Phthalazine derivatives useful as NOD-like receptor protein 3 inhibitors

Abstract

Novel compounds of structural formula (I), and pharmaceutically acceptable salts thereof, are inhibitors of NLRP3 and are useful in the treatment, prevention, management, amelioration, control and inhibition of diseases mediated by NLPR3. The compounds of the invention are useful in the treatment, prevention or management of diseases, disorders and conditions mediated by NLRP3, such as, but not limited to, gout, pseudogout, CAPS, NASH fibrosis, heart failure, idiopathic pericarditis, atopic dermatitis, inflammatory bowel disease, Alzheimer's disease, Parkinson's disease, and traumatic brain injury. # imgabs0 #

Description

Background Art

[0001] Inflammasomes serve as central signaling hubs of the innate immune system. They are multiprotein complexes assembled after activation of a specific set of intracellular pattern recognition receptors (PRRs) by a variety of pathogen-associated patterns (PAMPs) or danger-associated molecular patterns (DAMPs). It has been shown that inflammasomes can be formed by nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and proteins containing pyrin and HIN200 domains (Van Opdenbosch N and Lamkanfi M. Immunity, 2019 Jun 18; 50(6): 1352-1364). Inflammasome activation triggers a cascade of events that releases proinflammatory cytokines and promotes a form of inflammatory cell death called pyroptosis induced by gasdermin activation. Pyroptosis is a unique form of inflammatory cell death that not only leads to cytokine release, but also the release of other intracellular components that promote a broader immune response of the innate and adaptive immune systems. Therefore, inflammasome activation is a major regulator of the inflammatory cascade.

[0002] The (NOD)-like receptor protein 3 (NLRP3) inflammasome is the most intensively studied of all inflammasomes. NLRP3 can be activated by a variety of stimuli, including environmental crystals, pollutants, host-derived DAMPs, and protein aggregates (Tartey Sand Kanneganti TD. Immunology, 2019Apr; l56(4): 329-338). Danger-associated molecular patterns involving NLRP3 include uric acid and cholesterol crystals that cause gout and atherosclerosis, amyloid-P fibers that are neurotoxic in Alzheimer's disease, and asbestos particles that cause mesothelioma. (Kelley et al., Int J Mol Sci, 2019Jul 6; 20(13)). In addition, NLRP3 is activated by infectious agents such as Vibrio cholerae; fungal pathogens such as Aspergillus fumigatus and Candida albicans; adenovirus, influenza A virus, and SARS CoV 2 (Tartey and Kanneganti, 2019 (see above); Fung et al. Emerg Microbes Infect, 2020 Mar 14; 9(1): 558-570).

[0003] The activation mechanism of NLRP3 in humans remains unclear. It has been suggested that the NLRP3 inflammasome needs to be regulated at the transcriptional and post-transcriptional levels (Yang et al., Cell Death Dis, 2019 Feb 12; 10(2): 128). NOD-like receptor protein 3 (NLRP3) is a gene encoding a protein that consists of a pyrin domain at the N-terminus, a nucleotide binding site domain (NBD), and a leucine-rich repeat (LRR) motif at the C-terminus (Inoue et al., Immunology, 2013, 139, 11-18; Sharif et al., Nature, 2019 Jun; 570(7761): 338-343).

[0004] In response to sterile inflammatory danger signals PAMPs or DAMPs, NLRP3 interacts with the adaptor protein, apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, and the protease caspase-1 to form the NLRP3 inflammasome. Upon activation, the caspase-1 proenzyme undergoes autoproteolysis, cleaving pyroporin D (Gsdmd) to produce an N-terminal Gsdmd molecule, which causes pore formation in the plasma membrane and leads to a lytic cell death form called pyroptosis. Alternatively, caspase-1 cleaves the proinflammatory cytokines pro-IL-Iβ and pro-IL-18 to allow the release of their biologically active forms (Kelley et al., 2019-see above). NLRP3 inflammasome activation leads to the release of the inflammatory cytokines IL-lβ (interleukin-Iβ) and IL-18 (interleukin-18), which when dysregulated can lead to many diseases.

[0005] Dysregulation of the NLRP3 inflammasome or its downstream mediators has been implicated in many immune, inflammatory, autoimmune, and autoinflammatory diseases. NLRP3 inflammasome activation is associated with the following diseases and conditions: cryopyrin-associated periodic syndrome; sickle cell disease; systemic lupus erythematosus; allodynia; graft-versus-host disease; liver disorders (including nonalcoholic hepatitis (NASH), chronic liver disease, viral hepatitis, alcoholic steatohepatitis and alcoholic liver disease); inflammatory bowel disease (including Crohn's disease and ulcerative colitis); inflammatory joint disorders (including gout, pseudogout, arthropathy, osteoarthritis and rheumatoid arthritis); other rheumatic diseases (including dermatomyositis, Still's disease and juvenile idiopathic arthritis); kidney-related diseases (including hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-related inflammation, diabetic nephropathy ("diabetic nephropathy" and "diabetic kidney disease") and other inflammatory diseases) (Miyamae T. Paediatr Drugs, 2012 Apr 1, 14(2): 109-17; Szabo G and Petrasek J. Nat RevGastroenterol Hepatol, 2015Jul;12(7):387-400; Zhen Y and Zhang H. Front Immunol, 2019Feb 28;10:276; Vande Walle Let al., Nature, 2014Aug 7;512(7512):69-73; Knaufet al., Kidney Int,2013Nov;84(5):895-901;Krishnan et al.,Br J Pharmacol,2016Feb;l73(4):752-65);Shahzad et al.,Kidney Int,2015Jan;87(1):74-84;Jankovic,et al.J Exp Med.2013Sep 23;210(10):1899-910.). The development and progression of neuroinflammation-related disorders (such as brain infection, acute injury, multiple sclerosis, amyotrophic lateral sclerosis, and other neurodegenerative diseases such as Parkinson's and Alzheimer's diseases) are associated with NLRP3 inflammasome activation (Sarkar et al., NPJ Parkinsons Dis, 2017 Oct 17; 3:30).

[0006] Cardiovascular and metabolic diseases (such as atherosclerosis, type I and II diabetes and diabetic complications including nephropathy and retinopathy, peripheral arterial disease, acute heart failure and hypertension) are associated with NLRP3 (Ridker et al., CANTOS Trial Group. N Engl J Med, 2017 Sep 21; 377 (12): 1119-1131; and Toldo S and Abbate A Nat Rev Cardiol, 2018 Apr; 15 (4): 203-214). NLRP3-related skin diseases include wound healing and scar formation; inflammatory skin diseases (such as acne, atopic dermatitis, suppurative hidradenitis and psoriasis) (Kelly et al., Br J Dermatol, 2015 Dec; 1 73 (6)). NLRP3 inflammasome activity is also associated with respiratory conditions such as asthma, sarcoidosis, acute respiratory distress syndrome, severe acute respiratory syndrome (SARS) (Nieto-Torres et al., Virology, 2015 Nov; 485: 330-9)); and eye diseases including age-related macular degeneration (AMD) and diabetic retinopathy (Doyle et al., Nat Med, 2012 May; 18 (5): 791-8). Cancers associated with NLRP3 include myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer and colon cancer. (Ridker et al., Lancet, 2017 Oct 21; 390 (10105): 1833-1842; Derangere et al., Cell DeathDiffer. 2014 Dec; 21 (12): 1914-24; Basiorka et al., Lancet Haematol, 2018Sep;5(9):e393-e402, Zhang et al., Hum Immunol, 2018Jan;79(1):57-62).

[0007] Immune diseases and inflammatory conditions are often difficult to diagnose or treat effectively. Most treatments involve treating symptoms, slowing disease progression, lifestyle changes, and surgery.

[0008] There remains a need for NLRP3 inhibitors to provide new treatments for diseases and conditions associated with NLRP3 inflammasome activation and dysregulation. The compounds of the present invention can be used to treat and prevent diseases, disorders and conditions mediated by the formation and propagation of NLRP3 inflammasomes.

[0009] NLRP3 inhibitors are disclosed in the following publications: Nat. 2022, 1; Cell. 2021, 184, 1; J. Mol. Biol. 2021, 433, 167308; J. Med. Chem. 2021, 64, 101; Nat. Chem. Biol. 2019, 15, 556; Nat. 2019, 570, 338; Nat. Chem. Biol. 2019, 15, 560; PLOS Biol.2019,1; Nat.Med.2015,21,248; Cell.2014,156,1193; Nat.Immunol.2014,15,738; PNAS.2007,104,8041; Nat.2006,440,9; Immunity.2006,24,317. Several patent applications describe NLRP3 inhibitors, including WO 2021 / 239885, WO 2021 / 209552, WO 2021 / 209539, WO 2021 / 193897, WO 2020 / 018975, WO 2020 / 037116, WO 2020 / 021447, WO 2020 / 010143, WO 2019 / 079119, WO 2019 / 0166621, WO 2019 / 121691, US11,319,319 and US2020 / 0361898. Summary of the invention

[0010] The present invention relates to novel compounds of structural formula I:

[0011]

[0012] and pharmaceutically acceptable salts thereof.

[0013] Compounds of structural formula I, and embodiments thereof are NOD-like receptor protein 3 inhibitors (NLRP3) and can be used to treat or prevent diseases, disorders and conditions mediated by NLRP3, such as, but not limited to, gout, pseudogout (chondrocalcinosis), cryopyrin-associated periodic syndrome (CAPS), NASH, fibrosis, heart failure, idiopathic pericarditis, atopic dermatitis, inflammatory bowel disease, Alzheimer's disease, Parkinson's disease and traumatic brain injury.

[0014] The present invention also relates to a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier.

[0015] The present invention also relates to methods for treating, managing, preventing, alleviating, ameliorating, inhibiting or controlling disorders, diseases and conditions responsive to inhibition of NLRP3 receptors in a subject in need thereof by administering the compounds and pharmaceutical compositions of the present invention.

[0016] The present invention also relates to the use of the compounds of the present invention for the preparation of a medicament useful for treating diseases, disorders and conditions responsive to inhibition of the NLRP3 receptor.

