboxylate Rt=0.97;
331.2 [M+H]+ Prom. conn. P095 tert-Butyl-(2S,4R)-2-(((6-chloropyridazin-3-yl)amino)methyl)-4-fluoropyrrolidine-1-carboxylate Rt=0.98;
331.3 [M+H]+ Prom. conn. P096 (rac)-6-Chloro-N-((4-methylmorpholin-3-yl)methyl)pyridazin-3-amine Rt=0.39;
243.3 [M+H]+ Prom. conn. P097 (S)-3-((6-Chloropyridazin-3-yl)amino)-1,1,1-trifluoro-2-methylpropan-2-ol Rt=0.75;
256.1 [M+H]+ Prom. conn. P098 2-((6-Chloropyridazin-3-yl)amino)-2-methylpropan-1-ol Rt=0.61;
202.0 [M+H]+ Prom. conn. P099 (rac)-Benzyl-(cis)-3-((6-chloropyridazin-3-yl)amino)-2-methylpiperidine-1-carboxylate Rt=1.07;
361.2 [M+H]+ Industrial connection P100 (R)-6-Chloro-N-(piperidin-3-yl)pyridazin-3-amine Rt=0.39;
213.1 [M+H]+ Industrial connection P101 4-(2-((6-Chloropyridazin-3-yl)amino)ethyl)benzenesulfonamide Rt=0.63;
313.3 [M+H] ⁺ Industrial connection P102 (rac)-trans-6-Chloro-N-(5-fluoropiperidin-3-yl)pyridazin-3-amine Rt=0.38;
231.1 [M+H] ⁺ Industrial connection P103 (rac)-cis-6-Chloro-N-(5-fluoro-1-methylpiperidin-3-yl)pyridazin-3-amine Rt=0.32;
245.1 [M+H] ⁺ Industrial connection P104 (rac)-cis-6-Chloro-N-(5-fluoropiperidin-3-yl)pyridazin-3-amine Rt=0.33;
231.1 [M+H] ⁺

Additional modifications of piperazine intermediates

1-((R)-3-((6-Chloropyridazin-3-yl)amino)piperidin-1-yl)propan-2-ol, prom. comp. P105

Industrial connection P100(200 mg, 0.621 mmol) dissolved in 2 ml DMF before addition of K₂CO₃(429 mg, 3.11 mmol) and 1-chloropropan-2-ol (0.23 mL, 1.86 mmol). The yellow suspension was stirred at 100 °C for 4.5 h and then at 120 °C for 1.5 h. The mixture was cooled to rt, diluted with a small amount of water and purified by reverse-phase achiral HPLC to give the title compound as a pale 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, prom. comp. P106

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

SYNTHESIS OF SELECTED AMINES FOR THE ABOVE INTERMEDIATES

Dihydrochloride (R)-2-(3-aminopiperidin-1-yl)ethan-1-ol, ind. comp. A107

(1) tert-Butyl (R)-(1-(2-hydroxyethyl) piperidin-3-yl) carbamate, ind. comp. A108

A suspension of tert-butyl (R)-piperidin-3-ylcarbamate (10 g, 49.9 mmol), 2-bromoethane-1-ol (6.24 g, 49.9 mmol) and Na₂CO₃(10.58 g, 100 mmol) in 100 mL of acetonitrile was stirred at rt for 2 days. The suspension was filtered and the solid was washed several times with acetonitrile. The combined filtrates were evaporated. The residue was purified by column chromatography on silica gel using CH₂Cl₂and MeOH (0% to 10%) to give the title compound. LC-MS: Rt=0.40 min; MS m/z 245.1 [M+H]⁺

(2) Dihydrochloride (R)-2-(3-aminopiperidin-1-yl)ethan-1-ol, ind. comp. A107

A solution of ind. comp. 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 rt for 3 h. The precipitated material was filtered, washed several times with 1,4-dioxane and dried overnight at 60 °C under high vacuum to give the title compound. LC-MS: Rt = 0.15 min; MS m/z 145.2 [M+H] ⁺

1-(tert-Butyl)-2-methyl-5-aminopiperidine-1,2-dicarboxylate, ind. comp. A109

(1) 1-(tert-Butyl)-2-methyl-5-hydroxypiperidine-1,2-dicarboxylate, ind. comp. A110

1-tert-Butyl 2-methyl-5-oxopiperidine-1,2-dicarboxylate (500 mg, 1.943 mmol) was dissolved in 15 mL MeOH and cooled to 0 °C. NaBH ₄ (73.5 mg, 19.43 mmol) was added portionwise. After stirring for 3 h, half of the MeOH was removed under reduced pressure. The residue was diluted with EtOAc and washed successively with 0.5 M HCl, 0.5 M NaOH and brine. The organic extract was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound as a colorless oil. The mixture of diastereomers was used without further purification. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 4.95 (d, 1H), 4.70-4.54 (m, 1H), 3.97-3.84 (m, 1H), 3.68 and 3.67 (2 s (diastereomers), 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 (2 s (diastereomers), 9H), 1.04-0.94 (m, 1H).

(2) 1-(tert-Butyl)-2-methyl-5-azidopiperidine-1,2-dicarboxylate, ind. conn. A111

Prom. A110 (526 mg, 1.927 mmol) was dissolved in 10 mL of toluene and treated at rt with _PPh3 (1.064 g, 4.06 mmol) and Zn( _N3 ) ₂ (468 mg, 1.521 mmol). Then DIAD (0.789 mL, 4.06 mmol) was added dropwise to this mixture. After stirring at rt for 4 h, the reaction mixture was filtered through Hyflo and washed with EtOAc. The filtrate was evaporated and the crude material was purified by column chromatography on silica gel (50 g) using n-heptane and EtOAc (10% to 80%) to give the title compound as a mixture of diastereomers. ¹ H-NMR (400 MHz, DMSO-d ₆ ) 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 (2 s (diastereomers), 9H).

(3) 1-(tert-Butyl)-2-methyl-5-aminopiperidine-1,2-dicarboxylate, ind. comp. A109

To a suspension of Pd/C (159 mg, 0.15 mmol, Pd content 10%) in 10 mL MeOH was added a solution of ind. comp. A111 (426 mg, 1.498 mmol) in 30 mL MeOH. The mixture was hydrogenated at atmospheric pressure at rt for 1 h. The mixture 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 was used without further purification. ¹ H-NMR (400 MHz, DMSO-d ₆ ) 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) overlap with 1.38 (s, 9H).

SYNTHESIS OF EXAMPLES

Example pr. 001

(R)-2-(6-((1-Ethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

Prom. comp. P024 (770 mg, 1.663 mmol) and prom. comp. B010 (754 mg, 2.495 mmol) were dissolved in 8 mL _of 1,4-dioxane and 2 M _Na2CO3 (0.25 mL, 0.499 mmol) was added. Then Pd( _Ph3P ) ₄ (96 mg, 0.083 mmol) was added and the reaction mixture was purged with nitrogen for 5 min and then stirred at 120 °C for 1 h under microwave irradiation. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic extracts were evaporated and the residue was purified by column chromatography on silica gel using _CH2Cl2 and _MeOH (0% to 10%) to give the title compound. ^1H NMR (600 MHz, 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=0.42 min; MS mass/charge 241.3 [M+H] ⁺

Example pr. 002

2-(6-((( cis )-3-Hydroxy-3-methylcyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

A mixture of prom. P037 (50 mg, 0.145 mmol), prom. B005 (35.1 mg, 0.160 mmol) and 2 M _Na2CO3 (0.218 mL, 0.435 mmol) in 1 mL DME and 1 mL water was purged _with argon for 3 min. Then Pd( _PPh3 ) ₄ (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 _CH2Cl2 and MeOH (0% to 4%) to give the title compound as a pale yellow solid. ¹ H-NMR (400 MHz, 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=0.80 min; MS mass/charge 354.1 [M+H] ⁺

Example pr. 003

2-(6-(((1R,3S)-3-Hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

A mixture of ind. comp. P038 (50 mg, 0.220 mmol), ind. comp. B010 (73.0 mg, 0.242 mmol) _, and 2 M _Na2CO3 (0.329 mL, 0.659 mmol) in 5 mL of 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 portion of ind. comp. B010 (50.0 mg, 0.166 mmol) together with additional Pd( _PPh3 ) ₄ (5 mg, 4.33 μmol) and heating was continued for 24 h. The reaction mixture was allowed to cool to rt. It was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over _Na2SO4 , filtered and evaporated. The crude material was purified by SFC (column: Waters TORUS 2-PIC 130A, 250 x 30 _mm , 5 μm; 35 °C, eluent B: 17-25% MeOH over 10 min, flow rate: 100 mL/min, pressure: 120 bar) to afford the title compound as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) 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=0.78 min; MS m/z 368.2 [M+H] ⁺

Example pr. 004

(R)-2-(4-Methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol

A mixture of ind. comp. 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 of 1,4-dioxane was heated at 105 °C overnight. For complete conversion, another portion 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 material was purified by column chromatography on silica gel (40 g) using _CH2Cl2 and _MeOH (0% to 20%). The product-containing fractions were evaporated and triturated _{with CH2Cl2} to give the title compound as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) 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), 2.89-2.8 2 (m, 1H), 2.18 (s, 3H), 2.01 (s, 3H, overlap 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 mass/charge 367.3 [M+H] ⁺

Example pr. 005

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

A mixture of the amine, ind. comp. P030 (76 mg, 0.316 mmol), ind. comp. B010 boronate ₍ 124 mg, 0.410 mmol) and aqueous 2 M _Na2CO3 (0.474 mL, 0.947 mmol) in 2 mL of 1,4-dioxane was 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 h. Another portion of ind. comp. 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 cooled to rt, 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 material was purified by SFC (column: Waters Viridis 2-EP 130A, 250 x 30 _mm , 5 μm; 35 °C, eluent B: 16-24% MeOH over 10 min, flow rate: 100 ml/min, pressure: 120 bar) to afford the title compound as a white solid. ^1H NMR (400 MHz, 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=0.74 min; MS m/z 381.3 [M+H] ⁺

The following examples were synthesized analogously to the above procedures using the appropriate halopyridazine intermediates ( prom. comp. P ) and the corresponding boronic acids or boronate intermediates ( prom. comp. B ) or commercially available boronic acids ( BCA ), respectively, optionally followed by deprotection steps.

