NLRP3 inhibitor

Abstract

The present invention relates to a novel compound having the general formula (I) TIFF2025523930000032.tif36165 (wherein R 1 , R 2 , R 3 , R 4 and W are as described herein), a composition containing the compound, and a method of using the compound.

Description

Technical Field

[0001] Field of the Invention The present invention relates to organic compounds useful for treatment and / or prophylaxis in mammals, in particular compounds that modulate NLRP3 inhibition.

[0002] The present invention relates to novel compounds of formula I

Chemical Formula

[0003] Furthermore, the present invention includes all racemic mixtures, all their corresponding enantiomers and / or optical isomers.

Background Art

[0004] Background of the Invention The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its abnormal activation is pathogenic in genetic disorders such as cryopyrin-associated periodic syndromes (CAPS), and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease, and atherosclerosis.

[0005] NLRP3 is an intracellular signaling molecule that senses many pathogen-derived factors, environmental factors, and host-derived factors. When activated, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form large aggregates known as ASC specks. The polymerized ASC then interacts with the cysteine protease caspase-1 to form a complex called the inflammasome. This leads to the activation of caspase-1, which cleaves the precursor forms of the proinflammatory cytokines IL-1β and IL-18 (called pro-IL-1β and pro-IL-18, respectively), thereby activating these cytokines. Caspase-1 also mediates a type of inflammatory cell death known as pyroptosis. The ASC speck can also recruit and activate caspase-8, which can process pro-IL-1β and pro-IL-18 to cause apoptotic cell death.

[0006] Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms and secretes them from cells. Active caspase-1 also cleaves gasdermin-D to induce pyroptosis. Through the control of this pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high-mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation and enabling the release of IL-1α. In human cells, caspase-1 can also control the processing and secretion of IL-37. Several other caspase-1 substrates, such as components of the cytoskeleton and glycolytic pathway, can contribute to caspase-1-dependent inflammation.

[0007] NLRP3-dependent ASC specks are released into the extracellular environment where they can activate caspase-1, induce the processing of caspase-1 substrates, and propagate inflammation.

[0008] Cytokines active derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury. For example, IL-1β signaling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 act synergistically with IL-23 to induce IL-17 production by memory-CD4 Th17 cells and γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also act synergistically to induce IFN-γ production from NK cells that drive memory T cells and Th1 responses.

[0009] The hereditary CAPS diseases, Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID), are caused by gain-of-function mutations in NLRP3, and thus NLRP3 is defined as an important component of the inflammatory process. NLRP3 is also involved in the etiology of several complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0010] The role of NLRP3 in central nervous system diseases is becoming clear, and lung diseases have also been shown to be affected by NLRP3. Furthermore, NLRP3 is involved in the development of liver diseases, kidney diseases, and aging. Many of these associations have been defined using Nlrp3 - / - mice, but there is also insight into the specific activation of NLRP3 in these diseases. In type 2 diabetes (T2D), the deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

[0011] Several small molecules have been shown to inhibit the NLRP3 inflammasome. Glyburide does not respond to the activation of NLRC4 or NLRP1, but inhibits IL-1β production at micromolar concentrations in response to the activation of NLRP3. Other previously characterized weak NLRP3 inhibitors include parthenolide, 3,4-methylenedioxy-β-nitrostyrene, and dimethyl sulfoxide (DMSO), but these agents have limited efficacy and are non-specific.

[0012] Current treatments for NLRP3-related diseases include biological agents that target IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept. These approaches have proven successful in the treatment of CAPS, and these biological agents are being used in clinical trials for other IL-1β-related diseases.

[0013] There is a need to provide compounds with improved pharmacological and / or physiological and / or physicochemical properties and / or compounds that provide useful alternatives to known compounds.

SUMMARY OF THE INVENTION

[0014] SUMMARY OF THE INVENTION The present invention relates to novel compounds of formula I:

CHEMICAL FORMULA

[0015] The term "alkyl" represents a monovalent straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, unless otherwise specified, alkyl has 1 to 6 carbon atoms (C 1~6 -alkyl) or 1 to 4 carbon atoms (C 1~4 -alkyl). Examples of C 1~6 -alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and pentyl. Specific alkyl groups include methyl and ethyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons can be included. Thus, for example, "butyl" can include n-butyl, sec-butyl, iso-butyl, and t-butyl, and "propyl" can include n-propyl and isopropyl.

[0016] The term "alkoxy" represents a group of the formula -O-R', where R' is a C 1~6 -alkyl group. Examples of C 1~6 -alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, and tert-butoxy.

[0017] The term "cyano" represents a -C≡N group.