[0017] The present invention also relates to treating diseases, disorders and conditions by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent useful for treating such diseases, disorders and conditions. The present invention also relates to processes for preparing the compounds of the present invention. DETAILED DESCRIPTION

[0018] The present invention relates to novel compounds of structural formula I:

[0019]

[0020] or a pharmaceutically acceptable salt thereof, wherein

[0021] T is independently selected from the following group:

[0022] 1)CR 3 ,and

[0023] 2)N,

[0024] Provided that zero, one or two of T, U, V and W are N;

[0025] U is independently selected from the following group:

[0026] 1)CR 4 ,and

[0027] 2) N;

[0028] V is independently selected from the group consisting of:

[0029] 1)CR 5 ,and

[0030] 2) N;

[0031] W is independently selected from the following group:

[0032] 1)CR 6 ,and

[0033] 2) N;

[0034] R 1 Select from the following group:

[0035] 1)-C 3-12 Cycloalkyl,

[0036] 2) -C 3-12 Cycloalkenyl, and

[0037] 3) -C 2-12 Cycloheteroalkyl,

[0038] Where R 1 is unsubstituted or substituted with one to six residues selected from R a Substituents are substituted;

[0039] R 2 Select from the following group:

[0040] 1) aryl, and

[0041] 2) heteroaryl,

[0042] Where R 2 is unsubstituted or substituted with one to five b Substituents are substituted;

[0043] R 3 Select from the following group:

[0044] 1) Hydrogen,

[0045] 2) OH,

[0046] 3) CN,

[0047] 4) CF3,

[0048] 5) CF2H,

[0049] 6) -C 1-6 alkyl,

[0050] 7)-OC 1-6 alkyl,

[0051] 8) Halogen,

[0052] 9)-C 3-6 Cycloalkyl,

[0053] 10) -C 2-6 Cycloheteroalkyl,

[0054] 11) -C 1-6 Alkyl-OC 1-6 alkyl,

[0055] 12)-(CH2) r C(O)R h ,

[0056] 13)-(CH2) r C(O)N(R i )2,

[0057] 14)-(CH2) r N(R j )C(O)R h ,

[0058] 15)-(CH2)r N(R j )C(O)OR h ,

[0059] 16)-(CH2) r N(R j )C(O)N(R i )2,

[0060] 17)-(CH2) r N(R j )C(O)N(R i )2,

[0061] 18)-(CH2) r N(R j )S(O) m R h ,

[0062] 19)-(CH2) r N(R j )S(O) m N(R i )2,

[0063] 20)-(CH2) r N(R j )S(O) m N(R i )2, and

[0064] 21)-(CH2) r N(R i )2,

[0065] Where R 3 is unsubstituted or substituted with one to five d Substituents are substituted;

[0066] R 4 Select from the following group:

[0067] 1) Hydrogen,

[0068] 2) OH,

[0069] 3) CN,

[0070] 4) CF3,

[0071] 5) CF2H,

[0072] 6) -C 1-6 alkyl,

[0073] 7)-OC 1-6 alkyl,

[0074] 8) Halogen,

[0075] 9)-C 3-6 Cycloalkyl,

[0076] 10) -C 2-6 Cycloheteroalkyl,

[0077] 11) -C 1-6 Alkyl-OC 1-6 alkyl,

[0078] 12)-(CH2) s C(O)R h ,

[0079] 13)-(CH2) s C(O)N(R i )2,

[0080] 14)-(CH2) s N(R j )C(O)R h ,

[0081] 15)-(CH2) s N(R j )C(O)OR h ,

[0082] 16)-(CH2) s N(R j )C(O)N(R i )2,

[0083] 17)-(CH2) s N(R j )C(O)N(R i )2,

[0084] 18)-(CH2) s N(R j )S(O) m R h ,

[0085] 19)-(CH2) s N(R j )S(O) m N(R i )2,

[0086] 20)-(CH2) s N(R j )S(O) m N(R i )2, and

[0087] 21)-(CH2) s N(Ri )2,

[0088] Where R 4 is unsubstituted or substituted with one to five e Substituents are substituted;

[0089] R 5 Select from the following group:

[0090] 1) Hydrogen,

[0091] 2) OH,

[0092] 3) CN,

[0093] 4) CF3,

[0094] 5) CF2H,

[0095] 6) -C 1-6 alkyl,

[0096] 7)-OC 1-6 alkyl,

[0097] 8) Halogen,

[0098] 9)-C 3-6 Cycloalkyl,

[0099] 10) -C 2-6 Cycloheteroalkyl,

[0100] 11) -C 1-6 Alkyl-OC 1-6 alkyl,

[0101] 12)-(CH2) t C(O)R h ,

[0102] 13)-(CH2) t C(O)N(R i )2,

[0103] 14)-(CH2) t N(R j )C(O)R h ,

[0104] 15)-(CH2) t N(R j )C(O)OR h ,

[0105] 16)-(CH2) t N(R j )C(O)N(R i )2,

[0106] 17)-(CH2) t N(R j )C(O)N(R i )2,

[0107] 18)-(CH2) t N(R j )S(O) m R h ,

[0108] 19)-(CH2) t N(R j )S(O) m N(R i )2,

[0109] 20)-(CH2) t N(R j )S(O) m N(R i )2, and

[0110] 21)-(CH2) t N(R i )2,

[0111] Where R 5 is unsubstituted or substituted with one to five f Substituents are substituted;

[0112] R 6 Select from the following group:

[0113] 1) Hydrogen,

[0114] 2) OH,

[0115] 3) CN,

[0116] 4) CF3,

[0117] 5) CF2H,

[0118] 6) -C 1-6 alkyl,

[0119] 7)-OC 1-6 alkyl,

[0120] 8) Halogen,

[0121] 9)-C 3-6 Cycloalkyl,

[0122] 10) -C 2-6 Cycloheteroalkyl,

[0123] 11) -C 1-6 Alkyl-OC 1-6 alkyl,

[0124] 12)-(CH2) u C(O)R h ,

[0125] 13)-(CH2) u C(O)N(R i )2,

[0126] 14)-(CH2) u N(R j )C(O)R h ,

[0127] 15)-(CH2) u N(R j )C(O)OR h ,

[0128] 16)-(CH2) u N(R j )C(O)N(R i )2,

[0129] 17)-(CH2) u N(R j )C(O)N(R i )2,

[0130] 18)-(CH2) u N(R j )S(O) m R h ,

[0131] 19)-(CH2) u N(R j )S(O) m N(R i )2,

[0132] 20)-(CH2) u N(R j )S(O) m N(R i )2, and

[0133] 21)-(CH2) u N(R i )2,

[0134] Where R 6 is unsubstituted or substituted with one to five substituents selected from Rg;

[0135] Each R a Independently selected from the group consisting of:

[0136] 1) CN,

[0137] 2) Oxo,

[0138] 3) -OH,

[0139] 4) Halogen,

[0140] 5) -C 1-6 alkyl,

[0141] 6)-OC 1-6 alkyl,

[0142] 7) -C 2-6 Alkenyl,

[0143] 8) -C 2-6 Alkynyl,

[0144] 9)-C 3-6 Cycloalkyl,

[0145] 10) -C 2-6 Cycloheteroalkyl,

[0146] 11) aryl,

[0147] 12) heteroaryl,

[0148] 13)-C(O)C 1-6 alkyl,

[0149] 14) -C 1-6 Alkyl-aryl,

[0150] 15) -C 1-6 Alkyl-heteroaryl,

[0151] 16) -C 1-6 Alkyl-C 3-6 Cycloalkyl,

[0152] 17) -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl,

[0153] 18) -C 2-6 Alkenyl-C 3-6 Cycloalkyl,

[0154] 19) -C 2-6 Alkenyl-C 2-6 Cycloheteroalkyl,

[0155] 20)-C 2-6 Alkenyl-aryl,

[0156] 21)-C 2-6 alkenyl-heteroaryl,

[0157] 22)-C 2-6Alkynyl-C 3-6 Cycloalkyl,

[0158] 23)-C 2-6 Alkynyl C 2-6 Cycloheteroalkyl,

[0159] 24)-C 2-6 Alkynyl-aryl,

[0160] 25)-C 2-6 Alkynyl-heteroaryl,

[0161] 26)-(CH2) p -OC 1-6 alkyl,

[0162] 27)-(CH2) p -OC 2-6 Alkenyl,

[0163] 28)-(CH2) p -OC 2-6 Alkynyl,

[0164] 29)-(CH2) p -OC 3-6 Cycloalkyl,

[0165] 30)-(CH2) p -OC 2-6 Cycloheteroalkyl,

[0166] 31)-(CH2) p -O-aryl,

[0167] 32)-(CH2) p -O-heteroaryl,

[0168] 33)-OC 1-6 Alkyl-C 3-6 Cycloalkyl,

[0169] 34)-OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl,

[0170] 35)-OC 1-6 Alkyl-aryl,

[0171] 36)-OC 1-6 Alkyl-heteroaryl,

[0172] 37)-(CH2) p -S(O) r R k ,

[0173] 38)-(CH2)p -S(O)N(R L )2, and

[0174] 39)-(CH2) p -N(R L )2,

[0175] Among them, each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 Substitution of alkyl groups;

[0176] Each R b Independently selected from the group consisting of:

[0177] 1) CN,

[0178] 2) -OH,

[0179] 3) Oxo,

[0180] 4) Halogen,

[0181] 5) -C 1-6 alkyl,

[0182] 6)-OC 1-6 alkyl,

[0183] 7) -C 3-6 Cycloalkyl,

[0184] 8) -C 2-6 Cycloheteroalkyl,

[0185] 9) aryl,

[0186] 10) heteroaryl,

[0187] 11) -C 1-6 Alkyl-aryl,

[0188] 12) -C 1-6 Alkyl-heteroaryl,

[0189] 13) -C 1-6 Alkyl-C 3-6 Cycloalkyl,

[0190] 14) -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl,

[0191] 15)-(CH2) q -OC 1-6 alkyl,

[0192] 16)-(CH2) q -OC3-6 Cycloalkyl,

[0193] 17)-(CH2) q -OC 2-6 Cycloheteroalkyl,

[0194] 18)-(CH2) q -O-aryl,

[0195] 19)-(CH2) q -O-heteroaryl,

[0196] 20)-OC 1-6 Alkyl-C 3-6 Cycloalkyl,

[0197] 21)-OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl,

[0198] 22)-OC 1-6 Alkyl-aryl,

[0199] 23)-OC 1-6 Alkyl-heteroaryl,

[0200] 24)-(CH2) q -S(O) r R m ,

[0201] 25)-(CH2) q N(R n )2,

[0202] 26)-C(O)R o ,and

[0203] 27)-C(O)NR n ,

[0204] Among them, each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Substitution of alkyl groups;

[0205] Each R d Independently selected from the group consisting of:

[0206] 1) CF3,

[0207] 2) halogen, and

[0208] 3) -C 1-6 alkyl,

[0209] wherein the alkyl group is unsubstituted or substituted with one to three radicals selected from: CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups;

[0210] Each R e Independently selected from the group consisting of:

[0211] 1) CF3,

[0212] 2) halogen, and

[0213] 3) -C 1-6 alkyl,

[0214] wherein the alkyl group is unsubstituted or substituted with one to three radicals selected from: CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups;

[0215] Each R f Independently selected from the group consisting of:

[0216] 1) CF3,

[0217] 2) halogen, and

[0218] 3) -C 1-6 alkyl,

[0219] wherein the alkyl group is unsubstituted or substituted with one to three radicals selected from: CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups;