No. pr. Structure and name ¹ H NMR LC-MS
(min; mass/charge) IntP
And
IntB Ex. 006
(R)-2-(6-((1-(2-Hydroxyethyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.15 (s, 1H), 7.22 (d,1H), 7.10 (s, 1H), 7.04 (s, 1H), 6 .87 (d, 1H), 6.78 (d, 1H), 4.45-4.34 (m, 1H), 4.19-4.01 (m, 1H), 3.50 (q, 2H ), 3.00-2.88 (m, 1H), 2.75-2.59 (m, 1H), 2.47-2.35 (m, 2H), 2.13 (s, 3H), 2.18-1.98 (m, 1H), 1.90-1.80 (m, 1H), 1.76-1.65 (m, 1H), 1.61-1.46 (m, 1H), 1.39-1.27 (m, 1H). Rt=0.70;
397.2 [M+H]+ Industrial connection P040
And
prom. conn. B010 Ex. 007
2-(6-((1-Isopropylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.18 (s, 1H), 7.28 (d, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 6 .90 (d, 1H), 4.11 (q, 1H), 3.16 (d, 2H), 2.12 (s, 3H), 2.06-1.34 (m, 5H), 1, 33-0.89 (m, 8H). Rt=0.71;
395.4 [M+H]+ Prom. conn. P042
And
prom. conn. B010 Ex. 008
(S)-2-(6-(((1-Ethylpyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.18 (s, 1H), 7.24 (d, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6 .95 (d, 1H), 6.80 (broad s, 1H), 3.72-3.61 (m, 1H), 3.26-3.07 (s, 2H), 3.03-2, 84 (m, 1H), 2.12 (s, 3H), 2.01-1.86 (m, 1H), 1.82-1.53 (m, 3H), 1.18-1.01 ( m, 3H). Rt=0.70;
381.4 [M+H]+ Prom. conn. P045
And
prom. conn. B010 Ex. 009
2-(6-((5,5-Difluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.19 (s, 1H), 7.31 (d, 1H), 7.13 (s, 1H), 7.12 (s, 1H), 7 .06 (s, 1H), 6.91 (d, 1H), 4.44-4.33 (m, 1H), 4.18-4.08 (m, 2H), 3.54-3.21 (d, 2H), 2.75-2.64 (m, 1H), 2.63-2.54 (m, 1H), 2.12 (s, 3H). Rt=0.71;
389.3 [M+H]+ Prom. conn. P046
And
prom. conn. B010 Ave. 010
3-Methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.29 (bs, 1H), 10.00 (bs, 1H), 7.66 (m, 1H), 7.43 (d, 1H), 7 .19 (d, 1H), 7.12 (s, 1H), 7.06 (s, 1H), 4.07 (d, 2H), 2.12 (s, 3H). Rt=1.13;
450.2 [M+H]+ Prom. conn. P047
And
prom. conn. B010 Ex. 011
(R)-3-((1-Ethylpiperidin-3-yl)amino)-6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile (600 MHz, DMSO-d ₆ ) δ (ppm) 10.30 (s, 1H), 7.92 (s, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 4 .38 (s, 1H), 3.10-2.58 (m, 2H), 2.46-2.31 (m, 2H), 2.25-2.00 (m, 1H), 2.15 (s, 3H), 1.96 -1.44 (m, 5H), 1.20-1.00 (m, 3H). Rt=0.77;
406.3 [M+H]+ Prom. conn. P049
And
prom. conn. B010 Ex. 012
(R)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.17 (s, 1H), 7.23 (d, 1H), 7.10 (s, 1H), 7.05 (d, 1H), 6 .89 (d, 1H), 4.17-4.05 (m, 1H), 2.35-2.21 (m, 3H), 2.12 (s, 3H), 1.92-1.83 (m, 2H), 1.81-1.72 (m, 1H), 1.64-1.52 (m, 1H), 1.40-1.29 (m, 1H). Rt=0.69;
367 [M+H]+ Industrial connection P025
And
prom. conn. B010 Ex. 013
(R)-2-(6-((1-(2-Hydroxyethyl)piperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.17 (s, 1H), 9.67 (s, 1H), 7.19 (d, 1H), 7.11 (d, 1H), 7 .07 (s, 1H), 6.26 (s, 1H), 5.39-5.23 (m, 1H), 4.77-4.51 (m, 1H), 3.84-3.62 (m, 2H), 3.25-3.14 (m, 1H), 2.20-2.11 (m, 2H), 2.11 (s, 3H), 2.15-1.50 (m , 6H). Rt=0.71;
411 [M+H]+ Prom. conn. P051
And
prom. conn. B010 Ex. 014
(R)-3-Methyl-2-(6-((pyrrolidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 7.26 (d, 1H), 7.11 (s, 1H), 7.07-7.01 (m, 2H), 6.93 (d, 1H), 3.54-3.46 (m, 2H), 3.45-3.39 (m, 1H), 3.03-2.97 (m, 1H), 2.96-2.89 ( m, 1H), 1.99-1.89 (m, 1H), 1.84-1.77 (m, 1H), 1.76-1.70 (m, 1H), 1.57-1, 47 (m, 1H). Rt=0.68;
353 [M+H]+ Prom. conn. P055
And
prom. conn. B010 Ex. 015
2-(6-((2-Hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.16 (s, 1H), 7.22 (d, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 7 .02 (d, 1H), 6.76 (t, 1H), 4.72 (s, 1H), 3.38 (d, 2H), 2.12 (s, 3H), 1.18 (s, 6H). Rt=0.77;
342 [M+H]+ Prom. conn. P057
And
prom. conn. B010 Ex. 016
2-(6-((2-(Dimethylamino)-2-methylpropyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.17 (s, 1H), 7.30-7.18 (m, 1H), 7.15-7.03 (m, 3H), 6, 61-6.33 (m, 1H), 3.48-3.36 (m, 2H), 2.22 (s, 6H), 2.12 (s, 3H), 1.08 (s, 6H) . Rt=0.69;
369 [M+H]+ Prom. conn. P058
And
prom. conn. B010 Ex. 017
(R)-3-Methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.18 (s, 1H), 7.27 (d, 1H), 7.21 (d, 1H), 7.11 (s, 1H), 7 .06 (s, 1H), 6.90 (d, 1H), 4.61-4.46 (m, 1H), 3.28-3.16 (m, 1H), 3.13-3.01 (m, 1H), 2.96-2.79 (m, 2H), 2.65-2.54 (m, 3H), 2.41-2.33 (m, 1H), 2.12 (s , 3H), 1.89-1.80 (m, 1H). Rt=0.65;
353 [M+H]+ Prom. conn. P059
And
prom. conn. B010 Ex. 018
(S)-3-Methyl-2-(6-((1-methylpyrrolidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.15 (s, 1H), 7.22 (d, 1H), 7.13-7.06 (m, 2H), 7.04 (s, 1H), 6.86 (d, 1H), 4.53-4.39 (m, 1H), 2.85-2.74 (m, 1H), 2.73-2.65 (m, 1H) , 2.49-2.45 (m, 1H), 2.45-2.40 (m, 1H), 2.34-2.22 (m, 4H), 2.12 (s, 3H), 1 .71-1.63 (m, 1H). Rt=0.68;
353 [M+H]+ Prom. conn. P071
And
prom. conn. B010 Ave. 019
2-(6-(2-Hydroxy-2-methylpropoxy)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.27 (s, 1H), 7.61 (d, 1H), 7.28 (d, 1H), 7.14 (s, 1H), 7 .07 (d, 1H), 4.73 (s, 1H), 4.24 (s, 2H), 2.10 (s, 3H), 1.24 (s, 6H). Rt=0.94;
343 [M+H]+ Industrial connection P060
And
prom. conn. B010 Ave. 020
(R)-3-Methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 9.99 (br s, 1H), 7.22 (d, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 6.93-6.84 (m, 2H), 3.37-3.32 (m, 2H) overlap with water signal, 3.28-3.21 (m, 1H), 3.00-2.91 (m, 1H), 2.74-2.64 (m, 1H), 2.55-2.51 (m, 1H) overlap with DMSO signal, 2.12 (s, 3H), 1.80-1.72 (m, 1H), 1.70-1.62 (m, 1H), 1.55-1.45 (m, 1H), 1.38-1.26 (m, 2H), 1.13-1.04 (m, 1H). Rt=0.68;
367.3 [M+H]+ Prom. conn. P061
And
prom. conn. B010 Ave. 021
(S)-3-Methyl-2-(6-((piperidin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 7.22 (d, 1H), 7.10 (s, 1H), 7.04 (br s, 1H), 6.92-6.85 (m, 2H), 3.40-3.22 (m, 3H) overlap with water signal, 3.00-2.93 (m, 1H), 2.77-2.65 (m, 1H), 2.55-2.51 (m, 1H) overlap with DMSO signal, 2.13 (s, 3H), 1.80-1.72 (m, 1H), 1.70-1.62 (m, 1H), 1.56-1.47 (m, 1H), 1.37-1.25 (m, 2H), 1.16-1.02 (m, 1H), no phenolic proton was observed. Rt=0.7;
367.3 [M+H]+ Prom. conn. P062
And
prom. conn. B010 Ex. 022
(S)-2-(6-(((4,4-Difluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.19 (s, 1H), 7.24 (d, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 6 .97 (t, 1H), 6.90 (d, 1H), 3.58-3.50 (m, 1H), 3.49-3.42 (m, 2H), 3.28-3.14 (m, 1H), 3.14-3.04 (m, 1H), 3.04-2.88 (m, 1H), 2.42-2.30 (m, 1H), 2.06-1 .91 (m, 1H). Rt=0.71;
389 [M+H]+ Prom. conn. P063
And
prom. conn. B010 Ex. 023
(R)-2-(6-(((4,4-Difluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.16 (s, 1H), 7.26 (d, 1H), 7.11 (s, 1H), 7.07-7.01 (m, 2H), 6.92 (d, 1H), 3.70-3.59 (m, 1H), 3.54-3.46 (m, 2H), 3.31-3.28 (m, 1H) , 3.25-3.12 (m, 1H), 2.47-2.39 (m, 1H), 2.10-1.98 (m, 1H). Rt=0.73;
389 [M+H]+ Prom. conn. P064
And
prom. conn. B010 Ex. 024
( trans )-2-(6-((2-Hydroxycyclopentyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.16 (s, 1H), 7.24 (d, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 6 .97-6.91 (m, 1H), 6.89 (d, 1H), 5.11 (s, 1H), 4.04-3.87 (m, 2H), 1.94-1.82 (m, 1H), 1.77-1.62 (m, 2H), 1.57-1.44 (m, 2H). Rt=0.80;