[0018] The term "cycloalkyl" represents a monocyclic or polycyclic saturated or partially unsaturated non-aromatic hydrocarbon. In some embodiments, unless otherwise described, cycloalkyl contains 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. In some embodiments, cycloalkyl is a saturated monocyclic or polycyclic hydrocarbon. In other embodiments, cycloalkyl contains one or more double bonds (e.g., cycloalkyl fused to an aryl or heteroaryl ring, or a non-aromatic monocyclic hydrocarbon containing one or two double bonds). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, spiro[3.3]heptanyl, and the like. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutanil, cyclopentyl, cyclohexyl or cycloheptyl.

[0019] The terms "halogen", "halide" and "halo" are used interchangeably herein and represent fluoro, chloro, bromo or iodo.

[0020] The term "haloalkyl" represents a C 1~6 -alkyl group in which at least one hydrogen atom of the C 1~6 -alkyl group is replaced by the same or different halogen atoms.

[0021] The term "haloalkoxy" represents a C 1~6 -alkoxy group in which at least one hydrogen atom of the C 1~6 -alkoxy group is replaced by the same or different halogen atoms.

[0022] The term "heterocyclic ring" refers to a monocyclic or bicyclic ring system of 4 to 10 ring atoms or 4 to 9 ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon, and is monovalent saturated or partially unsaturated. Examples of monocyclic saturated heterocyclic rings are oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl or piperazinyl. Examples of partially unsaturated heterocyclic rings are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. A specific example of a heterocyclic ring is tetrahydrofuran.

[0023] The term "N-linked bicyclic ring system" refers to a heterocyclic ring system of up to 10 ring atoms containing two rings having two common carbon atoms, and the bicyclic ring system is attached to the rest of the molecule via an N-heteroatom. Examples of N-linked bicyclic ring systems include (6-ethyl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl.

[0024] The term "N-linked spirocyclic ring system" refers to a heterocyclic ring system of up to 10 ring atoms containing two rings conjugated by a single carbon atom, and the spirocyclic ring system is attached to the rest of the molecule via an N-heteroatom.

[0025] The term "hydroxyl" refers to the -OH group.

[0026] The term "oxo" refers to a doubly bonded oxygen (=O), i.e., a reference to a carbonyl group.

[0027] The term "pharmaceutically acceptable salts" refers to salts of the free bases or free acids which retain the biological effectiveness and properties of the free bases or acids and which are not biologically or otherwise undesirable. The salts are formed from inorganic acids such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. In addition, these salts can be prepared by addition of the free acid to an inorganic base or an organic base. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. The compounds of formula I may also exist in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are salts formed with formic acid and salts formed with hydrochloric acid which give rise to hydrochloride, dihydrochloride or trihydrochloride.

[0028] The abbreviation uM means micromolar concentration and is equivalent to the symbol μM.

[0029] The abbreviation uL means microliter and is equivalent to the symbol μL.

[0030] The abbreviation ug means microgram and is equivalent to the symbol μg.

[0031] The compounds of formula I may contain several asymmetric centers and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0032] According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom can have the configuration of "R" or "S".

[0033] One embodiment of the present invention provides a compound according to formula I as described herein and a pharmaceutically acceptable salt or ester thereof, in particular a compound according to formula I as described herein and a pharmaceutically acceptable salt thereof, more particularly a compound according to formula I as described herein.

[0034] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 1 is cyano and R 2 is H, or R 1 and R 2 , and the atoms to which they are attached, form a 4- to 6-membered heterocyclic ring optionally substituted with one or two substituents independently selected from halo or alkyl and containing a single heteroatom O.

[0035] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 1 is cyano and R 2 is H, or R 1 and R 2 , and the atoms to which they are attached, form a 5-membered heterocyclic ring containing a single heteroatom O.

[0036] One embodiment of the present invention provides a compound according to formula I as described herein, wherein R 3 is H or alkyl.

[0037] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 3 is alkyl).

[0038] One embodiment of the present invention provides a compound of formula I as described herein, wherein R 4 is H).

[0039] One embodiment of the present invention provides a compound of formula I as described herein, wherein W is selected from ring systems A, B or C,

Chemical formula

[0040] One embodiment of the present invention provides a compound of formula I as described herein, wherein W is selected from ring systems A, B or C,

Chemical formula

[0041] One embodiment of the present invention provides a compound of formula I as described herein, wherein W is ring system C,

Chemical formula

[0042] One embodiment of the present invention provides a compound of formula I (wherein, R 1 is cyano and R 2 is H, or R 1 and R 2 , and the atoms to which they are attached form a 5-membered heterocyclic ring containing a single heteroatom O; R 3 is alkyl; R 4 is H; W is ring system C,