[0220] Each R g Independently selected from the group consisting of:

[0221] 1) CF3,

[0222] 2) halogen, and

[0223] 3) -C 1-6 alkyl,

[0224] wherein the alkyl group is unsubstituted or substituted with one to three radicals selected from: CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups;

[0225] Each R h Independently selected from the following group:

[0226] 1) Hydrogen,

[0227] 2) -C 1-6 alkyl,

[0228] 3) -C 3-6 Cycloalkyl, and

[0229] 4) -C 2-6 Cycloheteroalkyl,

[0230] Wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups;

[0231] Each R i Independently selected from the following group:

[0232] 1) Hydrogen,

[0233] 2) -C 1-6 alkyl,

[0234] 3) -C 3-6 Cycloalkyl, and

[0235] 4) -C 2-6 Cycloheteroalkyl,

[0236] Wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituted alkyl radicals selected from: CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups;

[0237] Each R j Independently selected from the following group:

[0238] 1) Hydrogen,

[0239] 2) -C 1-6 alkyl,

[0240] 3) -C 3-6 Cycloalkyl, and

[0241] 4) -C 2-6 Cycloheteroalkyl,

[0242] Wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituted alkyl radicals selected from: CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups;

[0243] Each R k Independently selected from the following group:

[0244] 1)-C 1-6 alkyl,

[0245] 2) -C 3-6 Cycloalkyl, and

[0246] 3) -C 2-6 Cycloheteroalkyl,

[0247] wherein alkyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH, and -OC 1-6 Substitution of alkyl groups;

[0248] Each RL Independently selected from the group consisting of:

[0249] 1) Hydrogen,

[0250] 2) -C 1-6 alkyl,

[0251] 3) -C 3-6 Cycloalkyl, and

[0252] 4) -C 2-6 Cycloheteroalkyl,

[0253] wherein alkyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH, and -OC 1-6 Substitution of alkyl groups;

[0254] Each R m Independently selected from the group consisting of:

[0255] 1)-C 1-6 alkyl,

[0256] 2) -C 3-6 Cycloalkyl, and

[0257] 3) -C 2-6 Cycloheteroalkyl,

[0258] Wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups;

[0259] Each R n Independently selected from the group consisting of:

[0260] 1) Hydrogen,

[0261] 2) C 1-6 alkyl,

[0262] 3) -C 3-6 Cycloalkyl, and

[0263] 4) -C 2-6 Cycloheteroalkyl,

[0264] wherein alkyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH, and -OC 1-6 Substitution of alkyl groups;

[0265] Each R o Independently selected from the group consisting of:

[0266] 1) OH,

[0267] 2) -C 1-6 alkyl,

[0268] 3) -C 3-6 Cycloalkyl, and

[0269] 4) -C 2-6 Cycloheteroalkyl,

[0270] wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituted alkyl radicals selected from -CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups;

[0271] r is 0, 1, 2, 3, 4, 5 or 6;

[0272] s is 0, 1, 2, 3, 4, 5, or 6;

[0273] t is 0, 1, 2, 3, 4, 5, or 6;

[0274] u is 0, 1, 2, 3, 4, 5, or 6;

[0275] p is 0, 1, 2, 3, 4, 5 or 6; and

[0276] q is 0, 1, 2, 3, 4, 5 or 6.

[0277] The present invention has many embodiments, which are summarized below. The present invention includes the compounds shown, and also includes individual diastereomers, enantiomers and epimers of the compounds, and diastereomeric and / or enantiomeric mixtures thereof, including racemic mixtures.

[0278] In one embodiment of the present invention, T is independently selected from the following group: CR 3 and N, provided that there is zero, one or two N in T, U, V and W. In another embodiment of the present invention, T is CR 3 , provided that zero, one or two of T, U, V and W are N. In another embodiment of the present invention, T is CR 3 In another embodiment of the present invention, T is N, provided that zero, one or two of U, V and W are N. In another embodiment of the present invention, T is N.

[0279] In another embodiment of the present invention, T is independently selected from the group consisting of: CR 3 and N, provided that one or two of T, U, V and W are N.

[0280] In another embodiment of the present invention, U is selected from the group consisting of: CR 4 and N.

[0281] In another embodiment of the present invention, U is CR 4 In another embodiment of the present invention, U is N.

[0282] In another embodiment of the present invention, V is selected from the group consisting of: CR 5 and N.

[0283] In another embodiment of the present invention, V is CR 5 In another embodiment of the present invention, V is N.

[0284] In another embodiment of the present invention, W is selected from the group consisting of: CR 6 and N. In another embodiment of the present invention, W is CR 6 In another embodiment of the present invention, W is N.

[0285] In another embodiment of the present invention, T is CR 3 ; U is CR 4 ; V is CR 5 ; and W is CR 6 In another embodiment of the present invention, T is N; U is CR 4 ; V is CR 5 ; and W is CR 6 In another embodiment of the present invention, T is CR 3 ; U is CR 4 ; V is N; and W is CR 6 In another embodiment of the present invention, T is CR 3 ; U is CR 4 ; V is CR 5 ; and W is N. In another embodiment of the present invention, T and U are N; V is CR 5 ; and W is CR 6 In another embodiment of the present invention, T and V are N; U is CR 4 ; and W is CR 6 In another embodiment of the present invention, T and W are N; U is CR 4 ; and V is CR 5 In another embodiment of the present invention, U and V are N; T is CR 3 ; and W is CR 6 In another embodiment of the present invention, U and W are N; T is CR 3 ; and V is CR 5 In another embodiment of the present invention, V and W are N; T is CR 3 ; and U is CR 4 In another embodiment of the present invention, T is CR 3 ; U is N; V is CR 5 ; and W is CR 6 .

[0286] In another embodiment of the present invention, R1 Selected from the following group: -C 3-12 Cycloalkyl, -C 3-12 Cycloalkenyl, and -C 2-12 Cycloheteroalkyl, wherein R 1 is unsubstituted or substituted with one to six residues selected from R a In one class of this embodiment, R 1 is unsubstituted or substituted with one to five a In another class of this embodiment, R 1 is unsubstituted or substituted with one to four a substituted by a substituent.

[0287] In another embodiment of the present invention, R 1 For -C 3-12 Cycloalkenyl, where R 1 is unsubstituted or substituted with one to six residues selected from R a In one class of this embodiment, R 1 is unsubstituted or substituted with one to five a In another class of this embodiment, R 1 is unsubstituted or substituted with one to four a substituted by a substituent.

[0288] In another embodiment of the present invention, R 1 Selected from the following group: -C 3-12 Cycloalkyl and -C 2-12 Cycloheteroalkyl, wherein R 1 is unsubstituted or substituted with one to six residues selected from R a In one class of this embodiment, R 1 is unsubstituted or substituted with one to five a In another class of this embodiment, R 1 is unsubstituted or substituted with one to four a substituted by a substituent.

[0289] In another embodiment of the present invention, R 1 For -C 3-12 Cycloalkyl, where R 1 is unsubstituted or substituted with one to six residues selected from R a In one class of this embodiment, R 1 is unsubstituted or substituted with one to five a In another class of this embodiment, R 1 is unsubstituted or substituted with one to four a substituted by a substituent.

[0290] In another embodiment of the present invention, R 1 C 2-12 Cycloheteroalkyl, wherein R 1 is unsubstituted or substituted with one to six residues selected from R a In one class of this embodiment, R 1 is unsubstituted or substituted with one to five a In another class of this embodiment, R 1 is unsubstituted or substituted with one to four a substituted by a substituent.

[0291] In another embodiment, R 1 is selected from the group consisting of morpholine, thiomorpholine, piperidine, piperazine, pyrrolidine, tetrahydropyran, octahydro-1H-pyrrolo[2,3-c]pyridine, 3-azabicyclo[3.1.0]hexane, 5-azaspiro[2.4]heptane, 1-oxa-7-azaspiro[4.4]nonane, 1-oxa-8-azaspiro[4.5]decane, 3-oxa-1,8-diazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 1-oxa-3,8-diazaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]decane, 1,8-diazaspiro[4.5]decane, and 1-oxa-4,9-diazaspiro[5.5]undecane, wherein R 1 is unsubstituted or substituted with one to six residues selected from R a In one class of this embodiment, R 1 is unsubstituted or substituted with one to five a In another class of this embodiment, R 1 is unsubstituted or substituted with one to four a substituted by a substituent.

[0292] In another embodiment, R 1 is selected from the group consisting of morpholine, thiomorpholine, piperidine, pyrrolidine, tetrahydropyran, octahydro-1H-pyrrolo[2,3-c]pyridine, 3-azabicyclo[3.1.0]hexane, 5-azaspiro[2.4]heptane, 1-oxa-7-azaspiro[4.4]nonane, 1-oxa-8-azaspiro[4.5]decane, 3-oxa-1,8-diazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 1-oxa-3,8-diazaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]decane, 1,8-diazaspiro[4.5]decane, and 1-oxa-4,9-diazaspiro[5.5]undecane, wherein R 1 is unsubstituted or substituted with one to six residues selected from Ra In one class of this embodiment, R 1 is unsubstituted or substituted with one to five a In another class of this embodiment, R 1 is unsubstituted or substituted with one to four a substituted by a substituent.

[0293] In another embodiment of the present invention, R 1 Selected from the group consisting of morpholine, piperidine, pyrrolidine, tetrahydropyran, octahydro-1H-pyrrolo[2,3-c]pyridine, wherein R 1 is unsubstituted or substituted with one to six residues selected from R a In one class of this embodiment, R 1 is unsubstituted or substituted with one to five a In another class of this embodiment, R 1 is unsubstituted or substituted with one to four a substituted by a substituent.

[0294] In another embodiment of the present invention, R 1 Selected from the group consisting of morpholine, pyrrolidine, tetrahydropyran, octahydro-1H-pyrrolo[2,3-c]pyridine, wherein R 1 is unsubstituted or substituted with one to six residues selected from R a In one class of this embodiment, R 1 is unsubstituted or substituted with one to five a In another class of this embodiment, R 1 is unsubstituted or substituted with one to four a substituted by a substituent.

[0295] In another embodiment of the present invention, R 1 is pyrrolidine, wherein R 1 is unsubstituted or substituted with one to six residues selected from R a In one class of this embodiment, R 1 is unsubstituted or substituted with one to five a In another class of this embodiment, R 1 is unsubstituted or substituted with one to four a substituted by a substituent.

[0296] In another embodiment of the present invention, R 2 Selected from the group consisting of aryl and heteroaryl, wherein R 2 is unsubstituted or substituted with one to five bsubstituted by a substituent.