354 [M+H]+ Industrial connection P065
And
prom. conn. B010 Ex. 025
3,5-Dichloro-2-(6-((2-hydroxyethyl)amino)pyridazin-3-yl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.57 (s, 1H), 7.21 (d, 1H), 7.13 (s, 1H), 7.02-6.96 (m, 1H), 6.95 (s, 1H), 6.90 (d, 1H), 4.89-4.73 (m, 1H), 3.65-3.54 (m, 2H), 3.51 -3.41 (m, 2H). Rt=0.60;
300 [M+H]+ Prom. conn. P066
And
prom. conn. B018 Ex. 026
2-(6-((2-Hydroxyethyl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.27 (s, 1H), 7.66 (s, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 6 .78-6.70 (m, 1H), 4.88-4.80 (m, 1H), 3.72-3.60 (m, 4H), 2.16 (s, 3H). Rt=0.95;
382 [M+H]+ Prom. conn. P067
And
prom. conn. B010 Ex. 027
3,5-Dichloro-2-(6-((2,2,2-trifluoroethyl)amino)pyridazin-3-yl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.58 (s, 1H), 7.61-7.54 (m, 1H), 7.33 (d, 1H), 7.16-7, 13 (m, 1H), 7.02 (d, 1H), 6.98-6.93 (m, 1H), 4.42-4.27 (m, 2H). Rt=1.02;
338 [M+H]+ Prom. conn. P068
And
prom. conn. B018 Ex. 028
3-Methyl-2-(6-((pyridin-2-ylmethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.16 (s, 1H), 8.60-8.50 (m, 1H), 7.82-7.70 (m, 1H), 7, 58-7.50 (m, 1H), 7.41 (d, 1H), 7.31-7.23 (m, 2H), 7.10 (s, 1H), 7.04 (s, 1H) , 7.00 (d, 1H), 4.71 (d, 2H), 2.11 (s, 3H). Rt=0.83;
361 [M+H]+ Prom. conn. P069
And
prom. conn. B010 Ex. 029
2-(6-((2-Amino-2-methylpropyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 7.31 (d, 1H), 7.19-7.13 (m, 1H), 7.12 (s, 1H), 7.06 (s, 1H), 6.99 (d, 1H), 3.59 (d, 2H), 2.14 (s, 3H), 1.27 (s, 6H). Rt=0.67;
341 [M+H]+ Industrial connection P070
And
prom. conn. B010 Ave. 030
3-Chloro-2-(6-((2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.79 (s, 1H), 7.37 (s, 1H), 7.26 (d, 1H), 7.19 (s, 1H), 7 .04 (d, 1H), 6.88-6.83 (m, 1H), 4.70 (s, 1H), 3.42-3.35 (m, 2H), 1.18 (s, 6H ). Rt=0.88;
362 [M+H]+ Prom. conn. P057
And
prom. conn. B001 Ex. 031
3-Chloro-2-(6-(( cis -3-hydroxycyclobutyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.79 (s, 1H), 7.37 (s, 1H), 7.31-7.22 (m, 2H), 7.18 (s, 1H), 6.81 (d, 1H), 5.12 (d, 1H), 4.03-3.78 (m, 2H), 2.78-2.63 (m, 2H), 1.94 -1.63 (m, 2H). Rt=0.83;
360 [M+H]+ Prom. conn. P072
And
prom. conn. B001 Ex. 032
3-Chloro-2-(6-(( trans -3-hydroxycyclobutyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.78 (s, 1H), 7.37 (s, 1H), 7.31 (d, 1H), 7.27 (d, 1H), 7 .18 (d, 1H), 6.80 (d, 1H), 5.07 (d, 1H), 4.44-4.26 (m, 2H), 2.30-2.10 (m, 4H ). Rt=0.81;
360 [M+H]+ Prom. conn. P073
And
prom. conn. B001 Ex. 033
(S)-3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 7.19 (d, 1H), 6.83-6.67 (m, 2H), 6.68-6.48 (m, 2H), 4, 03-3.78 (m, 1H), 3.16-3.04 (m, 1H), 2.87-2.69 (m, 1H), 2.48-2.44 (m, 1H), 2.41-2.30 (m, 1H), 1.99-1.90 (m, 1H), 1.70-1.60 (m, 1H), 1.48-1.31 (m, 2H ). Rt=0.66;
353 [M+H]+ Prom. conn. P074
And
prom. conn. B010 Ex. 034
3-Chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.78 (s, 1H), 8.34 (d, 1H), 7.68 (d, 1H), 7.56-7.46 (m, 1H), 7.37 (s, 1H), 7.31 (d, 1H), 7.24-7.17 (m, 2H), 6.96 (d, 1H), 4.61 (d, 2H ), 2.56 (s, 3H). Rt=0.79;
395 [M+H]+ Prom. conn. P075
And
prom. conn. B001 Ex. 035
5-Chloro-2-(6-(((2-methylpyridin-3-yl)methyl)amino)pyridazin-3-yl)-3-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.69 (s, 1H), 8.41-8.26 (m, 1H), 7.66 (d, 1H), 7.43-7, 39 (m, 1H), 7.30 (s, 1H), 7.27-7.17 (m, 3H), 6.92 (d, 1H), 4.60 (d, 2H), 2.55 (s, 3H). Rt=0.73;
395 [M+H]+ Prom. conn. P075
And
prom. conn. B001 Ex. 036
(S)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.17 (s, 1H), 7.23 (d, 1H), 7.10 (s, 1H), 7.05 (d, 1H), 6 .89 (d, 1H), 4.17-4.05 (m, 1H), 2.35-2.21 (m, 3H), 2.12 (s, 3H), 1.92-1.83 (m, 2H), 1.81-1.72 (m, 1H), 1.64-1.52 (m, 1H), 1.40-1.29 (m, 1H). Rt=0.67;
367 [M+H]+ Prom. conn. P076
And
prom. conn. B010 Ex. 037
3-Chloro-2-(6-((2-hydroxyethyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (600 MHz, DMSO-d ₆ ) δ (ppm) 10.79 (s, 1H), 7.37 (d, 1H), 7.26 (d, 1H), 7.19 (d, 1H), 7 .03 (t, 1H), 6.92 (d, 1H), 4.81 (t, 1H), 3.61 (q, 2H), 3.47 (q, 2H). Rt=0.78;
334 [M+H]+ Prom. conn. P066
And
prom. conn. B001 Ex. 038
TFA salt of (R)-5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) (ppm) 9.66 (s, 1H), 7.74 (d, 1H), 7.50 (d, 1H), 7.06 (d, 1H ), 6.98 (dd, 1H), 6.92-6.85 (m, 1H), 4.34-4.24 (m, 1H), 3.72 (d, 1H), 3.22 ( d, 1H), 2.91 (d, 1H), 2.84 (d, 3H), 2.78 (s, 1H), 2.75-2.63 (m, 1H), 1.88-1 .67 (m, 2H), 1.55-1.40 (m, 1H). Rt=0.76;
337.2 [M+H]+ Industrial connection P025
And
prom. conn. B022 Ex. 039
(R)-2-(6-((1-Methylpiperidin-3-yl)amino)pyridazin-3-yl)-3,5-bis(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) (ppm) 10.98 (s, 1H), 7.57-7.45 (m, 2H), 7.24 (d, 1H), 6.89 (d, 1H), 6.84 (d, 1H), 4.09 (s br, 1H), 2.86 (d, 1H), 2.58-2.55 (m, 1H), 2.19 (s, 3H), 2.10-2.03 (m, 1H), 1.99-1.94 (m, 1H), 1.88-1.82 (m, 1H), 1.77-1 .70 (m, 1H), 1.59-1.51 (m, 1H), 1.37-1.28 (m, 1H). Rt=0.75;
424.4 [M+H]+ Industrial connection P025
And
prom. conn. B023 Ex. 040
TFA salt of 2-(4,5-dimethyl-6-(((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) (ppm) 10.52 (s, 1H), 9.96-9.64 (m, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.61 (s br, 1H), 4.53-4.39 (m, 1H), 3.68-3.60 (m, 1H), 3.49-3.42 ( m, 1H), 2.93-2.76 (m, 5H), 2.25 (s, 3H), 2.08-1.92 (m, 8H), 1.86-1.60 (m, 2H). Rt=0.72 and 0.76 (atropisomers);
395.3 [M+H]+ Prom. conn. P087
And
prom. conn. B010 Ex. 041
5-((6-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-2-carboxylic acid (400 MHz, DMSO-d ₆ ) δ (ppm) (ppm) 10.17 (s, 1H), 7.26 (d, 1H), 7.10 (d, 1H), 7.05 (d, 1H ), 6.91 (d, 1H), 6.86 (d, 1H), 4.15 (s, 1H), 3.42 (s, 1H), 3.15 (d, 1H), 2.63 -2.57 (m, 1H), 2.25-2.12 (m, 5H), 1.54 (dp, 2H). Rt=0.70;
397.3 [M+H]+ Prom. conn. P088
And
prom. conn. B010 Ex. 042
(R)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)oxy)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) (ppm) 10.23 (s, 1H), 7.60 (d, 1H), 7.23 (d, 1H), 7.15 (s, 1H ), 7.08 (d, 1H), 5.29 (tt, 1H), 2.99-2.90 (m, 1H), 2.57-2.53 (m, 1H), 2.25- 2.18 (m, 1H), 2.21 (s, 3H), 2.11 (s, 3H), 2.07-1.99 (m, 1H), 1.81-1.72 (m, 1H), 1.64-1.45 (m, 2H). Rt=0.71;
368.4 [M+H]+ Prom. conn. P039
And
prom. conn. B010 Ex. 043
3-Methyl-2-(6-(pyrimidin-5-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.27 (s, 1H), 9.77 (s, 1H), 9.26 (s, 2H), 8.80 (s, 1H), 7 .55 (d, 1H), 7.29 (d, 1H), 7.14 (d, 1H), 7.08 (d, 1H), 2.15 (s, 3H). Rt=0.84;
348.3 [M+H]+ Prom. conn. P089
And
prom. conn. B010 Ex. 044
3,5-Dichloro-2-(6-(cyclopropylamino)pyridazin-3-yl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.56 (s, 1H), 7.38 (d, 1H), 7.30 (d, 1H), 7.14 (d, 1H), 6 .99-6.90 (m, 2H), 2.68-2.60 (m, 1H), 0.75 (dt, 2H), 0.55-0.37 (m, 2H). Rt=0.84;
296.1 [M+H]+ Prom. conn. P090
And
prom. conn. B018 Ex. 045