Chemical Structure

[0043] Specific examples of the compounds of formula I described herein are 5-[3-[(3aS,7aR)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aR,7aS)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol; 5-[3-[(3aR,7aS)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aS,7aR)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol; 4-[3-[(3aS,7aR)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile or 4-[3-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile; 4-[3-[(3aR,7aS)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile or 4-[3-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile; 5-[3-[(3aS,7aR)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol; 5-[3-[(3aR,7aS)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol; 4-[3-[(3aS,7aR)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile or 4-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile; 4-[3-[(3aR,7aS)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile or 4-[3-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile; and its pharmaceutically acceptable salts selected from

[0044] Preferred examples of the compounds of formula I described herein are 5-[3-[(3aS,7aR)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol; 5-[3-[(3aR,7aS)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol; 4-[3-[(3aS,7aR)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile or 4-[3-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile; 5-[3-[(3aS,7aR)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol; and pharmaceutically acceptable salts thereof selected from

[0045] A method for the production of the compounds of formula I described herein is an object of the present invention.

[0046] Another embodiment of the present invention provides a pharmaceutical composition or medicament containing a compound of the present invention and a therapeutically inert carrier, diluent or excipient, and a method of using the compound of the present invention for preparing such a composition and medicament. In one example, the compound of formula I can be formulated into a galenical dosage form by mixing at ambient temperature, at an appropriate pH, and at a desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used. The pH of the formulation mainly depends on the specific application and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula I is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula I is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0047] The composition is formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to the medical practitioner.

[0048] The compounds of the present invention can be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intralung, intradermal, intrathecal and epidural, and intranasal, and, if local treatment is desired, intralesional administration. Parenteral injection includes administration into muscle, vein, artery, intraperitoneal or subcutaneous.

[0049] The compounds of the present invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions can contain conventional ingredients in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, bulking agents and additional active agents.

[0050] Typical formulations are prepared by mixing the compounds of the invention with carriers or excipients. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also contain one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, flow promoters, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and other known additives to provide an excellent appearance of the drug (i.e., the compound of the invention or its pharmaceutical composition) or to assist in the manufacture of the pharmaceutical product (i.e., the medicine).

[0051] The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules, injection solutions or topical formulations. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as such adjuvants for tablets, sugar-coated tablets and hard gelatin capsules.

[0052] Adjuvants suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols, etc.

[0053] Adjuvants suitable for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0054] Adjuvants suitable for injection solutions are, for example, water, alcohol, polyols, glycerol, vegetable oils, etc.

[0055] Adjuvants suitable for suppositories are, for example, natural oils or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

[0056] Adjuvants suitable for topical ophthalmic preparations are, for example, cyclodextrin, mannitol or many other carriers and excipients known in the art.

[0057] Furthermore, pharmaceutical preparations may contain preservatives, solubilizers, viscosity increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for changing osmotic pressure, buffers, masking agents, or antioxidants. They may also contain further other therapeutically valuable substances.

[0058] Dosages can vary widely and, of course, are adapted to the individual requirements in each particular case. Generally, in the case of oral administration, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (for example, about 300 mg per person), is preferably divided into 1 to 3 individual doses, which can, if appropriate, consist of, for example, the same amount. In the case of topical administration, the preparation can contain 0.001 wt% to 15 wt% of the medicament, and the required dosage can be between 0.1 and 25 mg, and can be administered either by a single dose per day or per week, or by multiple doses per day (2 to 4 times) or by multiple doses per week, however, it will be obvious that it can exceed the upper or lower limits given herein if this is shown to be the case.

[0059] One embodiment of the invention is a compound of formula I as described herein for use as a therapeutically active substance.

[0060] One embodiment of the invention is a compound of formula I as described herein for use in the treatment or prevention of a disease, disorder or condition, wherein the disease, disorder or condition is responsive to NLRP3 inhibition.

[0061] One embodiment of the invention is a compound of formula I as described herein for the treatment or prevention of a disease, disorder or condition, wherein the disorder or condition is responsive to NLRP3 inhibition.

[0062] As used herein, the term "NLRP3 inhibition" refers to a complete or partial decrease in the activity level of NLRP3, including, for example, inhibition of active NLRP3 and / or inhibition of NLRP3 activation.

[0063] There is evidence regarding the role of NLRP3-induced IL-1 and IL-18 in the inflammatory response associated with, or resulting from, a number of different disorders (Menu et al., Clinical and Experimental Immunology, 166:1-15, 2011; Strowig et al., Nature, 481:278-286, 2012).