[0297] In one class of this embodiment, R 2 is unsubstituted or substituted with one to four b In another class of this embodiment, R 2 is unsubstituted or substituted with one to three selected from R b In another class of this embodiment, R 2 is unsubstituted or substituted with one or two selected from R b substituted by a substituent.

[0298] In another embodiment, R 2 is a heteroaryl group, wherein R 2 is unsubstituted or substituted with one to five b In another class of this embodiment, R 2 is unsubstituted or substituted with one to four b In another class of this embodiment, R 2 is unsubstituted or substituted with one to three selected from R b In another class of this embodiment, R 2 is unsubstituted or substituted with one or two selected from R b substituted by a substituent.

[0299] In another embodiment, R 2 is pyridine or benzofuran, wherein R 2 is unsubstituted or substituted with one to five b In one class of this embodiment, R 2 is unsubstituted or substituted with one to four b In another class of this embodiment, R 2 is unsubstituted or substituted with one to three selected from R b In another class of this embodiment, R 2 is unsubstituted or substituted with one or two selected from R b substituted by a substituent.

[0300] In another embodiment, R 2 is pyridine, where R 2 is unsubstituted or substituted with one to five b In a subclass of this class, R 2 is unsubstituted or substituted with one to four b In another subclass of this class, R 2 is unsubstituted or substituted with one to three selected from Rb In another subclass of this class, R 2 is unsubstituted or substituted with one or two selected from R b substituted by a substituent.

[0301] In another embodiment, R 2 is benzofuran, where R 2 is unsubstituted or substituted with one to five b In a subclass of this class, R 2 is unsubstituted or substituted with one to four b In another subclass of this class, R 2 is unsubstituted or substituted with one to three selected from R b In another subclass of this class, R 2 is unsubstituted or substituted with one or two selected from R b substituted by a substituent.

[0302] In another embodiment, R 2 is an aryl group, wherein R 2 is unsubstituted or substituted with one to five b In one class of this embodiment, R 2 is unsubstituted or substituted with one to four b In another class of this embodiment, R 2 is unsubstituted or substituted with one to three selected from R b In another class of this embodiment, R 2 is unsubstituted or substituted with one or two selected from R b In another class of this embodiment, R 2 is phenyl, where R 2 is unsubstituted or substituted with one to five b In a subclass of this class, R 2 is unsubstituted or substituted with one to four b In another subclass of this class, R 2 is unsubstituted or substituted with one to three selected from R b In another subclass of this class, R 2 is unsubstituted or substituted with one or two selected from R b substituted by a substituent.

[0303] In another embodiment of the present invention, R 3 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -(CH2) r C(O)R h 、-(CH2) r C(O)N(R i )2, -(CH2) r N(R j )C(O)R h 、-(CH2) r N(R j )C(O)OR h 、-(CH2) r N(R j )C(O)N(R i )2, -(CH2) r N(R j )C(O)N(R i )2, -(CH2) r N(R j )S(O) m R h 、-(CH2) r N(R j )S(O) m N(R i )2, -(CH2) r N(R j )S(O) m N(R i )2 and -(CH2) r N(R i )2, where R 3 is unsubstituted or substituted with one to five d substituted by a substituent.

[0304] In another embodiment of the present invention, R 3 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen and -C 1-6 Alkyl-OC 1-6 Alkyl, where R 3 is unsubstituted or substituted with one to five d substituted by a substituent.

[0305] In another embodiment of the present invention, R 3 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC1-6 Alkyl and halogen, where R 3 is unsubstituted or substituted with one to five d substituted by a substituent.

[0306] In another embodiment of the present invention, R 3 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl and -OC 1-6 Alkyl, where R 3 is unsubstituted or substituted with one to five d substituted by a substituent.

[0307] In another embodiment of the present invention, R 3 Selected from the group consisting of hydrogen, OH, CF3, CF2H, -C 1-6 Alkyl and -OC 1-6 Alkyl, where R 3 is unsubstituted or substituted with one to five d substituted by a substituent.

[0308] In another embodiment of the present invention, R 3 Selected from the group consisting of hydrogen, -C 1-6 Alkyl and -OC 1-6 Alkyl, where R 3 is unsubstituted or substituted with one to five d In one class of this embodiment, R 3 Independently selected from the group consisting of hydrogen, -CH3, and -OCH3.

[0309] In another embodiment of the present invention, R 3 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H and -C 1-6 Alkyl, where R 3 is unsubstituted or substituted with one to five d substituted by a substituent.

[0310] In another embodiment of the present invention, R 3 is selected from the group consisting of hydrogen, OH, CN, CF3, CF2H and -CH3, wherein R 3 is unsubstituted or substituted with one to five d substituted by a substituent.

[0311] In another embodiment of the present invention, R 3 Selected from the group consisting of hydrogen, OH, CF3, CF2H and -CH3, wherein R 3 is unsubstituted or substituted with one to five d substituted by a substituent.

[0312] In another embodiment of the present invention, R 3 Selected from the group consisting of hydrogen, CF3, CF2H and -C 1-6 Alkyl, where R 3 is unsubstituted or substituted with one to five d substituted by a substituent.

[0313] In another embodiment of the present invention, R 3 Selected from the group consisting of hydrogen, CF3, CF2H and -CH3, wherein R 3 is unsubstituted or substituted with one to five d substituted by a substituent.

[0314] In another embodiment of the present invention, R 3 Selected from the group consisting of hydrogen, CF3 and -C 1-6 Alkyl, where R 3 is unsubstituted or substituted with one to five d substituted by a substituent.

[0315] In another embodiment of the present invention, R 3 Selected from the group consisting of hydrogen and -C 1-6 Alkyl, where R 3 is unsubstituted or substituted with one to five d In one class of this embodiment, R 3 It is hydrogen or CH3.

[0316] In another embodiment of the present invention, R 3 For -C 1-6 Alkyl, where R 3 is unsubstituted or substituted with one to five d In one class of this embodiment, R 3 In another embodiment of the present invention, R 3 In another embodiment of the present invention, R 3 It is -CF3.

[0317] In another embodiment of the present invention, R 4 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -(CH2) s C(O)R h 、-(CH2) sC(O)N(R i )2,-(CH2) s N(R j )C(O)R h 、-(CH2) s N(R j )C(O)OR h 、-(CH2) s N(R j )C(O)N(R i )2, -(CH2) s N(R j )C(O)N(R i )2, -(CH2) s N(R j )S(O) m R h 、-(CH2) s N(R j )S(O) m N(R i )2, -(CH2) s N(R j )S(O) m N(R i )2 and -(CH2) s N(R i )2, where R 4 is unsubstituted or substituted with one to five e substituted by a substituent.

[0318] In another embodiment of the present invention, R 4 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl and -C 1-6 Alkyl-OC 1-6 Alkyl, where R 4 is unsubstituted or substituted with one to five e substituted by a substituent.

[0319] In another embodiment of the present invention, R 4 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen and -C 1-6 Alkyl-OC 1-6 Alkyl, where R 4 is unsubstituted or substituted with one to five e substituted by a substituent.

[0320] In another embodiment of the present invention, R 4 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl and halogen, where R 4 is unsubstituted or substituted with one to five e substituted by a substituent.

[0321] In another embodiment of the present invention, R 4 Selected from the group consisting of hydrogen, CN, CF3, CF2H, -C 1-6 Alkyl and halogen, where R 4 is unsubstituted or substituted with one to five e substituted by a substituent.

[0322] In another embodiment of the present invention, R 4 Selected from the group consisting of hydrogen, CF3, CF2H, -C 1-6 Alkyl and halogen, where R 4 is unsubstituted or substituted with one to five e substituted by a substituent.

[0323] In another embodiment of the present invention, R 4 Selected from the group consisting of hydrogen, CF3 and -C 1-6 Alkyl, where R 4 is unsubstituted or substituted with one to five e substituted by a substituent.

[0324] In another embodiment of the present invention, R 4 Selected from the group consisting of hydrogen and -C 1-6 Alkyl, where R 4 is unsubstituted or substituted with one to five e In one class of this embodiment of the invention, R 4 is independently selected from the group consisting of hydrogen, -CH3, -CF3 and -CHF2. In another class of this embodiment of the invention, R 4 is selected from the group consisting of hydrogen and -CH3. 4 is unsubstituted or substituted with one to five e substituted by a substituent.

[0325] In another embodiment of the present invention, R 4 For hydrogen.

[0326] In another embodiment of the present invention, R 4 For -C 1-6 Alkyl, where R 4is unsubstituted or substituted with one to five e In one class of this embodiment, R 4 It is -CH3.

[0327] In another embodiment of the present invention, R 5 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -(CH2) t C(O)R h 、-(CH2) t C(O)N(R i )2, -(CH2) t N(R j )C(O)R h 、-(CH2) t N(R j )C(O)OR h 、-(CH2) t N(R j )C(O)N(R i )2, -(CH2) t N(R j )C(O)N(R i )2, -(CH2) t N(R j )S(O) m R h 、-(CH2) t N(R j )S(O) m N(R i )2, -(CH2) t N(R j )S(O) m N(R i )2 and -(CH2) t N(R i )2, where R 5 is unsubstituted or substituted with one to five f substituted by a substituent.

[0328] In another embodiment of the present invention, R 5 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6Cycloalkyl, -C 2-6 Cycloheteroalkyl and -C 1-6 Alkyl-OC 1-6 Alkyl, where R 5 is unsubstituted or substituted with one to five f substituted by a substituent.

[0329] In another embodiment of the present invention, R 5 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen and -C 1-6 Alkyl-OC 1-6 Alkyl, where R 5 is unsubstituted or substituted with one to five f In another embodiment of the present invention, R 5 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl and halogen, where R 5 is unsubstituted or substituted with one to five f In another embodiment of the present invention, R 5 Selected from the group consisting of hydrogen, CN, CF3, CF2H, -C 1-6 Alkyl and halogen, where R 5 is unsubstituted or substituted with one to five f In another embodiment of the present invention, R 5 Selected from the group consisting of hydrogen, CF3, CF2H, -C 1-6 Alkyl and halogen, where R 5 is unsubstituted or substituted with one to five f substituted by a substituent.

[0330] In another embodiment of the present invention, R 5 Selected from the group consisting of hydrogen, -C 1-6 Alkyl and halogen, where R 5 is unsubstituted or substituted with one to five f In one class of this embodiment, R 5 is selected from the group consisting of hydrogen, -CH3, CHF2, and F. In another class of this embodiment, R 5 is selected from the group consisting of hydrogen, -CH3, and CHF2. In another class of this embodiment, R 5 is selected from the group consisting of hydrogen, -CH3 and F. In another embodiment of the present invention, R 5 Selected from the group consisting of hydrogen and -C 1-6 Alkyl, where R5 is unsubstituted or substituted with one to five f In one class of this embodiment, R 5 is selected from the group consisting of hydrogen, CHF2 and -CH3. In another embodiment of the present invention, R 5 For -C 1-6 Alkyl, where R 5 is unsubstituted or substituted with one to five f In one class of this embodiment, R 5 In another embodiment of the present invention, R 5 In another embodiment, R 5 is F. In another embodiment, R 5 is CHF2.