TFA salt of (R)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.60 (s, 1H), 7.21 (d, 1H), 7.11 (d, 1H), 6.95 (d, 1H), 6 .88 (d, 1H), 6.82 (d, 1H), 4.07 (s br, 1H), 2.88-2.83 (m, 1H), 2.56-2.53 (m, 1H), 2.08-1.98 (m, 1H), 1.97-1.90 (m, 1H), 1.88-1.78 (m, 1H), 1.75-1.68 ( m, 1H), 1.59-1.49 (m, 1H), 1.39-1.25 (m, 1H). Rt=0.66;
353.2 [M+H]+ Industrial connection P025
And
prom. conn. B018 Ex. 046
3-Methyl-2-(6-(pyridin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.24 (s, 1H), 9.56 (s, 1H), 8.88 (d, 1H), 8.36 (ddd, 1H), 8 .18 (dd, 1H), 7.50 (d, 1H), 7.37 (dd, 1H), 7.24 (d, 1H), 7.13 (s, 1H), 7.07 (s, 1H), 2.15 (s, 3H). Rt=0.80;
346.9 [M+H]+ Prom. conn. P091
And
prom. conn. B010 Ex. 047
(R)-3,5-Dimethyl-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 9.43 (s, 1H), 7.21 (d, 1H), 6.86 (d, 1H), 6.79 (s br, 1H), 6.56 (s, 1H), 6.55 (s, 1H), 4.29 (s br,1H), 3.32-3.29 (m, 4H), 2.21 (s, 3H), 2.03 (s, 3H), 1.95-1.81 (m, 2H), 1.71-1.58 (m, 1H), 1.46-1.35 (m, 1H). Rt=0.56;
313.3 [M+H]+ Industrial connection P025
And
prom. conn. B013 Ex. 048
(R)-2-(4,5-Dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.34 (s, 1H), 7.37 (d, 1H), 7.26-7.16 (m, 2H), 5.65 (d, 1H), 4.29-4.20 (m, 1H), 2.93-2.89 (m, 1H), 2.64-2.56 (m, 1H), 2.18 (s, 3H) , 2.06 (s, 3H), 1.97 (s, 3H), 1.95-1.82 (m, 4H), 1.74-1.66 (m, 1H), 1.60-1 .50 (m, 1H), 1.50-1.34 (m, 1H). Rt=0.71;
381.3 [M+H]+ Prom. conn. P087
And
BCA Ex. 049
(R)-3-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.78 (s, 1H), 7.37 (s, 1H), 7.27 (d, 1H), 7.20 (s, 1H), 6 .94 (sbr, 1H), 6.92 (d, 1H), 4.13 (sbr, 1H), 3.08-2.89 (m, 1H), 2.36-2.22 (m , 4H), 1.90-1.84 (m, 1H), 1.81-1.74 (m, 1H), 1.66-1.49 (m, 1H), 1.42-1.33 (m, 1H). Rt=0.72;
387.2 [M+H]+ Industrial connection P025
And
prom. conn. B001 Ex. 050
(R)-5-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 9.32 (s, 1H), 7.26 (s, 1H), 7.24 (s, 1H), 6.97 (d, 1H), 6 .70 (s, 1H), 6.66 (d, 1H), 4.18 (s, 1H), 2.91 (s, 1H), 2.59 (s, 1H), 2.27 (s, 6H), 2.11 (s, 2H), 1.84 (s, 1H), 1.75 (s, 1H), 1.63-1.57 (m, 1H), 1.43-1, 35 (m, 1H). Rt=0.66;
367.2 [M+H]+ Prom. conn. P027
And
commercial Ex. 051
(R)-5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 7.07 (d, 1H), 6.74 (d, 1H), 6.58 (s, 1H), 6.49 (d, 2H), 4 .07-3.99 (m, 1H), 2.89-2.83 (m, 1H), 2.58-2.54 (m, 1H), 2.17 (s, 3H), 2.04 -1.97 (m, 1H), 1.92-1.79 (m, 2H), 1.73-1.67 (m, 1H), 1.58-1.49 (m, 1H), 1 .33-1.24 (m, 1H). Rt=0.70;
387.3 [M+H]+ Industrial connection P025
And
prom. conn. B001 Ex. 052
TFA salt of 2-(6-((1,3-dimethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.19 (s, 1H), 9.11 (s, 1H), 7.30 (s, 1H), 7.12 (s, 1H), 7 .06 (s, 1H), 7.00 (d, 1H), 6.57 (s br, 1H), 4.66 (s, 1H), 3.09-2.58 (m, 4H), 2 .14 (s, 3H), 2.10-2.03 (m, 1H), 1.84-1.73 (m, 1H), 1.63-1.53 (m, 2H), 1.47 (s, 3H). Rt=0.73;
381.2 [M+H]+ Prom. conn. P092
And
prom. conn. B005 Ex. 053
(R)-2-(6-((1-Methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.28 (s, 1H), 7.37 (d, 1H), 7.34 (d, 1H), 7.29 (s, 1H), 7.24-7.16 (m, 2H), 4.23-4.12 (m, 1H), 2.87-2.75 (m, 1H), 2.47 (m, 1H, overlapping with DMSO signal), 2.20 (s, 3H), 2.17-2.00 (m, 2H), 1.88-1.68 (m, 2H), 1.62-1.50 (m, 1H), 1.45-1.33 (m, 1H) Rt=0.73;
421.1 [M+H]+ Prom. conn. P027
And
BCA Ex. 054
2-(6-((( cis )-3-Hydroxy-3-methylcyclobutyl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.13 (br s, 1H), 7.13-7.06 (m, 2H), 7.04 (s, 1H), 6.33 (d , 1H), 4.93 (br s, 1H), 4.20-4.05 (m, 1H), 2.45-2.36 (m, 2H), 2.13 (s, 3H), 2 .11 (s, 3H), 2.10-2.04 (m, 2H), 1.31 (s, 3H). Rt=0.80;
368.2 [M+H]+ Prom. conn. P035
And
prom. conn. B010 Ex. 055
2-(6-((( cis )-3-Hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.44 (s, 1H), 7.39 (d, 1H), 7.30-7.14 (m, 2H), 7.01 (d, 1H), 6.63 (s, 1H), 4.98 (s, 1H), 3.99-3.85 (m, 1H), 2.45-2.37 (m, 2H), 2.02 (s, 3H), 1.99-1.90 (m, 2H), 1.29 (s, 3H). Rt=0.74;
354.2 [M+H]+ Prom. conn. P036
And
BCA Ex. 056
2-(6-((( cis )-3-Hydroxy-3-methylcyclobutyl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.26 (br s, 1H), 7.65 (s, 1H), 7.14 (s, 1H), 7.07 (s, 1H), 6.73 (d, 1H), 4.95 (s, 1H), 4.32-4.21 (m, 1H), 2.47-2.39 (m, 2H), 2.23-2, 16 (m, 2H), 2.15 (s, 3H), 1.30 (s, 3H). Rt=1.05;
422.2 [M+H]+ Prom. conn. P028
And
prom. conn. B010 Ex. 057
2-(6-(((1S,3S)-3-Hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.16 (s, 1H), 7.21 (d, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 6 .84 (d, 1H), 6.71 (br d, 1H), 4.48 (br d, 1H), 4.32-4.23 (m, 1H), 3.94 (br s, 1H) , 2.13 (s, 3H), 1.87-1.74 (m, 2H), 1.73-1.65 (m, 1H), 1.64-1.57 (m, 1H), 1 .56-1.44 (m, 3H), 1.38-1.30 (m, 1H). Rt=0.79;
368.2 [M+H]+ Prom. conn. P078
And
prom. conn. B010 Ex. 058
2-(6-(((1R,3R)-3-Hydroxycyclohexyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.15 (s, 1H), 7.21 (d, 1H), 7.10 (br s, 1H), 7.04 (br s, 1H) , 6.84 (d, 1H), 6.70 (br d, 1H), 4.46 (br d, 1H), 4.33-4.23 (m, 1H), 3.95 (br s, 1H), 2.13 (s, 3H), 1.94-1.27 (m, 8H). Rt=0.79;
368.2 [M+H]+ Prom. conn. P077
And
prom. conn. B010 Ex. 059
(R)-3-((6-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-2-one (400 MHz, DMSO-d ₆ ) δ (ppm) 10.17 (br s, 1H) 7.25 (d, 1H), 7.10 (br s, 1H), 7.08 (d, 1H), 7.05 (br s, 1H), 6.99 (d, 1H), 4.63-4.53 (m, 1H), 3.34 (s, 2H, overlapping with water signal), 2.87 (s, 3H), 2.34-2.24 (m, 1H), 2.13 (s, 3H), 1.95-1.86 (m, 2H), 1.81-1.69 (m, 1H). Rt=0.83;
381.2 [M+H]+ Prom. conn. P079
And
prom. conn. B010 Ave. 060
(R)-2-(6-((2-Fluoro-3-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.13 (br s, 1H), 7.25 (d, 1H), 7.19-7.01 (m, 3H), 6.93 (d , 1H), 4.84 (s, 1H), 4.59-4.27 (m, 1H), 4.06-3.87 (m, 1H), 3.59-3.39 (m, 1H ), 2.12 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H). Rt=0.85;
374.2 [M+H]+ Prom. conn. P081
And
prom. conn. B010 Ex. 061
(R)-5-((6-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidin-2-one (400 MHz, DMSO-d ₆ ) δ (ppm) 10.15 (s, 1H), 7.73 (s, 1H), 7.25 (d, 1H), 7.10 (br s, 1H), 7.05 (br s, 1H), 7.00 (br t, 1H), 6.90 (d, 1H), 3.87-3.78 (m, 1H), 3.56-3.47 (m, 1H), 3.43-3.37 (m, 1H, overlapping with water signal), 2.25-2.09 (m, 3H) overlapping with 2.12 (s, 3H), 1.91-1.72 (m, 1H). Rt=0.74;
367.2 [M+H]+ Prom. conn. P080
And
prom. conn. B010 Ex. 062
3-Methyl-5-(trifluoromethyl)-2-(6-((6-(trifluoromethyl)piperidin-3-yl)amino)pyridazin-3-yl)phenol (400 MHz, DMSO-d ₆ ) mixture of isomers δ (ppm) 10.2 (br s, 1H), 7.69-7.49 (m, 2H), 7.23 (br d, 1H), 7, 09 (s, 1H), 7.04 (s, 1H), 7.00-6.85 (m, 2H), 4.05 (br s, 1H), 3.11-2.77 (m, 2H ), 2.13 (s, 3H), 2.07-1.56 (m, 4H). Rt=0.94;
421.3 [M+H]+ Prom. conn. P082
And
prom. conn. B010 Ex. 063
(R)-3-Methyl-2-(6-((1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.15 (br s, 1H), 7.23 (d, 1H), 7.09 (br s, 1H), 7.05 (br s, 1H ), 6.86 (d, 1H), 6.77 (d, 1H), 4.12-4.00 (m, 1H), 3.28-3.14 (m, 3H), 2.88- 2.81 (m, 1H), 2.43-2.34 (m, 1H), 2.31-2.22 (m, 1H), 2.13 (s, 3H), 1.97-1, 89 (m, 1H), 1.77-1.66 (m, 1H), 1.64-1.50 (m, 1H), 1.35-1.22 (m, 1H). Rt=1.09;
435.2 [M+H]+ Prom. conn. P083
And
prom. conn. B010 Ex. 064