[0064] In one embodiment, the disease, disorder or condition is selected from: (i) Inflammation; (ii) Autoimmune diseases; (iii) Cancer; (iv) Infectious diseases; (v) Central nervous system diseases; (vi) Metabolic diseases; (vii) Cardiovascular diseases; (viii) Respiratory diseases; (ix) Liver diseases; (x) Kidney diseases; (xi) Eye diseases; (xii) Skin diseases; (xiii) Lymphatic symptoms; (xiv) Mental disorders; (xv) Graft-versus-host disease; (xvi) Allodynia; (xvii) Symptoms associated with diabetes; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

[0065] In another embodiment, the disease, disorder or symptom is selected from: (i) Cancer; (ii) Infectious diseases; (iii) Central nervous system diseases; (iv) Cardiovascular diseases; (v) Liver diseases; (vi) Eye diseases; or (vii) Skin diseases.

[0066] In a further exemplary embodiment of the invention, the disease, disorder or symptom is inflammation. Examples of inflammation that can be treated or prevented include inflammatory responses associated with or resulting from the following: (i) Skin symptoms such as contact hypersensitivity, bullous pemphigoid, sunburn, psoriasis, atopic dermatitis, contact dermatitis, allergic contact dermatitis, seborrheic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bullosa, urticaria, erythema, or alopecia; (ii) Joint symptoms such as osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, rheumatoid arthritis, juvenile chronic arthritis, gout, or seronegative spondyloarthropathies (e.g., ankylosing spondylitis, psoriatic arthritis or Reiter's disease); (iii) Muscle symptoms such as polymyositis or myasthenia gravis; (iv) Gastrointestinal symptoms such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), colitis, gastric ulcer, celiac disease, proctitis, pancreatitis, eosinophilic gastroenteritis, mastocytosis, antiphospholipid syndrome, or food-related allergies that can affect sites distant from the intestine (e.g., migraine, rhinitis or eczema); (v) Respiratory symptoms such as chronic obstructive pulmonary disease (COPD), asthma (including eosinophilic, bronchial, allergic, intrinsic, extrinsic or dust asthma, especially chronic or refractory asthma, such as late-stage asthma and airway hyperresponsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, catarrhal rhinitis, hypertrophic rhinitis, pansinusitis, dry rhinitis, drug-induced rhinitis, membranous rhinitis, seasonal rhinitis, such as hay fever and vasomotor rhinitis), sinusitis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, farmer's lung, silicosis, asbestosis, volcanic ash-induced inflammation, adult respiratory distress syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (vi) Vascular symptoms such as atherosclerosis, Behcet's disease, vasculitis, or Wegener's granulomatosis; (vii) Autoimmune symptoms such as systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenic purpura, or Graves' disease; (viii) Eye symptoms such as uveitis, allergic conjunctivitis, or vernal conjunctivitis; (ix) Neurological symptoms such as multiple sclerosis or encephalomyelitis; (x) Infectious or infection-related symptoms such as acquired immunodeficiency syndrome (AIDS), acute or chronic bacterial infections, acute or chronic parasitic infections, acute or chronic viral infections, acute or chronic fungal infections, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, laryngotracheitis, malaria, hemorrhagic dengue fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis (including co-infection with Mycobacterium tuberculosis and HIV), Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis / epididymitis, Legionella, Lyme disease, influenza A, Epstein-Barr virus infection, viral encephalitis / aseptic meningitis, or pelvic inflammatory disease; (xi) Renal symptoms such as mesangial proliferative glomerulonephritis, nephrotic syndrome, nephritis, glomerulonephritis, obesity-related glomerulopathy, acute renal failure, acute kidney injury, uremia, nephritic syndrome, renal fibrosis including chronic crystalline nephropathy, or renal hypertension; (xii) Lymphatic symptoms such as Castleman's disease; (xiii) Symptoms of the immune system, or symptoms involved therein, such as hyper IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohistiocytosis, or graft-versus-host disease; (xiv) Liver symptoms such as chronic active hepatitis, non-alcoholic fatty liver disease (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis, fulminant hepatitis, liver fibrosis, or liver failure; (xv) Cancers including the above cancers; (xvi) Burns, wounds, trauma, bleeding or stroke; (xvii) Radiation exposure; (xviii) Metabolic diseases such as type 2 diabetes (T2D), atherosclerosis, obesity, gout or pseudogout; and / or (xix) Pains such as inflammatory pain hypersensitivity, pelvic pain, allodynia, neuropathic pain, or cancer-induced bone pain.

[0067] One embodiment of the present invention is the use of a compound of formula I described herein in the treatment or prevention of a disease, disorder or symptom selected from Alzheimer's disease and Parkinson's disease.

[0068] One embodiment of the present invention is the use of a compound of formula I described herein for use in the treatment or prevention of a disease, disorder or symptom selected from asthma or COPD.