[0331] In another embodiment of the present invention, R 6 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -(CH2) u C(O)R h 、-(CH2) u C(O)N(R i )2, -(CH2) u N(R j )C(O)R h 、-(CH2) u N(R j )C(O)OR h 、-(CH2) u N(R j )C(O)N(R i )2, -(CH2) u N(R j )C(O)N(R i )2, -(CH2) u N(R j )S(O) m R h 、-(CH2) u N(R j )S(O) m N(R i )2, -(CH2) u N(R j )S(O) m N(Ri )2 and -(CH2) u N(R i )2, where R 6 is unsubstituted or substituted with one to five g substituted by a substituent.

[0332] In another embodiment of the present invention, R 6 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl and -C 1-6 Alkyl-OC 1-6 Alkyl, where R 6 is unsubstituted or substituted with one to five g substituted by a substituent.

[0333] In another embodiment of the present invention, R 6 Selected from the group consisting of hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen and -C 1-6 Alkyl-OC 1-6 Alkyl, where R 6 is unsubstituted or substituted with one to five g substituted by a substituent.

[0334] In another embodiment of the present invention, R 6 Selected from the group consisting of hydrogen, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl and halogen, where R 6 is unsubstituted or substituted with one to five g substituted by a substituent.

[0335] In another embodiment of the present invention, R 6 Selected from the group consisting of hydrogen, CF3, CF2H, -C 1-6 Alkyl and -OC 1-6 Alkyl, where R 6 is unsubstituted or substituted with one to five g substituted by a substituent.

[0336] In another embodiment of the present invention, R 6 Selected from the group consisting of hydrogen, CF3, -C 1-6 Alkyl and -OC 1-6 Alkyl, where R 6 is unsubstituted or substituted with one to fiveg In one class of this embodiment, R 6 Selected from the group consisting of hydrogen, CF3, -CH3 and -OCH3.

[0337] In another embodiment of the present invention, R 6 Selected from the group consisting of hydrogen, -C 1-6 Alkyl and -OC 1-6 Alkyl, where R 6 is unsubstituted or substituted with one to five g In one class of this embodiment, R 6 Selected from the group consisting of hydrogen, -CH3, and -OCH3.

[0338] In another embodiment of the present invention, R 6 Selected from the group consisting of hydrogen and -C 1-6 Alkyl, where R 6 is unsubstituted or substituted with one to five g In one class of this embodiment, R 6 is independently selected from the group consisting of hydrogen and CH3. 6 For -C 1-6 Alkyl, where R 6 is unsubstituted or substituted with one to five g In one class of this embodiment, R 6 In another embodiment of the present invention, R 6 For hydrogen.

[0339] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Cycloheteroalkyl, -C 2-6Alkenyl-aryl, -C 2-6 Alkenyl-heteroaryl, -C 2-6 Alkynyl-C 3-6 Cycloalkyl, -C 2-6 Alkynyl C 2-6 Cycloheteroalkyl, -C 2-6 Alkynyl-aryl, -C 2-6 Alkynyl-heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkynyl, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -OC 2-6 Cycloheteroalkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, -(CH2) p -S(O) r R k 、-(CH2) p -S(O)N(R L )2 and -(CH2) p -N(R L )2, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0340] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl-heteroaryl, -C 2-6 Alkynyl-C 3-6 Cycloalkyl, -C 2-6 Alkynyl C 2-6 Cycloheteroalkyl, -C 2-6 Alkynyl-aryl, -C 2-6 Alkynyl-heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkynyl, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -OC 2-6 Cycloheteroalkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, -(CH2) p -S(O) r R k 、-(CH2) p -S(O)N(R L )2 and -(CH2) p -N(R L )2, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0341] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -(CH2) p -S(O) r R k 、-(CH2) p -S(O)N(R L )2 and -(CH2) p -N(R L )2, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0342] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -(CH2) p -S(O) r R k 、-(CH2) p -S(O)N(R L )2 and -(CH2) p -N(R L )2, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0343] In another embodiment of the present invention, each R a Independently selected from the group consisting of oxo, -OH, halogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, aryl, -C(O)C 1-6 Alkyl and -(CH2) p -N(R L )2, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl, and -OC 1-6 In one class of this embodiment, each R ais independently selected from the group consisting of oxo, -OH, F, -CH3, -CH2CH3, -CF2H, -CF3, -CH2OH, -C(CH3)2OH, cyclopropyl, phenyl, -C(O)CH3, and -CH2N(CH3)2, wherein each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0344] In another embodiment of the present invention, each R a Independently selected from the group consisting of oxo, -OH, halogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, aryl, -C(O)C 1-6 Alkyl and -(CH2) p -N(R L )2, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl, and -OC 1-6 In one class of this embodiment of the invention, each R a is independently selected from the group consisting of oxo, -OH, F, -CH3, -CH2CH3, -CF2H, -CF3, -CH2OH, -C(CH3)2OH, cyclopropyl, phenyl, -C(O)CH3, and -CH2N(CH3)2, wherein each R a is unsubstituted or substituted with one to six radicals selected from F, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0345] In another embodiment of the present invention, each R a Independently selected from the group consisting of -OH and -C 1-6 Alkyl, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 In one class of this embodiment of the invention, each R a Independently selected from the group consisting of -OH and -C 1-6 Alkyl, where each R a is unsubstituted or substituted with one to six radicals selected from F, CF3, OH, C 1-6 Alkyl and -OC 1-6 In another class of this embodiment of the invention, each R aIn another class of this embodiment of the invention, each R a Independently selected from the group consisting of -OH and -CH3.

[0346] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl-heteroaryl, -C 2-6 Alkynyl-C 3-6 Cycloalkyl, -C 2-6 Alkynyl C 2-6 Cycloheteroalkyl, -C 2-6 Alkynyl-aryl, -C 2-6 Alkynyl-heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkynyl, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -OC 2-6 Cycloheteroalkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, -(CH2) p -S(O) r R k , and -(CH2) p -N(R L )2, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0347] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl-heteroaryl, -C 2-6 Alkynyl-C 3-6 Cycloalkyl, -C 2-6 Alkynyl C 2-6 Cycloheteroalkyl, -C 2-6 Alkynyl-aryl, -C 2-6 Alkynyl-heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkynyl, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -OC 2-6 Cycloheteroalkyl, -(CH2) p-O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, -(CH2) p -S(O) r R k and -(CH2) p -N(R L )2, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0348] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, and -(CH2) p -N(R L )2, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0349] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl and -(CH2) p -N(R L )2, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0350] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl-heteroaryl, -C 2-6 Alkynyl-C 3-6 Cycloalkyl, -C 2-6 Alkynyl C 2-6 Cycloheteroalkyl, -C 2-6 Alkynyl-aryl, -C 2-6 Alkynyl-heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkynyl, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -OC 2-6 Cycloheteroalkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl and -(CH2) p -S(O) r R k , where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0351] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl-heteroaryl, -C 2-6 Alkynyl-C 3-6 Cycloalkyl, -C 2-6 Alkynyl C 2-6 Cycloheteroalkyl, -C 2-6 Alkynyl-aryl, -C 2-6 Alkynyl-heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkynyl, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -OC 2-6 Cycloheteroalkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl-aryl, and -OC 1-6 Alkyl-heteroaryl, wherein each R ais unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0352] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl-heteroaryl, -C 2-6 Alkynyl-C 3-6 Cycloalkyl, -C 2-6 Alkynyl C 2-6 Cycloheteroalkyl, -C 2-6 Alkynyl-aryl, -C 2-6 Alkynyl-heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkynyl, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -OC 2-6 Cycloheteroalkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl-aryl, -OC 1-6Alkyl-heteroaryl, and -(CH2) p -S(O) r R k , where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl, and -OC 1-6 The alkyl group is substituted with a substituent.

[0353] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Cycloheteroalkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl-heteroaryl, -C 2-6 Alkynyl-C 3-6 Cycloalkyl, -C 2-6 Alkynyl C 2-6 Cycloheteroalkyl, -C 2-6 Alkynyl-aryl, -C 2-6 Alkynyl-heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkynyl, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -OC 2-6 Cycloheteroalkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl-aryl, and -OC 1-6 Alkyl-heteroaryl, wherein each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0354] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, and -C(O)C 1-6 Alkyl, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0355] In another embodiment of the present invention, each R a Independently selected from the group consisting of CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl and -C(O)C 1-6 Alkyl, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0356] In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6Cycloheteroalkyl, -(CH2) q -OC 1-6 Alkyl, -(CH2) q -OC 3-6 Cycloalkyl, -(CH2) q -OC 2-6 Cycloheteroalkyl, -(CH2) q -O-aryl, -(CH2) q -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, -(CH2) q -S(O) r R m 、-(CH2) q N(R n )2. -C(O)R o and -C(O)NR n , where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0357] In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, -OH, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -(CH2) q -OC 1-6 Alkyl, -(CH2) q -OC 3-6 Cycloalkyl, -(CH2) q -OC 2-6 Cycloheteroalkyl, -(CH2) q -O-aryl, -(CH2) q -O-heteroaryl, -OC 1-6 Alkyl-C3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, -(CH2) q -S(O) r R m 、-(CH2) q N(R n )2. -C(O)R o and -C(O)NR n , where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -C 1-6 Alkyl-aryl, -C 1-6 Alkyl-heteroaryl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -(CH2) q -OC 1-6 Alkyl, -(CH2) q -OC 3-6 Cycloalkyl, -(CH2) q -OC 2-6 Cycloheteroalkyl, -(CH2) q -O-aryl, -(CH2) q -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, -OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, -(CH2) q -S(O) r R m 、-(CH2) q N(R n )2. -C(O)R o and -C(O)NR n, where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0358] In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -(CH2) q -S(O) r R m 、-(CH2) q N(R n )2. -C(O)R o and -C(O)NR n , where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -(CH2) q -S(O) r R m 、-(CH2) q N(R n )2. -C(O)R o and -C(O)NR n , where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0359] In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C2-6 Cycloheteroalkyl, aryl, heteroaryl, -(CH2) q -S(O) r R m 、-(CH2) q N(R n )2. -C(O)R o and -C(O)NR n , where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -(CH2) q -S(O) r R m 、-(CH2) q N(R n )2. -C(O)R o and -C(O)NR n , where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0360] In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -(CH2) q -S(O) r R m 、-(CH2) q N(R n )2. -C(O)R o and -C(O)NR n , where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC1-6 In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, aryl, heteroaryl, -(CH2) q -S(O) r R m ,-(CH2) q N(R n )2. -C(O)R o , and -C(O)NR n , where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0361] In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -(CH2) q -S(O) r R m ,-(CH2) q N(R n )2. -C(O)R o , and -C(O)NR n , where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In one class of this embodiment, each R b are independently selected from the group consisting of OH, Cl, F, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, halogen, -C 1-6Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -(CH2) q -S(O) r R m 、-(CH2) q N(R n )2. -C(O)R o , and -C(O)NR n , where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In one class of this embodiment, each R b are independently selected from the group consisting of Cl, F, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0362] In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -(CH2) q -S(O) r R m 、-(CH2) q N(R n )2. -C(O)R o , and -C(O)NR n , where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In one class of this embodiment, each R b are independently selected from the group consisting of OH, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C1-6 Alkyl and -OC 1-6 In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Cycloheteroalkyl, -(CH2) q -S(O) r R m 、-(CH2) q N(R n )2. -C(O)R o , and -C(O)NR n , where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In one class of this embodiment, each R b are independently selected from the group consisting of -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0363] In another embodiment of the present invention, each R b are independently selected from the group consisting of CN, -OH, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another embodiment of the present invention, each R b are independently selected from the group consisting of CN, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0364] In another embodiment of the present invention, each R bIndependently selected from the group consisting of CN, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteroalkyl, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteroalkyl, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0365] In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteroalkyl, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteroalkyl, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0366] In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC1-6 Alkyl and -C 3-6 Cycloalkyl, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0367] In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, -OH, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another embodiment of the present invention, each R b Independently selected from the group consisting of CN, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0368] In another embodiment of the present invention, each R b Independently selected from the group consisting of -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC1-6 In another embodiment of the present invention, each R b Independently selected from the group consisting of halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0369] In another embodiment of the present invention, each R b Independently selected from the group consisting of: -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another embodiment of the present invention, each R b Independently selected from the group consisting of: -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The alkyl group is substituted with a substituent.