(R)-3-Methyl-2-(6-((1-methylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.35 (br s, 1H), 7.67 (s, 1H), 7.14 (s, 1H), 7.07 (s, 1H), 6.14 (br d, 1H), 4.50 (br s, 1H), 2.67 (br s, 1H), 2.40-2.08 (m, 3H) overlapping with 2.21 (s, 3H) and 2.15 (s, 3H), 1.76-1.47 (m, 4H). Rt=0.81;
435.3 [M+H]+ Prom. conn. P026
And
prom. conn. B010 Ex. 065
(R)-2-(5-Methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO- _d6 ) δ (ppm) 14.53 (s, 1H), 8.14 (s, 1H), 8.08 (d, 1H), 7.25-7.19 (overlap d , 1H and s, 1H), 6.30 (d, 1H), 4.29-4.19 (m, 1H), 2.97-2.88 (m, 1H), 2.68-2.60 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H), 2.01-1.82 (m, 3H), 1.75-1.66 (m, 1H), 1.63-1.50 (m, 1H), 1.49-1.38 (m, 1H). Rt=0.81;
367.3 [M+H]+ Industrial connection P030
And
BCA Ex. 066
2-(6-((( cis )-3-Hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) very broad signals δ (ppm) 10.29 (s, 1H), 7.67 (s, 1H), 7.37 (s, 1H), 7.30-7.03 (m, 3H), 5.06 (s, 1H), 4.15-3.87 (m, 1H), 2.47-2.36 (m, 2H, overlapping with DMSO signal), 2.09-1.86 (m, 2H), 1.30 (s, 3H). Rt=0.94;
408.2 [M+H]+ Prom. conn. P029
And
BCA Ex. 067
2-(6-((( cis )-3-Hydroxy-3-(trifluoromethyl)cyclobutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.14 (s, 1H), 7.36 (d, 1H), 7.26 (d, 1H), 7.10 (s, 1H), 7 .05 (s, 1H), 6.84 (d, 1H), 6.65 (s, 1H), 4.24-4.11 (m, 1H), 2.95-2.85 (m, 2H ), 2.24-2.15 (m, 2H), 2.11 (s, 3H). Rt=0.94;
408.2 [M+H]+ Prom. conn. P084
And
prom. conn. B005 Ex. 068
5-Chloro-2-(6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.29 (s, 1H), 7.18 (d, 1H), 7.02-6.85 (m, 3H), 6.60 (s, 1H), 4.97 (s, 1H), 4.05-3.73 (m, 1H), 2.40 (dd, 2H), 2.02 (s, 3H), 1.94 (dd, 2H ), 1.28 (s, 3H). Rt=0.66;
320.1 [M+H]+ Prom. conn. P036
And
BCA Ex. 069
5-Chloro-2-(6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.03 (s, 1H), 7.62 (d, 1H), 7.18-7.09 (m, 2H), 6.96-6, 84 (m, 2H), 5.04 (s, 1H), 4.10-3.94 (m, 1H), 2.48-2.39 (m, 2H), 2.03-1.92 ( m, 2H), 1.30 (s, 3H). Rt=0.88;
374.1 [M+H]+ Prom. conn. P029
And
BCA Ave. 070
( R )-5-Chloro-2-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.03 (s, 1H), 7.39-7.22 (m, 2H), 7.14 (d, 1H), 7.01-6.83 (m, 2H), 4.23-4.09 (m, 1H), 2.86-2.73 (m, 1H), 2.47-2.43 (m, 1H, overlapping with DMSO signal), 2.19 (s, 3H), 2.16-2.08 (m, 1H), 2.07-1.95 (m, 1H), 1.88-1.78 (m, 1H), 1.77-1.66 (m, 1H), 1.62-1.48 (m, 1H), 1.45-1.31 (m, 1H). Rt=0.72;
387.2 [M+H]+ Prom. conn. P027
And
BCA Ex. 071
( R )-5-Chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.29 (s, 1H), 7.18 (d, 1H), 6.97-6.90 (m, 2H), 6.68 (s, 1H), 6.59 (d, 1H), 4.09-3.97 (m, 1H), 2.92-2.80 (m, 1H), 2.60-2.52 (m, 1H) , 2.18 (s, 3H), 2.01 (s, 3H), 2.00-1.96 (m, 1H), 1.94-1.87 (m, 1H), 1.86-1 .78 (m, 1H), 1.76-1.65 (m, 1H), 1.61-1.46 (m, 1H), 1.36-1.21 (m, 1H). Rt=0.60;
333.2 [M+H]+ Prom. conn. P031
And
BCA Ex. 072
2-(6-((2-Hydroxy-2-methylpropyl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.13 (s, 1H), 7.15 (s, 1H), 7.09 (s, 1H), 7.05 (s, 1H), 5 .94 (t, 1H), 5.10 (s, 1H), 3.51 (d, 2H), 2.17 (s, 3H), 2.11 (s, 3H), 1.17 (s, 6H). Rt=0.81;
356.2 [M+H]+ Prom. conn. P085
And
prom. conn. B010 Ex. 073
2-(6-((2-Hydroxy-2-methylpropyl)amino)-4-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, CDCl ₃ ) δ (ppm) 7.03 (s, 1H), 6.96 (s, 1H), 6.65 (s, 1H), 5.50 (s, 1H), 3.39 (d, 2H), 2.04 (s, 3H), 1.97 (s, 3H), 1.29 (s, 3H), 1.29 (s, 3H). Rt=0.73;
356.3 [M+H]+ Prom. conn. P086
And
prom. conn. B005 Ex. 074
(R)-3-Methyl-2-(6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ +TFA) δ (ppm) 9.14 (br s, 1H), 8.89 (br s, 1H), 8.73-8.52 (br s, 1H), 7 .97 (d, 1H), 7.66 (d, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 4.13-4.03 (m, 1H), 3, 48-3.41 (m, 1H), 3.26-3.15 (m, 1H), 3.07-2.92 (m, 2H), 2.22 (s, 3H), 2.15- 2.07 (m, 1H), 2.02-1.91 (m, 1H), 1.82-1.57 (m, 2H) Rt=0.71;
353.3 [M+H]+ Prom. conn. P093
And
prom. conn. B010 Ex. 075
2-(6-((((2S,4S)-4-Fluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, CD ₃ OD) δ (ppm) 7.34 (d, 1H), 7.08 (s, 1H), 7.03-6.96 (m, 2H), 5.34-5.13 (m, 1H), 3.68-3.60 (m, 2H), 3.58-3.49 (m, 1H), 3.30-3.21 (m, 1H), 2.93 (ddd , 1H), 2.40-2.23 (m, 1H), 2.20 (s, 3H), 1.97-1.79 (m, 1H). Rt=0.73;
371.3 [M+H]+ Prom. conn. P094
And
prom. conn. B010 Ex. 076
2-(6-((((2S,4R)-4-Fluoropyrrolidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, CD ₃ OD) δ (ppm) 7.35 (d, 1H), 7.11-7.07 (s, 1H), 7.04-6.98 (m, 2H), 5.35 -5.18 (m, 1H), 3.81-3.69 (m, 1H), 3.62 (dd, 1H), 3.53 (dd, 1H), 3.29-3.09 (m , 2H), 2.36-2.22 (m, 1H), 2.20 (s, 3H), 1.86-1.67 (m, 1H). Rt=0.71;
371.3 [M+H]+ Prom. conn. P095
And
prom. conn. B010 Ex. 077
(rac)-3-Methyl-2-(6-(((4-methylmorpholin-3-yl)methyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.13 (s, 1H), 7.23 (d, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6 .94 (d, 1H), 6.77 (t, 1H), 3.83-3.76 (m, 1H), 3.74-3.64 (m, 2H), 3.56-3.47 (m, 1H), 3.39-3.25 (m, 2H), 2.71-2.66 (m, 1H), 2.32 (s, 3H, overlap with m, 1H), 2.28 -2.18 (m, 1H), 2.12 (s, 3H). Rt=0.72;
383.3 [M+H]+ Prom. conn. P096
And
prom. conn. B010 Ex. 078
HCl salt of (S)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (400 MHz, CD ₃ OD) δ (ppm) 7.92 (d,1H), 7.75 (d, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 3, 88-3.71 (m, 2H), 2.30 (s, 3H), 1.50 (s, 3H). Rt=1.03;
396.3 [M+H]+ Prom. conn. P097
And
prom. conn. B010 Ex. 079
2-(6-((1-Hydroxy-2-methylpropan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.18 (s, 1H), 7.22 (d, 1H), 7.11 (s, 1H), 7.05 (d, 1H), 6 .94 (d, 1H), 6.48 (s, 1H), 5.38 (t, 1H), 3.60 (d, 2H), 2.15 (s, 3H), 1.38 (s, 6H). Rt=0.88;
342.3 [M+H]+ Prom. conn. P098
And
prom. conn. B010 Ave. 080
(R)-2-(6-((1-(2-Hydroxy-2-methylpropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (400 MHz, DMSO-d ₆ ) δ (ppm) 10.13 (s, 1H), 7.22 (d, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 6 .87 (d, 1H), 6.72 (d, 1H), 4.13-4.01 (m, 1H), 3.07-2.98 (m, 1H), 2.78-2.71 (m, 1H), 2.29-2.16 (m, 4H), 2.12 (s, 3H), 1.89-1.80 (m, 1H), 1.72-1.66 (m , 1H), 1.59-1.52 (m, 1H), 1.32-1.23 (m, 1H), 1.08 (s, 6H). Rt=0.78;
425.3 [M+H]+ Industrial connection P103
And
prom. conn. B010 Ex. 081
2-(6-((( cis )-3-Hydroxy-3-methylcyclobutyl)amino)-4-methylpyridazin-3-yl)-5-(trifluoromethoxy)phenol (400 MHz, DMSO-d6) δ (ppm) 10.46 (s, 1H), 7.28 (d, 1H), 7.17-7.04 (m, 1H), 6.90-6.84 (m, 2H), 6.65 (s, 1H), 4.98 (s, 1H), 3.98-3.81 (m, 1H), 2.47-2.36 (m, 2H), 2.03 (s, 3H), 1.95 (td, 2H), 1.28 (s, 3H). Rt=0.89;
370.1 [M+H]+ Prom. conn. P036
And
BCA Ex. 082
(R)-2-(4-Methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenol (400 MHz, DMSO-d6) δ (ppm) 10.43 (s, 1H), 7.28 (d, 1H), 6.86 (s, 2H), 6.69 (s, 1H), 6, 60 (d, 1H), 4.14-3.93 (m, 1H), 2.96-2.77 (m, 1H), 2.61-2.51 (m, 1H), 2.18 ( s, 3H), 2.01 (s, 3H), 1.98 (s, 1H), 1.94-1.78 (m, 2H), 1.75-1.65 (m, 1H), 1 .61-1.45 (m, 1H), 1.36-1.21 (m, 1H). Rt=0.84;
383.1 [M+H]+ Prom. conn. P031
And
BCA