[0069] One embodiment of the present invention is the use of a compound of formula I described herein for use in the treatment or prevention of a disease, disorder or symptom selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0070] One embodiment of the present invention is a compound of formula I described herein for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0071] One embodiment of the present invention is a compound of formula I described herein for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0072] One embodiment of the present invention is a compound of formula I described herein for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0073] One embodiment of the present invention is the use of a compound of formula I described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease.

[0074] One embodiment of the present invention is the use of a compound of formula I described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD.

[0075] One embodiment of the present invention is the use of a compound of formula I described herein for the preparation of a medicament for the treatment or prevention of a disease, disorder or condition selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis).

[0076] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder or condition selected from Alzheimer's disease and Parkinson's disease, the method comprising administering an effective amount of a compound of formula I described herein.

[0077] One embodiment of the present invention is a method for the treatment or prevention of a disease, disorder or condition selected from asthma or COPD, the method comprising administering an effective amount of a compound of formula I described herein.

[0078] One embodiment of the present invention is a method for treating or preventing a disease, disorder or symptom selected from inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), the method comprising administering an effective amount of a compound of formula I as described herein.

[0079] One embodiment of the present invention relates to a method for inhibiting NLRP3, the method comprising administering an effective amount of a compound of formula I as described herein.

[0080] Also, one embodiment of the present invention is a compound of formula I as described herein when manufactured according to any one of the described processes.

[0081] One embodiment of the present invention is a pharmaceutical composition comprising a compound of formula I as described herein and a therapeutically inert carrier.

[0082] One embodiment of the present invention is a compound of formula I as described herein for treating or preventing a disease, disorder or symptom selected from: (i) Inflammation; (ii) Autoimmune diseases; (iii) Cancer; (iv) Infectious diseases; (v) Central nervous system diseases; (vi) Metabolic diseases; (vii) Cardiovascular diseases; (viii) Respiratory diseases; (ix) Liver diseases; (x) Kidney diseases; (xi) Eye diseases; (xii) Skin diseases; (xiii) Lymphatic symptoms; (xiv) Mental disorders; (xv) Graft-versus-host disease; (xvi) Allodynia; (xvii) Symptoms related to diabetes; and (xviii) Any disease in which an individual is determined to have a germline or somatic non-silent mutation in NLRP3.

Mode for Carrying Out the Invention

[0083] Assay Procedure NLRP3 and Pyroptosis It is well established that the activation of NLRP3 leads to cell pyroptosis and that this feature plays an important role in the development of clinical diseases (Yang-gang Liu et al., Cell Death & Disease, 2017, 8(2), e2579; Alexander Wree et al., Hepatology, 2014, 59(3), 898 - 910; Alex Baldwin et al., Journal of Medicinal Chemistry, 2016, 59(5), 1691 - 1710; Ema Ozaki et al., Journal of Inflammation Research, 2015, 8, 15 - 27; Zhen Xie & Gang Zhao, Neuroimmunology Neuroinflammation, 2014, 1(2), 60 - 65; Mattia Cocco et al., Journal of Medicinal Chemistry, 2014, 57(24), 10366 - 10382; T. Satoh et al., Cell Death & Disease, 2013, 4, e644). Therefore, inhibitors of NLRP3 are expected to block pyroptosis and the release of pro-inflammatory cytokines (such as IL-1β) from cells.

[0084] THP-1 Cells: Culture and Preparation THP-1 cells (ATCC number TIB-202) were grown in RPMI containing 10% fetal bovine serum (FBS) (Sigma number F0804), 1 mM sodium pyruvate (Sigma number S8636), and L-glutamine (Gibco number 11835) supplemented with penicillin (100 units / ml) / streptomycin (0.1 mg / ml) (Sigma number P4333). The cells were passaged regularly and grown to confluence (about 10 6 cells / ml). On the day of the experiment, THP-1 cells were harvested and resuspended in RPMI medium (without FBS). The cells were then counted and viability (>90%) was confirmed by trypan blue (Sigma number T8154). Appropriate dilution was performed to obtain a concentration of 625,000 cells / ml. Lipopolysaccharide (LPS) (Sigma number L4524) was added to this diluted cell solution to obtain a final assay concentration (FAC) of 1 μg / ml. 40 μl of the final preparation was dispensed into each well of a 96-well plate. The plate thus prepared was used for compound screening.