[0370] In another embodiment of the present invention, each R b Independently selected from the group consisting of: -OH, -C 1-6 Alkyl and -OC 1-6 Alkyl, where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In one class of this embodiment, each R b Independently selected from the group consisting of: -OH, -C 1-6 Alkyl and -OC 1-6 Alkyl, where each R bis unsubstituted or substituted with one to six radicals selected from F, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another class of this embodiment, each R b is independently OH, -CH3, -CF3, -CF2H or -OCF2H. In another embodiment of the present invention, each R b Independently selected from the group consisting of: -C 1-6 Alkyl and -OC 1-6 Alkyl, where each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In one class of this embodiment, each R b Independently selected from the group consisting of: -C 1-6 Alkyl and -OC 1-6 Alkyl, where each R b is unsubstituted or substituted with one to six radicals selected from F, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another class of this embodiment, each R b are independently -CH3, -CF3, -CF2H or -OCF2H.

[0371] In another class of this embodiment, each R b In another class of this embodiment, each R b In another embodiment, each R b In another class of this embodiment, each R b In another class of this embodiment, each R b In another embodiment, each R b Independently selected from the group consisting of -OH, -CH3, -CF3, -OCF2H, and cyclopropane.

[0372] In another embodiment, each R b In another embodiment, each Rb It is CF3.

[0373] In another embodiment of the present invention, each R c are independently selected from the group consisting of hydrogen, halogen, and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0374] In another embodiment, each R c are independently selected from the group consisting of hydrogen, and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R c In another embodiment, R c For hydrogen.

[0375] In another embodiment, R c For -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R c It is -CH3.

[0376] In another embodiment of the present invention, each R d Independently selected from the group consisting of CF3, halogen, and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0377] In another embodiment of the present invention, each R d Independently selected from the group consisting of halogen and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R d In another embodiment of the present invention, each R d It is a halogen.

[0378] In another embodiment of the present invention, each R d For -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R dIt is -CH3.

[0379] In another embodiment of the present invention, each R e Independently selected from the group consisting of CF3, halogen, and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0380] In another embodiment of the present invention, each R e Independently selected from the group consisting of halogen and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R e In another embodiment of the present invention, each R e It is a halogen.

[0381] In another embodiment of the present invention, each R e For -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R e It is -CH3.

[0382] In another embodiment of the present invention, each R f Independently selected from the group consisting of CF3, halogen, and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0383] In another embodiment of the present invention, each R f Independently selected from the group consisting of halogen and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R f In another embodiment of the present invention, each R f It is a halogen.

[0384] In another embodiment of the present invention, each R f For -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each Rf It is -CH3.

[0385] In another embodiment of the present invention, each R g Independently selected from the group consisting of CF3, halogen, and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0386] In another embodiment of the present invention, each R g Independently selected from the group consisting of halogen and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R g In another embodiment of the present invention, each R g It is a halogen.

[0387] In another embodiment of the present invention, each R g For -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from: CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R g It is -CH3.

[0388] In another embodiment of the present invention, each R h Independently selected from the group consisting of hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R h For -C 2-6 Cycloheteroalkyl, wherein the cycloheteroalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0389] In another embodiment of the present invention, each R h Independently selected from the group consisting of hydrogen, -C 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R h For -C3-6 Cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0390] In another embodiment of the present invention, each R h Independently selected from the group consisting of hydrogen and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In another embodiment of the present invention, R h In another embodiment of the present invention, R h For -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0391] In another embodiment of the present invention, each R i Independently selected from the group consisting of hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three radicals selected from: CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R i For -C 2-6 Cycloheteroalkyl, wherein the cycloheteroalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0392] In another embodiment of the present invention, each R i Independently selected from the group consisting of hydrogen, -C 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R i For -C 3-6 Cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0393] In another embodiment of the present invention, each R i Independently selected from the group consisting of hydrogen and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6In another embodiment of the present invention, R i In another embodiment of the present invention, R i For -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0394] In another embodiment of the present invention, each R j Independently selected from the group consisting of hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three radicals selected from: CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R j For -C 2-6 Cycloheteroalkyl, wherein the cycloheteroalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0395] In another embodiment of the present invention, each R j Independently selected from the group consisting of hydrogen, -C 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R j For -C 3-6 Cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0396] In another embodiment of the present invention, each R j Independently selected from the group consisting of hydrogen and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In another embodiment of the present invention, R j In another embodiment of the present invention, R j For -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0397] In another embodiment of the present invention, each R kIndependently selected from the group consisting of: -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R k For -C 2-6 Cycloheteroalkyl, wherein the cycloheteroalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0398] In another embodiment of the present invention, each R k Independently selected from the group consisting of: -C 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R k For -C 3-6 Cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0399] In another embodiment of the present invention, R k For -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0400] In another embodiment of the present invention, each R L Independently selected from the group consisting of hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R L For -C 2-6 Cycloheteroalkyl, wherein the cycloheteroalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0401] In another embodiment of the present invention, each R L Independently selected from the group consisting of hydrogen, -C 1-6 Alkyl and -C 3-6Cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R L For -C 3-6 Cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0402] In another embodiment of the present invention, each R L Independently selected from the group consisting of hydrogen and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In another embodiment of the present invention, R L In another embodiment of the present invention, R L For -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R L It is -CH3.

[0403] In another embodiment of the present invention, each R m Independently selected from the group consisting of: -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R m For -C 2-6 Cycloheteroalkyl, wherein the cycloheteroalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0404] In another embodiment of the present invention, each R m Independently selected from the group consisting of: -C 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R m For -C 3-6 Cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0405] In another embodiment of the present invention, R m For -C 1-6 Alkyl, wherein alkyl, wherein alkyl is unsubstituted or substituted with one to three selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0406] In another embodiment of the present invention, each R n Independently selected from the group consisting of hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R n For -C 2-6 Cycloheteroalkyl, wherein the cycloheteroalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0407] In another embodiment of the present invention, each R n Independently selected from the group consisting of hydrogen, -C 1-6 Alkyl and -C 3-6 Cycloalkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R n For -C 3-6 Cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0408] In another embodiment of the present invention, each R n Independently selected from the group consisting of hydrogen and C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 In another embodiment of the present invention, each R n In another embodiment of the present invention, each R n For -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three radicals selected from: -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0409] In another embodiment of the present invention, each R oIndependently selected from the group consisting of OH, -C 1-6 Alkyl, -C 3-6 Cycloalkyl and -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituted radicals selected from -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0410] In another embodiment of the present invention, each R o Independently selected from the group consisting of OH and -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from -CF3, halogen, OH and -OC 1-6 In another embodiment of the present invention, each R o In another embodiment of the present invention, each R o For -C 1-6 Alkyl, wherein the alkyl is unsubstituted or substituted with one to three substituted alkyl groups selected from -CF3, halogen, OH and -OC 1-6 The alkyl group is substituted with a substituent.

[0411] In another embodiment of the invention, r is 0, 1, 2, 3, 4, 5 or 6. In another embodiment, r is 0, 1, 2, 3, 4, or 5. In another embodiment, r is 1, 2, 3, 4, 5 or 6. In another embodiment, r is 1, 2, 3, 4, or 5. In another embodiment, r is 0, 1, 2, 3 or 4. In another embodiment, r is 1, 2, 3 or 4. In another embodiment, r is 0, 1, 2 or 3. In another embodiment, r is 1, 2 or 3. In another embodiment, r is 0, 1 or 2. In another embodiment, r is 0. In another embodiment, r is 1. In another embodiment, r is 2. In another embodiment, r is 3. In another embodiment, r is 4. In another embodiment, r is 5. In another embodiment, r is 6.

[0412] In another embodiment of the invention, s is 0, 1, 2, 3, 4, 5 or 6. In another embodiment, s is 0, 1, 2, 3, 4, or 5. In another embodiment, s is 1, 2, 3, 4, 5 or 6. In another embodiment, s is 1, 2, 3, 4, or 5. In another embodiment, s is 0, 1, 2, 3 or 4. In another embodiment, s is 1, 2, 3 or 4. In another embodiment, s is 0, 1, 2 or 3. In another embodiment, s is 1, 2 or 3. In another embodiment, s is 0, 1 or 2. In another embodiment, s is 0. In another embodiment, s is 1. In another embodiment, s is 2. In another embodiment, s is 3. In another embodiment, s is 4. In another embodiment, s is 5. In another embodiment, s is 6.

[0413] In another embodiment of the invention, t is 0, 1, 2, 3, 4, 5 or 6. In another embodiment, t is 0, 1, 2, 3, 4, or 5. In another embodiment, t is 1, 2, 3, 4, 5 or 6. In another embodiment, t is 1, 2, 3, 4, or 5. In another embodiment, t is 0, 1, 2, 3 or 4. In another embodiment, t is 1, 2, 3 or 4. In another embodiment, t is 0, 1, 2 or 3. In another embodiment, t is 1, 2 or 3. In another embodiment, t is 0, 1 or 2. In another embodiment, t is 0. In another embodiment, t is 1. In another embodiment, t is 2. In another embodiment, t is 3. In another embodiment, t is 4. In another embodiment, t is 5. In another embodiment, t is 6.