The following examples, Ex 083(A/B) to Ex 096(A/B), were prepared as racemates according to procedures similar to Ex 001, using the appropriate amine and boronate defined herein, followed by a separation step by chiral chromatography.

Example of project 083A and project 083B

3-Methyl-2-(6-(((8R,8aR)-octahydroindolyzin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol and 3-methyl-2-(6-(( (8S,8aS)-octahydroindolyzin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol

The racemate of (rac)-3-methyl-2-(6-(((8r,8ar)-octahydroindolizin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (prepared as described for example ex. 001 , starting from inv. P041 and inv. B010 ) was separated by chiral normal phase chromatography (column: Chiralpak AD, 250×30 mm, 5 μm; rt, eluent: n-heptane:EtOH=90:10 +0.05% DEA; flow rate: 20 ml/min; cycle time: 15 min) to give two enantiomers, representing ex. 083A (first elution, Rt=25 min) and ex. 083B (second elution, Rt=31 min) respectively.

Ave. 083A ^1H NMR (400 MHz, DMSO -d6 ) δ 10.14 (s, 1H), 7.21 ₍ d, 1H), 7.12-7.08 (m, 1H), 7.07-7 .02 (m, 1H), 6.88-6.75 (m, 2H), 3.96-3.77 (m, 1H), 3.29-3.20 (m, 2H), 3.13 -2.93 (m, 2H), 2.16-2.09 (m, 4H), 2.05-1.88 (m, 2H), 1.72-1.45 (m, 5H), 1 .17-1.04 (m, 1H). LC-MS: Rt=0.73 min; MS mass/charge 393.2 [M+H]+

Ave. 083B ^1H NMR (600 MHz, DMSO -d6 ) δ 10.19 (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=0.73 min; MS mass/charge 393.2 [M+H]+

Example of project 084A and project 084B

(R)-2-(6-(((1-(2-Hydroxyethyl)piperidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol and (S)-2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

The racemate of 2-(6-(((1-(2-hydroxyethyl)piperidin-2-yl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described for example ex. 001 , starting from inv. P044 and inv. B010 ) was separated by chiral normal phase chromatography (column: Chiralpak AD, 250×30 mm, 5 μm; rt, eluent: n-heptane:EtOH=80:20 +0.05% DEA; flow rate: 20 ml/min; cycle time: 30 min) to give two enantiomers, representing ex. 084A (first elution, Rt=15 min) and ex. 084B (second elution, Rt=23.5 min) respectively.

Ave. 084A ^1H NMR (600 MHz, 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=0.72 min; MS m/z 411.3 [M+H]+

Ave. 084B ¹ H NMR (600 MHz, DMSO-d ₆ ) 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=0.72 min; MS m/z 411.3 [M+H]+

Example pr. 085A and pr. 085B

3-Methyl-2-(6-(((1S,2S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (pr. 085A) and

3-methyl-2-(6-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (pr. 085B)

(85A) and (85B)

The racemic product (prepared as described for example ex. 001 , starting from inv. P048 and inv. B010 ) was separated by chiral normal phase chromatography (column: Chiralpak IG, 250×30 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 give two enantiomers, representing ex. 085A (first elution, Rt=7 min) and ex. 085B (second elution, Rt=11.9 min), respectively. The stereochemistry was determined by X-ray crystallography.

Ave. 085A ^1H NMR (600 MHz, 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, 3H), 2.13 (s, 3H), 2.05-1.94 (m, 1H), 1.86-1.61 ( m, 4H), 1.55-1.29 (m, 3H). LC-MS: Rt=0.71 min; MS mass/charge 393.2 [M+H]+

Ave. 085B ¹ H NMR (600 MHz, DMSO-d ₆ ) 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, 3H), 2.13 (s, 3H), 2.01-1.92 (m, 1H), 1.80-1.61 ( m, 4H), 1.48-1.28 (m, 3H). LC-MS: Rt=0.71 min; MS mass/charge 393.2 [M+H]+

Example of project 086A and project 086B

2-(6-(((1R,2R,5R)-8-(2-Hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(trifluoromethyl)phenol (project 086B) and

2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl- 5-(trifluoromethyl)phenol (project 086A)

(86A) and

(86B)

The racemate of 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 for example Ex. 001 , starting from inv. P050 and inv. B010 ) was separated by chiral SFC (column: Chiralpak IG, 250×30 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 give two enantiomers, representing Ex. 086A (first elution, Rt=5.2 min) and Ex. 086B (second elution, Rt=6.5 min), respectively. Stereochemistry was determined by ROESY-NMR.

Pr. 086A ^1H NMR (600 MHz, DMSO - _d6 ) δ 10.17 (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=0.71 min; MS m/z 423.3 [M+H]+

Pr. 086B ^1H NMR (600 MHz, DMSO - _d6 ) δ 10.17 (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=0.71 min; MS m/z 423.3 [M+H]+

Example of project 087A and project 087B

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

The racemate of 2-(6-((-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described for example ex. 001 , starting from inv. P052 and inv. B010 ) was separated by chiral SFC (column: Chiralpak IG-LL, 250×30 mm, 5 μm, 40°C, eluent B: MeOH 22% +0.1% ammonia; flow rate: 80 ml/min; pressure: 120 bar, cycle time: 20 min) to give two diastereoisomers, representing ex. 087A (first elution, Rt=8.2 min) and ex. 087B (second elution, Rt=11.3 min) respectively.

Pr. 087A ^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), 4.44-4.34 (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]+

Pr. 087B ^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]+

Example pr. 088A and pr. 088B

(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-1,2-diol

The racemate of 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-2-methylpropane-1,2-diol (prepared as described for example ex. 001 , starting from inv. P053 and inv. B010 ) was separated by chiral SFC (column: Chiralpak IG, 250×30 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 give two enantiomers, representing ex. 088A (first elution, Rt=8.7 min) and ex. 088B (second elution, Rt=13.8 min), respectively.

Ave. 088A ^1H NMR (600 MHz, 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=0.7 min; MS mass/charge 358.1 [M+H]+

Ave. 088B ¹ H NMR (600 MHz, DMSO-d ₆ ) 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=0.7 min; MS mass/charge 358.1 [M+H]+

Example of project 089A and project 089B

(1S,2R,3S)-3-((6-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol and (1R,2S,3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol

The racemate of 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)cyclopentane-1,2-diol (prepared as described for example ex. 001 , starting from inv. P054 and inv. B010 ) was separated by chiral SFC (column: i-LuxCel (IC), 250×30 mm, 5 μm; eluent B: MeOH 15% +0.1% ammonia; flow rate: 80 ml/min; cycle time: 30 min) to give two diastereoisomers, representing ex. 089A (first elution, Rt=14.3 min) and ex. 089B (second elution, Rt=22.2 min), respectively.

Pr. 089A ^1H NMR (600 MHz, DMSO-d ₆ ) 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), 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=0.7 min; MS m/z 370.3 [M+H]+

Ave. 089B ¹ H NMR (600 MHz, DMSO-d ₆ ) 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=0.7 min; MS m/z 370.3 [M+H]+

Example pr. 090A and pr. 090B

(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

The racemate of 2-(6-((2-hydroxy-3-methylbutyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described for example ex. 001 , starting from inv. P056 and inv. B010 ) was separated by chiral SFC (column: Chiralpak IB-N, 250×30 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 give two enantiomers, representing ex. 090A (first elution, Rt=9.6 min) and ex. 090B (second elution, Rt=13 min), respectively.

Ave. 090A ^1H NMR (600 MHz, 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=0.85 min; MS mass/charge 356.2 [M+H]+

Ave. 090B ^1H NMR (600 MHz, DMSO-d ₆ ) 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=0.85 min; MS mass/charge 356.2 [M+H]+

Example of project 091A and project 091B

3-Methyl-2-(6-(((2S,3S)-2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol and 3-methyl-2-(6- (((2R,3R)-2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol

The racemate of 3-methyl-2-(6-((2-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (prepared as described for example Ex. 001 starting from inv. P099 and inv. B010 ) was separated by chiral SFC (column: Lux i-Cellulose 5, 250 x 30 mm, 5 μm, 40 °C, eluent B: MeOH 23% + 0.1% NH3, flow rate: 80 ml/min, pressure: 120 bar, cycle time: 20 min) to give the title compounds, which are Ex. 091A (first elution, Rt = 9.17 min) and Ex. 091B (second elution, Rt = 12.01 min) respectively.

Ave. 091A ^1H NMR (400 MHz, CD ₃ OD) 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=0.73 min; MS mass/charge 367.1 [M+H] ⁺

Ave. 091B ^1H NMR (400 MHz, CD ₃ OD) 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, 1H), 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=0.73 min; MS mass/charge 367.1 [M+H] ⁺

Example of project 092A and project 092B

2-(6-(((R)-1-((S)-2-Hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol and 2-(6-(((R)-1-((R)-2-hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

A mixture of diastereomers of 2-(6-(((3R)-1-(2-hydroxypropyl)piperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described for example Ex. 001 , starting from inv. P105 and inv. B010 ) was separated by chiral SFC (column: ChiralPak AD, 250 x 30 mm, 5 μm, 40 °C, eluent B: EtOH 25% + 0.1% NH3, flow rate: 80 ml/min, pressure: 120 bar, cycle time: 20 min) to give the title compounds, which are Ex. 092A (first elution, Rt = 8.7 min) and Ex. 092B (second elution, Rt=12.0 min), respectively.

Ave. 092A ^1H NMR (400 MHz, DMSO-d ₆ ) 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, 1H), 3.48-3.40 (m, 1H), 2.95-2.87 (m, 1H), 2.28-2.16 (m, 3H), 2 .12 (s, 3H), 1.86-1.78 (m, 1H), 1.76-1.67 (m, 1H), 1.58-1.47 (m, 1H), 1.43-1.34 (m, 1H), 1.03 (d, 3H). LC-MS: Rt=0.73 min; MS mass/charge 411.2 [M+H] ⁺

Ave. 092B ¹ H NMR (400 MHz, DMSO-d ₆ ) 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), 4.29-4.24 (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=0.73 min; MS mass/charge 411.2 [M+H] ⁺

Example of project 093A and project 093B

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

A mixture of diastereomers of 2-(6-((5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described for example Ex. 003 , starting from inv. P102 and inv. B005 ) was separated by chiral SFC (column: Lux i-Cellulose-5, 250 x 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 give the title compounds, which are Ex. 093A (first elution, Rt=6.9 min) and Ex. 093B (second elution, Rt=11.5 min) respectively.