[0085] THP-1 Cell Pyroptosis Assay For compound screening, a stepwise assay of the following method was followed. 1. Seed THP-1 cells (25,000 cells / well) containing 1.0 μg / ml LPS in 40 μl of RPMI medium (without FBS) in a 96-well black wall clear bottom cell culture plate coated with poly-D-lysine (VWR number 734-0317) 2. Add 5 μl of the compound (8-point log dilution using a maximum dose of 10 μM) or vehicle (DMSO 0.1% FAC) to the appropriate wells 3. Incubate at 37 °C, 5% CO2 for 3 hours 4. Add 5 μl of nigericin (Sigma number N7143) (FAC 5 μM) to all wells 5. Incubate at 37 °C, 5% CO2 for 1 hour 6. At the end of the incubation period, spin the plate at 300 × g for 3 minutes and remove the supernatant 7. Next, add 50 μl of resazurin (Sigma number R7017) (100 μM resazurin in RPMI medium without FBS) and incubate the plate at 37 °C and 5% CO2 for an additional 1 - 2 hours. 8. The plate was read on an Envision reader at Ex560 nm and Em590 nm. 9. IC 50 Fit the data to a non - linear regression equation (log inhibitor vs. response variable slope 4 - parameter).

[0086] Summarize the results of the pyroptosis assay as THP IC 50 in Table 1 below.

[0087] Human whole - blood IL - 1β release assay For systemic delivery, the ability of the compound to inhibit NLRP3 when present in the bloodstream is highly important. Therefore, the NLRP3 inhibitory activity of several compounds in human whole - blood was examined according to the following protocol.

[0088] Human whole - blood in Li - heparin tubes was obtained from healthy donors of a volunteer donor panel. 1. Plate out 80 μl of whole - blood containing 1 μg / ml of LPS in a 96 - well clear - bottom cell culture plate (Corning number 3585). 2. Add 10 μl of the compound (8 - point half - log dilution at a maximum dose of 10 μM) or vehicle (0.1% DMSO in FAC) to the appropriate wells. 3. Incubate at 37 °C, 5% CO2 for 3 hours. 4. Add 10 μl of nigericin (Sigma number N7143) (10 μM in FAC) to all wells. 5. Incubate at 37 °C, 5% CO2 for 1 hour. 6. At the end of the incubation period, spin the plate at 300 × g for 5 minutes to pellet the cells, remove 20 μl of the supernatant, and add it to a 96 - well v - bottom plate for IL - 1β analysis (Note: These plates containing the supernatant can be stored at - 80 °C for later analysis). 7. IL-1β was measured according to the manufacturer's protocol (Perkin Elmer - AlphaLisa IL-1 Kit AL220F-5000). 8. IC 50 Fit the data to a non-linear regression equation (log inhibitor vs. response variable slope 4-parameter).

[0089] Summarize the results of the human whole blood assay as HWB IC 50 in Table 1 below.

Table 1

[0090] The present invention will now be described by the following examples which have no limiting features.

[0091] When a preparation example is obtained as a mixture of enantiomers, the pure enantiomers can be obtained by the methods described herein or methods known to those skilled in the art, such as chiral chromatography or crystallization.

Examples

[0092] Unless otherwise specified, all examples and intermediates were prepared under a nitrogen atmosphere.

Table 2

[0093] Examples 1A and 1B: 5-[3-[(3aS,7aR)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol and 5-[3-[(3aR,7aS)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol [Chemistry]

[0094] Process A: tert-Butyl 1-(6-chloro-5-methyl-1,2,4-triazin-3-yl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate [Chemistry] To a mixture of 3,6-dichloro-5-methyl-1,2,4-triazine (CAS No. 132434-82-3, 500 mg, 3.05 mmol, 1.00 equivalent) and tert-butyl 1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine-6-carboxylate (CAS No. 1196147-27-9, 898 mg, 3.97 mmol, 1.30 equivalents) in 1,4-dioxane (9.0 mL) was added N,N-diisopropylethylamine (414 mg, 0.56 mL, 3.21 mmol, 1.05 equivalents). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and water. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 40 g, gradient 0% - 30% ethyl acetate in heptane) to give the title compound (952 mg, 84% yield) as a yellow oil. LCMS: m / z 354.2 [M+H] + , ESI pos.

[0095] Process B: 1-(6-Chloro-5-methyl-1,2,4-triazin-3-yl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine hydrochloride [Chemistry] A solution of tert-butyl 1-(6-chloro-5-methyl-1,2,4-triazin-3-yl)-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate (Example 1, Step A) (938 mg, 2.52 mmol, 1.00 equiv) in dichloromethane (8.0 mL) and methanol (4.0 mL) was added dropwise with 4 M HCl in dioxane (6 mL, 24 mmol, 9.53 equiv). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give the title compound (1.09 g, yield 97%, purity 65%) as an orange foam, which was used without further purification. LCMS: m / z 254.2 [M+H] + , ESI pos.