[0414] In another embodiment of the present invention, u is 0, 1, 2, 3, 4, 5 or 6. In another embodiment, u is 0, 1, 2, 3, 4, or 5. In another embodiment, u is 1, 2, 3, 4, 5 or 6. In another embodiment, u is 1, 2, 3, 4, or 5. In another embodiment, u is 0, 1, 2, 3 or 4. In another embodiment, u is 1, 2, 3 or 4. In another embodiment, u is 0, 1, 2 or 3. In another embodiment, u is 1, 2 or 3. In another embodiment, u is 0, 1 or 2. In another embodiment, u is 0. In another embodiment, u is 1. In another embodiment, u is 2. In another embodiment, u is 3. In another embodiment, u is 4. In another embodiment, u is 5. In another embodiment, u is 6.

[0415] In another embodiment of the invention, p is 0, 1, 2, 3, 4, 5 or 6. In another embodiment, p is 0, 1, 2, 3, 4, or 5. In another embodiment, p is 1, 2, 3, 4, 5 or 6. In another embodiment, p is 1, 2, 3, 4, or 5. In another embodiment, p is 0, 1, 2, 3 or 4. In another embodiment, p is 1, 2, 3 or 4. In another embodiment, p is 0, 1, 2 or 3. In another embodiment, p is 1, 2 or 3. In another embodiment, p is 0, 1 or 2. In another embodiment, p is 0. In another embodiment, p is 1. In another embodiment, p is 2. In another embodiment, p is 3. In another embodiment, p is 4. In another embodiment, p is 5. In another embodiment, p is 6.

[0416] In another embodiment of the invention, q is 0, 1, 2, 3, 4, 5 or 6. In another embodiment, q is 0, 1, 2, 3, 4, or 5. In another embodiment, q is 1, 2, 3, 4, 5 or 6. In another embodiment, q is 1, 2, 3, 4, or 5. In another embodiment, q is 0, 1, 2, 3 or 4. In another embodiment, q is 1, 2, 3 or 4. In another embodiment, q is 0, 1, 2 or 3. In another embodiment, q is 1, 2 or 3. In another embodiment, q is 0, 1 or 2. In another embodiment, q is 0. In another embodiment, q is 1. In another embodiment, q is 2. In another embodiment, q is 3. In another embodiment, q is 4. In another embodiment, q is 5. In another embodiment, q is 6.

[0417] In another embodiment of the present invention, the present invention relates to compounds of formula Ia:

[0418]

[0419] or a pharmaceutically acceptable salt thereof.

[0420] In another embodiment of the present invention, the present invention relates to compounds of formula Ib:

[0421]

[0422] or a pharmaceutically acceptable salt thereof.

[0423] In another embodiment of the present invention, the present invention relates to compounds of formula Ic:

[0424]

[0425] or a pharmaceutically acceptable salt thereof.

[0426] In another embodiment of the present invention, the present invention relates to compounds of formula Id:

[0427]

[0428] or a pharmaceutically acceptable salt thereof.

[0429] In another embodiment of the present invention, the present invention relates to compounds of formula Ie:

[0430]

[0431] or a pharmaceutically acceptable salt thereof.

[0432] In another embodiment of the present invention, the present invention relates to compounds of formula If:

[0433]

[0434] or a pharmaceutically acceptable salt thereof.

[0435] In another embodiment of the present invention, the present invention relates to a compound of formula Ig:

[0436]

[0437] or a pharmaceutically acceptable salt thereof.

[0438] In another embodiment of the present invention, the present invention relates to compounds of formula Ih:

[0439]

[0440] or a pharmaceutically acceptable salt thereof.

[0441] In another embodiment of the present invention, the present invention relates to compounds of formula Ii:

[0442]

[0443] or a pharmaceutically acceptable salt thereof.

[0444] In another embodiment of the present invention, the present invention relates to compounds of formula Ij:

[0445]

[0446] or a pharmaceutically acceptable salt thereof.

[0447] In another embodiment of the present invention, the present invention relates to compounds of formula Ik:

[0448]

[0449] Compounds of structural formula I include compounds of structural formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij and Ik, and pharmaceutically acceptable salts, hydrates and solvates thereof.

[0450] Another embodiment of the present invention is directed to compounds of formula I, wherein:

[0451] R 1 C 2-12 Cycloheteroalkyl, wherein R 1 is unsubstituted or substituted with one to six residues selected from R a Substituents are substituted;

[0452] R 2 is a heteroaryl group, wherein R 2 is unsubstituted or substituted with one to five b Substituents are substituted;

[0453] R 3 Select from the following group:

[0454] 1) Hydrogen, and

[0455] 2) -C 1-6 alkyl,

[0456] Where R 3 is unsubstituted or substituted with one to five d Substituents are substituted;

[0457] R 4 Select from the following group:

[0458] 1) Hydrogen,

[0459] 2) OH,

[0460] 3) CN,

[0461] 4) CF3,

[0462] 5) CF2H,

[0463] 6) -C 1-6 alkyl,

[0464] 7)-OC 1-6 alkyl,

[0465] 8) halogen, and

[0466] 9)-C 1-6 Alkyl-OC 1-6 alkyl,

[0467] Where R 4 is unsubstituted or substituted with one to fivee Substituents are substituted;

[0468] R 5 Independently selected from the group consisting of:

[0469] 1) Hydrogen,

[0470] 2) OH,

[0471] 3) CN,

[0472] 4) CF3,

[0473] 5) CF2H,

[0474] 6) -C 1-6 alkyl,

[0475] 7)-OC 1-6 alkyl,

[0476] 8) halogen, and

[0477] 9)-C 1-6 Alkyl-OC 1-6 alkyl,

[0478] Where R 5 is unsubstituted or substituted with one to five f substituted with a substituent; and

[0479] R 6 Select from the following group:

[0480] 1) Hydrogen,

[0481] 2) -C 1-6 Alkyl and

[0482] 3)-OC 1-6 alkyl,

[0483] Where R 6 is unsubstituted or substituted with one to five g Substituents are substituted;

[0484] and the other substituents are as defined above;

[0485] or a pharmaceutically acceptable salt thereof.

[0486] Another embodiment of the present invention is directed to compounds of formula I, wherein:

[0487] W is CR 6 ;

[0488] R 1 Independently selected from the following group:

[0489] 1) Morpholine,

[0490] 2) Thiomorpholine,

[0491] 3) piperidine,

[0492] 4) piperazine,

[0493] 5) pyrrolidine,

[0494] 6) Tetrahydropyran,

[0495] 7) octahydro-1H-pyrrolo[2,3-c]pyridine,

[0496] 8) 3-azabicyclo[3.1.0]hexane,

[0497] 9) 5-azaspiro[2.4]heptane,

[0498] 10) 1-oxa-7-azaspiro[4.4]nonane,

[0499] 11) 1-oxa-8-azaspiro[4.5]decane,

[0500] 12) 3-oxa-1,8-diazaspiro[4.5]decane,

[0501] 13) 2,8-diazaspiro[4.5]decane,

[0502] 14) 1-oxa-3,8-diazaspiro[4.5]decane,

[0503] 15) 2-oxa-8-azaspiro[4.5]decane,

[0504] 16) 1,8-diazaspiro[4.5]decane, and

[0505] 17) 1-oxa-4,9-diazaspiro[5.5]undecane,

[0506] Where R 1 is unsubstituted or substituted with one to six residues selected from R a Substituents are substituted;

[0507] R 2 is an aryl group, wherein R 2 is unsubstituted or substituted with one to five b Substituents are substituted;

[0508] R 3 is hydrogen;

[0509] R 4 Select from the following group:

[0510] 1) Hydrogen, and

[0511] 2) -C 1-6 alkyl,

[0512] Where R 4 is unsubstituted or substituted with one to five e Substituents are substituted;

[0513] R 5 Select from the following group:

[0514] 1) Hydrogen,

[0515] 2) -C 1-6 Alkyl and

[0516] 3) Halogen,

[0517] Where R 5 is unsubstituted or substituted with one to five f substituted by a substituent; and R 6 is hydrogen;

[0518] and the other substituents are as defined above;

[0519] or a pharmaceutically acceptable salt thereof.

[0520] Illustrative but non-limiting examples of compounds of the present invention that can be used as NLRP3 inhibitors are the following compounds:

[0521] 1)(S)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrolidin-3-ol;

[0522] 2)(S)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]-pyridazin-4-yl)-3-methylpyrrolidin-3-ol;

[0523] 3) (cis)-4-(5-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-2,6-dimethylmorpholine;

[0524] 4) 2-(4-((cis)-2,6-dimethylmorpholinyl)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol;

[0525] 5) 2-(1-((cis)-2,6-dimethylmorpholinyl)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol;

[0526] 6) 2-(5-((cis)-2,6-dimethylmorpholinyl)pyrido[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol;

[0527] 7) (cis)-4-(1-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-2,6-dimethylmorpholine;

[0528] 8) 2-(8-((cis)-2,6-dimethylmorpholinyl)pyridazino[4,5-c]pyridazin-5-yl)-5-(trifluoromethyl)-phenol;

[0529] 9) 2-(4-((cis)-2,6-dimethylmorpholinyl)pyridazino[4,5-d]pyridazin-1-yl)-5-(trifluoromethyl)-phenol;

[0530] 10) (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidin-3-ol;

[0531] 11) (cis)-4-(1-(benzofuran-5-yl)pyrido[3,4-d]pyridazin-4-yl)-2,6-dimethylmorpholine;

[0532] 12) (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidin-3-ol;

[0533] 13) (3S,4s,5R)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazino[4,5-d]pyridazin-1-yl)-3,4,5-trimethylpiperidin-4-ol;

[0534] 14) 2-(4-((cis)-2,6-dimethylmorpholinyl)-5-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol;

[0535] 15) 2-(4-((cis)-2,6-dimethylmorpholinyl)-8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol;

[0536] 16) (3S,4s,5R)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-3,4,5-trimethylpiperidin-4-ol;

[0537] 17) (3S,4s,5R)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3,4,5-trimethylpiperidin-4-ol;

[0538] 18) (3S,4r,5R)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-3,5-dimethylpiperidin-4-ol;

[0539] 19) (3S,4r,5R)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethylpiperidin-4-ol;

[0540] 20) 2-(4-((cis)-2,6-dimethylmorpholinyl)-6-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol;

[0541] 21) 2-(4-((cis)-2,6-dimethylmorpholinyl)-7-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol;

[0542] 22)(S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-3-methylpyrrolidin-3-ol;