Ave. 093A ^1H NMR (400 MHz, DMSO- _d6 ) δ (ppm) 10.17 (s, 1H), 7.23 (d, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 6.85 (d, 1H), 6.81 (d, 1H), 4.89-4.72 (m, 1H), 4.25-4.15 (m, 1H), 3.12 -3.05 (m, 1H), 2.94-2.84 (m, 1H), 2.82-2.68 (m, 1H), 2.44-2.35 (m, 2H), 2 ,24-2.13 (m, 1H), 2.13 (s, 3H), 1.86-1.68 (m, 1H); LC-MS: Rt=0.85 min; MS m/z 371.2 [M+H] ⁺

Ave. 093B ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 10.14 (s, 1H), 7.24 (d, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6.85 (d, 1H), 6.82 (d, 1H), 4.93-4.75 (m, 1H), 4.28-4.18 (m, 1H), 3.16 -3.10 (m, 1H), 2.99-2.90 (m, 1H), 2.86-2.71 (m, 1H), 2.49-2.40 (m, 2H), 2 ,26-2.15 (m, 1H), 2.13 (s, 3H), 1.88-1.70 (m, 1H); LC-MS: Rt=0.85 min; MS m/z 371.2 [M+H] ⁺

Example of project 094A and project 094B

2-(6-(((3S,5S)-5-Fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol and 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

A mixture of diastereomers of 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol was prepared as follows: rac- arr. 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. Additional formaldehyde (0.038 mL, 0.51 mmol, 37% in water), NaBH(OAc) ₃ (43 mg, 0.205 mmol) and AcOH (1 drop) were added. After stirring for an additional 2 h, the reaction mixture was quenched by adding NaHCO ₃ solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by achiral RP chromatography. Fractions containing pure product were combined and brought to pH 8-9 using saturated NaHCO ₃ solution, then extracted twice with EtOAc. The organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The diastereomeric products were separated by chiral SFC (column: Lux i-Cellulose-5, 250 x 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 afford the title compounds, which are ex 094A (first elution, Rt=3.99 min) and ex 094B (second elution, Rt=4.52 min), respectively.

Pr. 094A ^1H NMR (400 MHz, DMSO-d ₆ ) 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), -4.33 (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] ⁺

Pr. 094B ¹ H NMR (400 MHz, DMSO-d ₆ ) 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), -4.33 (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] ⁺

Example of project 095A and project 095B

2-(6-(((3S,5R)-5-Fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol and 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

A mixture of diastereomers of 2-(6-((5-fluoro-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described for example Ex. 001 , starting from inv. P103 and inv. B005 ) was separated by chiral SFC (column: Lux Amylose-1, 250 x 30 mm, 5 μm, 40 °C, eluent B: 17% [iPrOH + 0.1% NH3], flow rate: 80 mL/min, pressure: 120 bar, cycle time: 20 min) to give the title compounds, which are Ex. 095A (first elution, Rt = 13.58 min) and Ex. 095B (second elution, Rt=15.01 min), respectively.

Pr. 095A ^1H NMR (400 MHz, DMSO-d ₆ ) 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=0.83 min; MS m/z 385.3 [M+H] ⁺

Pr. 095B ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=0.83 min; MS m/z 385.2 [M+H] ⁺

Example of project 096A and project 096B

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

A mixture of diastereomers of 2-(6-((5-fluoropiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (prepared as described for example Ex. 001 , starting from inv. P104 and inv. B005 ) was separated by chiral SFC (column: Lux Amylose-1, 250 x 30 mm, 5 μm, 40 °C, eluent B: 40% [MeOH + 0.1% NH3], flow rate: 80 mL/min, pressure: 120 bar, cycle time: 20 min) to give the title compounds, which are Ex. 096A (first elution, Rt = 4.79 min) and Ex. 096B (second elution, Rt=9.34 min) respectively.

Ave. 096A ^1H NMR (400 MHz, DMSO-d ₆ ) 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).

LC-MS: Rt=0.82 min; MS mass/charge 371.2 [M+H] ⁺

Ave. 096B ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

LC-MS: Rt=0.82 min; MS mass/charge 371.2 [M+H] ⁺

Example pr. 097

(3S,5R)-5-((6-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)-1-methylpiperidin-3-ol

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 analogously to example Ex. 002 using intermediate Ind. Comp. P043 and boronic acid Ind. Comp. B005 , in 3 mL _CH2Cl2 was _treated with 4 M HCl in 1,4-dioxane (4.23 mL, 16.91 mmol) at rt for 2 h. The reaction mixture was evaporated. The resulting solid was dissolved in a mixture of 2 mL DMSO and 2 _{mL 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 rt for 18 h. The reaction mixture was evaporated and the crude material was purified by column chromatography on silica gel using _CH2Cl2 and _MeOH containing 5% ammonia (0% to 30%) to give the title compound as an off-white solid. ^1H NMR (600 MHz, 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, 1 H), 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=0.61 min; MS mass/charge 383.2 [M+H] ⁺ .

Example pr. 098

2-(6-(((1-Hydroxycyclopentyl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

(1) 2-(6-Chloropyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, prom. conn. X109

A mixture of ind. comp. B010 (150 mg, 0.497 mmol), 3,6-dichloropyridazine (89 mg, 0.596 mmol), Pd( _Ph3P ) ₄ (28.7 mg, 0.025 mmol) and 2 M _Na2CO3 (0.75 mL, 1.5 mmol) in 3.9 mL of 1,4-dioxane was purged with nitrogen. The vial was sealed and heated at 120 _° C under microwave irradiation for 1 h. The reaction mixture was diluted with brine and extracted three 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 (25 g) using cyclohexane and EtOAc (0% to 50%) to give the title compound. ¹ H NMR (600 MHz, DMSO-d ₆ ) 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 = 0.95 min; MS m/z 289.1 [M+H] ⁺

(2) 2-(6-(((1-Hydroxycyclopentyl)methyl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

A mixture of ind. comp. 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 over 10 min, flow rate: 100 ml/min, pressure: 120 bar) to give the title compound. ^1H NMR (400 MHz, DMSO- _d6 ) δ (ppm) 8.37 (s, 1H), 7.22 (d, 1H), 7.09 (s, 1H), 7.05 (s, 1H), 7.01 (d, 1H), 6.81-6.71 (m, 1H), 4.66 (s, 1H), 3.4 9 (d, 2H), 2.13 (s, 3H), 1.79-1.54 (m, 8H). LC-MS: Rt=0.84 min; MS mass/charge 368.2 [M+H] ⁺

Example pr. 099

5-((6-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one

(1) 2-(6-Chloro-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol, prom. conn. X110

A mixture of 3,6-dichloro-4-methylpyridazine (1.60 g, 9.52 mmol), (2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)boronic acid (2.09 g, 9.52 mmol) and 2 M _Na2CO3 (14.28 mL, 28.6 mmol) in 95 mL of 1,4-dioxane was purged _with argon for 5 min. Pd( _PPh3 ) ₄ (0.66 g, 0.57 mmol) was then added and the mixture was stirred under argon at 120 °C for 1 h. 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 _Na2SO4 , filtered and evaporated. The crude product was triturated with 5 mL _{of CH2Cl2} overnight. The resulting solid was collected by filtration, washed with a small amount _{of CH2Cl2} and dried to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO- _d6 ) δ 10.36 (s, 1H), 7.80 (d, 1H), 7.17 (s, 1H), 7.11 (s, 1H), 2.45 (s, 3H), 2.09 (s, 3H). LC-MS: Rt=1.07min, MS m/z 303.0 [M+H]+

(2) 5-((6-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one

LiOtBu (167 mg, 1.982 mmol) and PdCl2(dppf) (12.09 mg, 0.017 mmol) were added to a suspension of ind. compound 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 was capped and heated at 105 °C overnight. After cooling to rt, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (3×50 mL). _The combined organic extracts were dried over _Na2SO4 , filtered and evaporated. The crude material was purified by column chromatography on silica gel (25 g) first using n-heptane and EtOAc (0% to 100%), then _CH2Cl2 and _MeOH (0% to 30%) to give the title compound as a brown solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.14 (s, 1H), 7.18-7.15 (m, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 6.16 (d, 1H), 4.68-4.51 (m, 1H), 3.63 (dd, 1H), 3 .31-3.25 (m, 1H), 2.83 (s, 3H), 2.42-2.35 (m, 2H), 2.16 (s, 3H), 2.11 (s, 3H), 2.09-1.94 (m, 2H). LC-MS: Rt=0.93 min; MS mass/charge 395.3 [M+H]+

Example pr. 100

(R)-3-Methyl-2-(5-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5-(trifluoromethyl)phenol

The compound was synthesized analogously to the procedure described for example example 099 using tert-butyl (R)-3-aminopiperidine-1-carboxylate in step (2) followed by TFA-mediated Boc cleavage and extraction with NaHCO ₃ to give the title compound as an off-white solid. ^1H NMR (400 MHz, 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 (s, 6H), 1.99-1.91 (m, 1H), 1.70-1.43 (m, 3H), 1.27-1.20 (m, 2H). LC-MS: Rt=0.86 min; MS mass/charge 367.1 [M+H] ⁺ .

Example pr. 101

(R)-2-(6-((1-Ethylpiperidin-3-yl)amino)-5-methylpyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol

The compound was synthesized analogously to the procedure described for Example 099 using (R)-1-ethylpiperidin-3-amine in step (2) to give the title compound as an off-white solid. ¹ H NMR (400 MHz, MeOH-d ₄ ) 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, 2 H), 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=0.87 min; MS mass/charge 395.2 [M+H] ⁺

Example pr. 102

(R)-3-((6-(2-Hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidin-2-one

The compound was synthesized analogously to the procedure described for Example 099 using (R)-3-amino-1-methylpiperidin-2-one hydrochloride in step (2) to give the title compound as an off-white solid. ^1H NMR (400 MHz, 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=0.87 min; MS mass/charge 395.2 [M+H] ⁺

Example pr. 103

4-(2-((6-(2-Hydroxy-4,6-dimethylphenyl)pyridazin-3-yl)amino)ethyl)benzenesulfonamide

(1) 4-(2-((6-(2-Methoxy-4,6-dimethylphenyl)pyridazin-3-yl)amino)ethyl), prom. conn. X111

Prom. P101 (400 mg, 1.279 mmol), Prom. B017 (493 mg, 1.918 mmol) and Pd( _Ph3P ) ₄ (148 mg, 0.128 mmol) were dissolved in 10 mL of DME. 2 M _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 material was purified by column chromatography on silica gel (12 g) using _CH2Cl2 and _MeOH (0% to 10%). The product containing fractions were evaporated to dryness and triturated with MeOH to give the title compound as an off-white solid. LC-MS: Rt=0.80 min; MS m/z 413.2 [M+H] ⁺

(2) 4-(2-((6-(2-Hydroxy-4,6-dimethylphenyl)pyridazin-3-yl)amino)ethyl)benzenesulfonamide

Prom. compound X111 (65 mg, 0.137 mmol) was suspended in 5 mL _CH2Cl2 , then _BBr3 (1 _M in _CH2Cl2 , 0.206 mL, 0.206 mmol) was added. The resulting orange suspension _was stirred at rt for 3 h. The reaction mixture was evaporated to dryness and the residue was purified by achiral RP chromatography. Fractions containing pure product were combined and brought to pH 8-9 with saturated _NaHCO3 solution, then extracted twice with _CH2Cl2 . _The combined organic extracts were evaporated to give the title compound as a beige solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ (ppm) 9.46 (s, 1H), 7.78 (d, 2H), 7.49 (d, 2H), 7.31 (s, 2H), 7.20 (d, 1H), 6.96-6.91 (m, 1H), 6.84 (d, 1H), 6.6 0-6.55 (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=0.71 min; MS mass/charge 399.2 [M+H] ⁺

Example pr. 104

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

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 rt for 90 min. The reaction mixture was quenched with saturated _NaHCO3 solution and _extracted with _CH2Cl2 . The crude material was purified by achiral RP chromatography to give the title compound as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=0.86 min; MS mass/charge 397.2 [M+H]+

BIOLOGICAL ANALYSES AND DATA

The activity of the compound according to the present invention can be assessed by the following methodsin vitro. The compound of formula (I) or a pharmaceutically acceptable salt thereof exhibits valuable pharmacological properties, such as, properties of propensity to inhibit NLRP3 activity, such as as indicated in the tests given in the following sections and are therefore indicated for therapy associated with NLRP3 inflammasome activity.