[0096] Step C: 1-(6-Chloro-5-methyl-1,2,4-triazin-3-yl)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine [Chemical formula] A suspension of 1-(6-chloro-5-methyl-1,2,4-triazin-3-yl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine hydrochloride (Example 1, Step B) (500 mg, 1.12 mmol, 1.00 eq., purity 65%) in dichloromethane (7.0 mL) was added with acetaldehyde (125 mg, 0.160 mL, 2.83 mmol, 2.53 eq.), followed by addition of sodium acetate (185 mg, 2.26 mmol, 2.01 eq.) under ice-bath cooling. Sodium triacetoxyborohydride (358 mg, 1.69 mmol, 1.51 eq.) was added in three portions at 0 °C. After the addition was complete, the ice-bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was carefully quenched with saturated aqueous NaHCO3 and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was absorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient of 0% - 5% methanol in dichloromethane) to give the title compound (246 mg, 74% yield) as a yellow oil. LCMS: m / z 282.2 [M+H] + , ESI pos.

[0097] Step D: 4-benzyloxy-5-bromo-2,3-dihydrobenzofuran

Chemical formula

[0098] Step E: 2-(4-benzyloxy-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Chemical formula

[0099] Step F: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-4-ol

Chem.

[0100] Step G: 5-[3-(6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol

Chemical Structure

[0101] Step H: 5-[3-[(3aS,7aR)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol and 5-[3-[(3aR,7aS)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol

Chemical formula

[0102] Examples 2A and 2B: 4-[3-[(3aS,7aR)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile and 4-[3-[(3aR,7aS)-6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile

Chemical formula

[0103] Step A: 4-[3-(6-Ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile

Chemical formula

[0104] 1-(6-Chloro-5-methyl-1,2,4-triazin-3-yl)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine (Example 1, Step C) (99 mg, 0.33 mmol, 1.00 eq) in 1,4-dioxane (2.0 mL) and water (1.0 mL) was combined with (4-cyano-2-hydroxy-phenyl)boronic acid (commercially available, no CAS, 88 mg, 0.54 mmol, 1.62 eq), potassium carbonate (212 mg, 1.53 mmol, 4.60 eq), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (41 mg, 0.05 mmol, 0.15 eq). Argon was bubbled through the mixture, and the resulting mixture was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and half-saturated aqueous NH4Cl. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% - 10% methanol in dichloromethane) to afford the title compound (62 mg, 48% yield) as a yellow foam. LCMS: m / z 365.2 [M+H] + ,ESI pos.

[0105] Step B: 4-[3-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile and 4-[3-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile

Chemical Structure

[0106] Examples 3A and 3B: 5-[3-[(3aS,7aR)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol and 5-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol

Chemical formula

[0107] Step A: 1-(6-Chloro-5-methyl-1,2,4-triazin-3-yl)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine

Chemical formula

[0108] A suspension of 1-(6-chloro-5-methyl-1,2,4-triazin-3-yl)-2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridine hydrochloride (Example 1, Step B) (578 mg, 1.29 mmol, 1.00 eq., purity 65%) in 1,2-dichloroethane (12 mL) was added with triethylamine (203 mg, 0.280 mL, 2.01 mmol, 1.55 eq.). The mixture was stirred at room temperature for 5 minutes. Formaldehyde, 37% aqueous solution (218 mg, 0.20 mL, 2.69 mmol, 2.07 eq.) was added, followed by the addition of sodium triacetoxyborohydride (1.10 g, 5.18 mmol, 4.00 eq.) portionwise. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was carefully quenched with saturated aqueous NaHCO3 and extracted 4 times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was adsorbed onto ISOLUTE HM-N and purified by flash chromatography (silica gel, 12 g, gradient 0% - 10% methanol in dichloromethane) to give the title compound (335 mg, 92% yield) as a yellow oil. LCMS: m / z 268.1 [M+H] + , ESI pos.

[0109] Step B: 5-[5-methyl-3-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol

Chemical Structure

[0110] Step C: 5-[3-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol and 5-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-2,3-dihydrobenzofuran-4-ol

Chemical formula

[0111] Examples 4A and 4B: 4-[3-[(3aS,7aR)-6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile and 4-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile

Chemical formula

[0112] Step A: 3-Hydroxy-4-[5-methyl-3-(6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-1,2,4-triazin-6-yl]benzonitrile

Chemical formula

[0113] Step B: 4-[3-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile and 4-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl]-5-methyl-1,2,4-triazin-6-yl]-3-hydroxy-benzonitrile

Chem.