IL-1β secretion assay

THP-1 monocytic cells (ATCC: TIB-202) were maintained according to the manufacturer's instructions in RPMI medium (RPMI/HEPES + 10% fetal bovine serum + sodium pyruvate + 0.05 mM beta-mercaptoethanol (1000x stock) + penicillin-streptomycin mixture). Cells were differentiated in bulk with 0.5 μM phorbol 12-myristate 13-acetate (PMA; Sigma #P8139) for 3 h, the medium was changed, and the cells were seeded at 50,000 cells/well in 384-well flat-bottomed cell culture plates (Greiner, #781986) and allowed to differentiate overnight. Serial dilutions of compound 1:3.16 in DMSO were added at a 1:100 ratio to cells and incubated for 1 h. NLRP3 inflammasome was activated by addition of 15 μM (final concentration) nigericin (Enzo Life Sciences, #BML-CA421-0005) and cells were incubated for 3 h. 10 μL of supernatant was removed and IL-1β levels were monitored by HTRF assay (CisBio, #62IL1PEC) according to the manufacturer's instructions. Viability and pyroptosis were monitored by adding PrestoBlue Cell Viability Reagent (Life Technologies, #A13261) directly to the cell culture plate.

TNF-α secretion analysis

THP-1 monocytic cells were maintained according to the supplier’s instructions in RPMI medium as described above. Undifferentiated cells were seeded at 50,000 cells/well in 384-well flat-bottomed cell culture plates (Greiner, #781986) and left undisturbed overnight. Experimental compounds were prepared and added as described above. TNF-α secretion was triggered by the addition of either 1 μg/ml LPS (Sigma, #L4391) or 100 ng/ml Pam3CSK4 (Invivogen, #tlrl-pms) depending on the experiment, and the cells were incubated for 3 h. 10 μl of supernatant was removed and TNF-α levels were monitored using the HTRF assay (CisBio, #62TNFPEC) according to the manufacturer's instructions. Viability was monitored as described above.

Interpretation of data

IC ₅₀ values were calculated from the plot of percentage inhibition versus inhibitor concentration using logistic approximation according to:

y=A2 + (A1 - A2)/(1 + (x/IC ₅₀ ) ^ p),

where y represents the % inhibition at inhibitor concentration x, A1 represents the lowest inhibition value, i.e. 0%, and A2 represents the highest inhibition value, i.e. 100%. The exponent p represents the Hill coefficient. Curve fitting was performed using a proprietary software package.

NLRP3-dependent IL-1β secretion was stimulated in PMA-differentiated THP-1 cells by addition of nigericin and serum cytokine levels were measured 3 hours later. As discussed above, activation of the NLRP3 inflammasome requires both the NF-kB-dependent priming step and addition of an NLRP3 activator. To ensure that the priming step was not interfered with by inhibitors, NF-kB-dependent TNF-α secretion stimulated by Pam3CSK4 was monitored as a reverse screen. The inhibitory effect (IC ₅₀ ) of the compounds of the invention for both assays is summarized in the table below.

Example No. IL-1β
IC ₅₀ [µM] TNF-α,
IC ₅₀ [µM] 1 0,0008 >100 2 0,0102 >100 3 0.0255 >100 4 0,0004 >100 5 0,0030 >33 6 0,0009 >100 7 0.0019 >100 8 0,0241 >100 9 0.0931 >100 10 0.3490 >33 11 0,0013 >100 12 0,0006 >100 13 0,0012 >100 14 0.0857 >100 15 0.0859 >100 16 0.0363 >100 17 0.0331 >33 18 0.1652 >100 19 0.0936 >100 20 0.0823 >100 21 0,0484 >100 22 0,0807 >100 23 0.0934 >100 24 0.1199 37 25 0,1769 35 26 0.1653 >100 27 0,1809 >100 28 0.2884 >100 29 0.1689 >100 30 0.2144 >100 31 0,1667 >100 32 0.2184 85 33 0.0565 >100 34 0.4956 >100 35 0.2428 >100 36 0.3783 >100 37 0.3807 >100 38 _ _ 39 0.0032 >100 40 0.0068 >33 41 0,0030 42 0.0253 >100 43 0.2814 25 44 0.4216 >100 45 0.0032 >100 46 0.0936 >100 47 0,0008 >100 48 0,0008 >100 49 0,0016 >100 50 0.0023 >100 51 0.0026 >100 52 0.1856 >100 53 0,0004 >33 54 0,0118 35 55 0.0458 45 56 0,0083 >100 57 0.2235 84 58 0.0584 >100 59 0.0359 >100 60 0.1395 >100 61 0.0658 >100 62 0,1620 >100 63 0.0227 32 64 0.0059 >100 65 0,0074 >33 66 0,1871 >33 67 0,0401 46 68 0.0893 >100 69 0.4308 >33 70 0.0035 >100 71 0,0008 >100 72 0,0449 >100 73 0.1538 55 74 0.0026 >100 75 0,0183 >100 76 0.0897 >100 77 0.0619 >100 78 0,1977 >100 79 0.3704 >100 80 0,0047 >33 81 0.1299 >100 82 0,0007 >100 83a 0,0008 >100 83b 0.0694 >100 84a 0.0425 >100 84b 0.0533 >33 85a 0.1476 >100 85b 0,0013 >100 86a 0,1746 >100 86b 0.0018 >100 87a 0,0063 >100 87b 0.5069 77 88a 0.0623 41 88b 0,0605 >100 89a 0.0597 >100 89b 0,1816 >100 90a 0.0642 >33 90b 0,1150 >100 91a 2,2236 >100 91b 0,1811 >100 92a 0.0033 >100 92b 0.0036 45 93a 0.0066 93b 0,440 94a 0,0016 94b 0,730 95a 0,013 95b 0.92 96a 0,470 96b 0.026 97 0.0076 >100 98 0,1150 >100 99 0,0750 >100 100 0,0060 >100 101 0.0019 >100 102 0.049 103 0.1359 16 104 0,0590 >100

Claims (324)

1. Compound of formula (I) (I) or a pharmaceutically acceptable salt thereof, where R ¹ is Cl, CH ₃ , -OCF ₃ or CF ₃ ; R ² is H, halogen, C ₁ -C ₄ alkyl or halo-C ₁ -C ₄ alkyl; R ³ , R ⁴ are H, CN, C ₁ -C ₄ alkyl or halo-C ₁ -C ₄ alkyl; Z represents -O- or -NH-(CH ₂ ) _n -, where n is 0, 1, or 2; R ⁵ is selected from the following structures: , wherein R ^5a is independently selected from C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl, and H; and R ^5b is independently selected from -OH, C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ alkyl, H, halogen, oxo, halogen-C ₁ -C ₄ alkyl, and -CO ₂ H; and m is 0 or 1; or R ⁵ is selected from the following structures: , where R ^5d is independently selected from H, halogen, halo-C ₁ -C ₄ alkyl and C ₁ -C ₄ alkyl. 2. The compound according to claim 1 or its pharmaceutically acceptable salt, characterized by formula (II) (II), where R ¹ , R ² , R ³ , R ⁴ and R ⁵ are defined in paragraph 1. 3. The compound according to claim 1 or its pharmaceutically acceptable salt, characterized by formula (III) (III), where n is 0, 1, or 2; and R ¹ , R ² , R ³ , R ^{4 ,} and R ⁵ are defined in paragraph 1. 4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein at least one of R ² and R ³ is H. 5. A compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R ¹ is -OCF ₃ or CF ₃ . 6. A compound or a pharmaceutically acceptable salt thereof 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; TFA salts of 5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol; TFA salts of (S)-5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol; TFA salts of (R)-5-chloro-3-fluoro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol; 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; TFA salts of 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; TFA salts of 2-(4,5-dimethyl-6-(((S)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; TFA salts of 2-(4,5-dimethyl-6-(((R)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 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; TFA salts of 3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol; TFA salts of (S)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol; TFA salts of (R)-3,5-dichloro-2-(6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)phenol; 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; TFA salts of 2-(6-((1,3-dimethylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 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; HCl salt of 3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; HCl salt of (R)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; HCl salt of (S)-3-methyl-2-(6-((3,3,3-trifluoro-2-hydroxy-2-methylpropyl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 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-((octahydroindolyzin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((8R,8aR)-octahydroindolyzin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((8R,8aS)-octahydroindolyzin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((8S,8aR)-octahydroindolyzin-8-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((8S,8aS)-octahydroindolyzin-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]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1S,2S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1S,2R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1S,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1S,2S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1R,2S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1R,2S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 3-methyl-2-(6-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol; 2-(6-((8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,2S,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1R,2R,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,2S,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,2R,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((1S,2S,5S)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-((6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol; 2-(6-(((3R,6R)-6-(hydroxymethyl)-1-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; 1-oxide (3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine; (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide; TFA salts of 3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide; TFA salts of (3S)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide; TFA salts of (3R)-3-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-yl)amino)-1-methylpiperidine 1-oxide or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition having inhibitory activity against the NOD-like receptor protein 3 (NLRP3) inflammasome signaling pathway, comprising a therapeutically effective amount of a compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. 8. Use of a compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease or disorder in which NLRP3-mediated signaling contributes to the pathological process and/or the manifestation of symptoms and/or the progression of said disease or disorder. 9. The use according to claim 8, wherein the disease or disorder is selected from diseases/disorders associated with inflammasomes, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases, such as forms of autoinflammatory febrile syndrome (e.g., cryopyrin-associated periodic syndrome), liver-related diseases/disorders (eg, chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis and alcoholic liver disease), disorders associated with inflammatory arthritis (eg, gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, for example, acute, chronic), diseases associated with the kidneys (eg, hyperoxaluria, lupus nephritis, type I/type II diabetes mellitus and associated complications (eg, nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-associated inflammation), diseases associated with neuroinflammation (eg, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), cardiovascular/metabolic diseases/disorders (eg, reduction of cardiovascular risk (CvRR), hypertension, atherosclerosis, type I and type II diabetes mellitus and its associated complications, peripheral arterial disease (PAD), acute heart failure), inflammatory skin diseases (eg, hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/disorders (eg, colon cancer, lung cancer, myeloproliferative neoplasms, forms of leukemia, forms of myelodysplastic syndrome (MDS), myelofibrosis).