[0114] Example A The compound of formula I can be used as an active ingredient in a manner known per se for producing tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

[0115] Example B The compound of formula I can be used as an active ingredient in a manner known per se for producing capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Claims

1. Compound of formula I 【Chemistry 1】 (R １ is H, halo, alkyl, haloalkyl, haloalkoxy, or cyano; R ２ H is; or R １ and R ２ Furthermore, the atoms to which they are bonded form a 4-6 membered cycloalkyl or 4-6 membered heterocyclic ring, and the cycloalkyl and heterocyclic rings are optionally substituted with one or two substituents independently selected from halo, alkyl, or oxo; R ３ is selected from H, alkyl, cyano or haloalkyl, and R ４ is selected from H, alkyl, halo, cyano or -CH ２ -alkoxy, and R ３ and R ４ are both not H; W is an 8-10 member "N-linked" bicyclic ring system or an 8-10 member "N-linked" spirocyclic ring system, wherein the N-linked bicyclic ring system or N-linked spirocyclic ring system contains at least two N heteroatoms and may be optionally substituted with up to four substituents independently selected from hydroxyl, alkyl, halogen, or cyano; and its pharmaceutically acceptable salts.

2. R １ is cyano or haloalkyl, and R ２ Is H or R １ and R ２ The compound according to claim 1, wherein the atoms to which they are bonded form a 4- to 6-membered heterocyclic ring containing a single heteroatom O which is optionally substituted with one or two substituents independently selected from halo or alkyl.

3. R １ is cyano and R ２ Is H or R １ and R ２ The compound according to claim 1 or claim 2, wherein the atoms to which they are bonded form a five-membered heterocyclic ring containing a single heteroatom O.

4. R ３ The compound according to claim 1 or 2, wherein the compound is H or alkyl.

5. R ３ The compound according to claim 1 or 2, wherein the alkyl group is alkyl.

6. R ４ The compound according to claim 1 or 2, wherein is H.

7. W is selected from ring systems A, B, or C. 【Chemistry 2】 During the ceremony, Y is CH ２ , O or NR ｙ And; R ｙ However, it is H or alkyl; R ｘ However, it is H or alkyl; The compound according to claim 1 or 2, wherein the ring system A, B, or C may be further substituted with one cyano substituent or up to two halo substituents.

8. Y is CH ２ or O, R ｘ The compound according to claim 7, wherein the compound is H or alkyl.

9. R １ is cyano and R ２ Is H or R １ and R ２ , and the atoms to which they are bonded form a five-membered heterocyclic ring containing a single heteroatom O; R ３ is alkyl; R ４ H is, W is a ring system C, 【Transformation 3】 R ｘ The compound according to claim 1, wherein the alkyl group is and its pharmaceutically acceptable salts.

10. 5-[3-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol; 5-[3-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol; 4-[3-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-3-hydroxybenzonitrile or 4-[3-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-3-hydroxybenzonitrile; 4-[3-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-3-hydroxybenzonitrile or 4-[3-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-3-hydroxybenzonitrile; 5-[3-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol; 5-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol; 4-[3-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-3-hydroxybenzonitrile or 4-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-3-hydroxybenzonitrile; 4-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-3-hydroxybenzonitrile or 4-[3-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-3-hydroxybenzonitrile; A compound according to claim 1 or 2, selected from the above, and a pharmaceutically acceptable salt thereof.

11. 5-[3-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol; 5-[3-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol; 4-[3-[(3aS,7aR)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-3-hydroxybenzonitrile or 4-[3-[(3aR,7aS)-6-ethyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-3-hydroxybenzonitrile; 5-[3-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol or 5-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-2,3-dihydrobenzofuran-4-ol; 4-[3-[(3aS,7aR)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-3-hydroxybenzonitrile or 4-[3-[(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridine-1-yl]-5-methyl-1,2,4-triazine-6-yl]-3-hydroxybenzonitrile; A compound according to claim 1 or 2, selected from the above, and a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound according to claim 1 or 2 and a therapeutically inert carrier.

13. A pharmaceutical composition according to claim 12 for use in the treatment or prevention of a disease, disorder or symptom, wherein the disease, disorder or symptom is responsive to NLRP3 inhibition.

14. The pharmaceutical composition according to claim 12 for use in the treatment or prevention of a disease, disorder, or symptom selected from asthma or COPD.

15. The pharmaceutical composition according to claim 12 for use in the treatment or prevention of a disease, disorder or symptom selected from Parkinson's disease or Alzheimer's disease.

16. Use of the compound according to claim 1 or 2 for the preparation of a medicament for the treatment or prevention of a disease, disorder or symptom selected from asthma or COPD.

17. Use of the compound according to claim 1 or 2 for the preparation of a medicament for the treatment or prevention of a disease, disorder or symptom selected from Parkinson's disease or Alzheimer's disease.

18. A pharmaceutical composition according to claim 12 for inhibiting NLRP3.

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