[0543] 23) 2-(8-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0544] 24)(3S,4s,5R)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3,4,5-trimethylpiperidin-4-ol;

[0545] 25) 8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-oxa-1,8-diazaspiro[4.5]decan-2-one;

[0546] 26) (cis)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-2,6-dimethylthiomorpholine 1,1-dioxide;

[0547] 27) (R)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-(trifluoromethyl)pyrrolidin-3-ol;

[0548] 28) (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-(trifluoromethyl)pyrrolidin-3-ol;

[0549] 29) (R)-3-(difluoromethyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol;

[0550] 30)(S)-3-(difluoromethyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol;

[0551] 31) (R)-2-(8-(1-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0552] 32) (S)-2-(8-(1-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0553] 33) 2-(8-(1-oxa-8-azaspiro[4.5]dec-8-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0554] 34) 2-(8-(2-oxa-8-azaspiro[4.5]dec-8-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0555] 35) 9-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;

[0556] 36) 2-(8-((cis)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0557] 37) 1-(8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1,8-diazaspiro[4.5]dec-1-yl)ethan-1-one;

[0558] 38) 1-(8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-2,8-diazaspiro[4.5]dec-2-yl)ethan-1-one;

[0559] 39) 8-(5-(2-hydroxy-4-(trifluoro-methyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one;

[0560] 40) 2-(8-(4,4-dimethyl-1-oxa-8-azaspiro[4.5]dec-8-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0561] 41)(R)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-phenylpyrrolidin-3-ol;

[0562] 42)(S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-phenylpyrrolidin-3-ol;

[0563] 43) 8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-methyl-1,8-diazaspiro[4.5]decan-2-one;

[0564] 44) 8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one;

[0565] 45) 2-(8-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0566] 46) 8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-oxa-8-azaspiro[4.5]decan-2-one;

[0567] 47) (R)-4,4-difluoro-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol;

[0568] 48) (S)-4,4-difluoro-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol;

[0569] 49) (R)-5-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-5-azaspiro[2.4]heptan-7-ol;

[0570] 50)(S)-5-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-5-azaspiro[2.4]heptan-7-ol;

[0571] 51) (R)-3-cyclopropyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol;

[0572] 52)(S)-3-cyclopropyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol;

[0573] 53) (R)-3-((dimethylamino)methyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido-[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol;

[0574] 54)(S)-3-((dimethylamino)methyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido-[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol;

[0575] 55) (R)-3-ethyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-pyrrolidin-3-ol;

[0576] 56) (S)-3-ethyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-pyrrolidin-3-ol;

[0577] 57) (R)-2-(8-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0578] 58) (S)-2-(8-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0579] 59) (R)-2-(8-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0580] 60)(S)-2-(8-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0581] 61) 2-(8-((2R,6R)-2-(hydroxymethyl)-6-methylmorpholinyl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0582] 62) 2-(8-((2S,6S)-2-(hydroxymethyl)-6-methylmorpholinyl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0583] 63) 2-(8-((2S,6S)-2-(hydroxymethyl)-6-methylmorpholinyl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0584] 64) 2-(8-((2R,6R)-2-(hydroxymethyl)-6-methylmorpholinyl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0585] 65) 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-methyl-4(trifluoromethyl)-phenyl)phthalazine;

[0586] 66)(2R,4s,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol;

[0587] 67) (2R,4r,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol;

[0588] 68) (S)-1-(2-(difluoromethyl)-5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridin

[0589] [2,3-d]pyridazin-8-yl)-3-methylpyrrolidin-3-ol; and

[0590] 69)(S)-1-(3-(difluoromethyl)-5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridin

[0591] [2,3-d]pyridazin-8-yl)-3-methylpyrrolidin-3-ol;

[0592] or a pharmaceutically acceptable salt thereof.

[0593] Other illustrative but non-limiting examples of compounds of the present invention that can be used as NLRP3 inhibitors are the following compounds:

[0594] 1)(S)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrolidin-3-ol;

[0595] 2)(S)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]-pyridazin-4-yl)-3-methylpyrrolidin-3-ol;

[0596] 3) 2-(4-((cis)-2,6-dimethylmorpholinyl)pyridazino[4,5-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol;

[0597] 4) (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-3-methylpyrrolidin-3-ol;

[0598] 5) 2-(8-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol;

[0599] 6)(2R,4s,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol; and

[0600] 7)(2R,4r,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol;

[0601] or a pharmaceutically acceptable salt thereof.

[0602] While the specific stereochemistries described above are preferred, other stereoisomers, including diastereomers, enantiomers, epimers, and mixtures thereof may also have utility in treating diseases mediated by NLRP3.

[0603] The synthetic methods for preparing the compounds are disclosed in the following examples. If the synthetic details are not provided in the examples, the compounds can be prepared by those of ordinary skill in the art of medicinal chemistry or synthetic organic chemistry using the synthetic information provided herein. In the case of undefined stereochemical centers, the structure represents a mixture of stereoisomers at the center. For such compounds, individual stereoisomers including enantiomers, diastereomers and mixtures thereof are also compounds of the invention.

[0604] definition:

[0605] "Ac" is acetyl, which is CH3C(=O)-.

[0606] "Alkyl" refers to a saturated carbon chain which may be straight or branched, or a combination thereof, unless the carbon chain is otherwise defined. Other groups having the prefix "alk", such as alkoxy and alkanoyl, may also be straight or branched, or a combination thereof, unless the carbon chain is otherwise defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.

[0607] "Alkenyl" refers to a carbon chain containing at least one carbon-carbon double bond, and which may be linear or branched, or a combination thereof, unless otherwise defined. Examples of alkenyl include ethenyl, propenyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

[0608] "Alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, and which may be linear or branched, or a combination thereof, unless otherwise defined. Examples of alkynyl groups include acetylene, propyne, 3-methyl-1-pentyne, 2-heptyne, and the like.

[0609] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, spirocyclic, fused or bridged carbocyclic ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. In one embodiment, cycloalkyl is -C 3-12 Cycloalkyl. In another embodiment of the present invention, cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In another embodiment, cycloalkyl is cyclopropyl.

[0610] "Cycloalkenyl" refers to a monocyclic, bicyclic, spirocyclic, fused or bridged carbocyclic ring having a specified number of carbon atoms and at least one double bond. Examples of cycloalkenyl groups include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like. In one embodiment, a cycloalkenyl group is -C 3-12 Cycloalkenyl.

[0611] "Cycloheteroalkyl" refers to a saturated monocyclic, bicyclic, spirocyclic, fused or bridged ring or ring system having a specified number of carbon atoms and containing at least one ring heteroatom selected from N, NH, S (including SO and SO2) and O. The cycloheteroalkyl ring may be substituted with ring carbon and / or ring nitrogen or ring sulfur. Examples of cycloheteroalkyl include tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, azetidinyl, piperazinyl, piperidinyl, morpholinyl, oxetanyl and tetrahydropyranyl. In one embodiment of the present invention, the cycloheteroalkyl is: C 2-12In another embodiment, the cycloheteroalkyl group is selected from the group consisting of morpholine, thiomorpholine, piperidine, piperazine, pyrrolidine, tetrahydropyran, octahydro-1H-pyrrolo[2,3-c]pyridine, 3-azabicyclo[3.1.0]hexane, 5-azaspiro[2.4]heptane, 1-oxa-7-azaspiro[4.4]nonane, 1-oxa-8-azaspiro[4.5]decane, 3-oxa-1,8-diazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 1-oxa-3,8-diazaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]decane, 1,8-diazaspiro[4.5]decane, and 1-oxa-4,9-diazaspiro[5.5]undecane.

[0612] "Heterocycloalkenyl" refers to a monocyclic, bicyclic, spirocyclic, fused or bridged ring or ring system having the specified number of carbon atoms and containing at least one double bond and at least one heteroatom selected from N, NH, S (including SO and SO2) O. Examples of heterocycloalkenyl groups include dihydropyran and dihydrofuran, and the like.

[0613] "Aryl" refers to a monocyclic, bicyclic or tricyclic carbocyclic aromatic ring or ring system containing 6-14 carbon atoms, wherein at least one ring is aromatic. Examples of aryl groups include phenyl and naphthyl. In one embodiment, aryl is phenyl.

[0614] "Heteroaryl" refers to a monocyclic, bicyclic or tricyclic ring or ring system containing 5-14 ring atoms and at least one ring heteroatom selected from N, NH, S (including SO and SO2) and O, wherein at least one heteroatom-containing ring is aromatic. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, quinolinazolyl, dibenzofuranyl, and the like. In one embodiment, heteroaryl is pyridine or benzofuran. In another embodiment, heteroaryl is pyridine. In another embodiment, heteroaryl is benzofuran.

[0615] "Halogen" includes fluorine, chlorine, bromine and iodine. In one embodiment, halogen is fluorine, chlorine or bromine. In another embodiment, halogen is fluorine or chlorine. In another embodiment, halogen is chlorine or bromine. In another embodiment, halogen is fluorine or bromine. In another embodiment, halogen is fluorine. In another embodiment, halogen is chlorine. In another embodiment, halogen is bromine.

[0616] "Me" means methyl.

[0617] "Oxo" means =0.

[0618] "Saturated" means containing only single bonds.

[0619] "Unsaturated" means containing at least one double bond or triple bond. In one embodiment, unsaturated means containing at least one double bond. In another embodiment, unsaturated means containing at least one triple bond.

[0620] When any variable (such as R 1 , R a When a (, etc.) occurs more than one time in any constituent or in Formula I, its definition at each occurrence is independent of its definition at every other occurrence. Furthermore, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds. A slash across a bond in a substituent variable represents a point of attachment.

[0621] In the nomenclature used throughout this disclosure, the point of attachment is described first, followed by the terminal portion of the designated side chain. For example, C 1-5 Alkylcarbonylamino C 1-6 Alkyl substituents are equivalent to:

[0622]

[0623] When selecting compounds of the present invention, one of ordinary skill in the art will recognize that various substituents, namely R 1 , R 2 Etc., can be selected according to the well-known chemical structure connectivity and stability principles.

[0624] The term "substituted" shall be construed to include multiple degrees of substitution of a specified substituent. When multiple substituent moieties are disclosed or claimed, the substituted compound may be independently mono- or poly-substituted with one or more of the disclosed and claimed substituent moieties. By independently substituted, it is meant that the (two or more) substituents may be the same or different.

[0625] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, salts, and / or dosage forms that are safe and suitable for administration to humans and animals using sound medical judgment and in compliance with all applicable governmental regulations.

[0626] The compounds of formula I may contain one or more asymmetric centers and may thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is intended to encompass all such isomeric forms of the compounds of formula I.

[0627] The independent syntheses of optical isomers and diastereomers or their chromatographic separations may be achieved according to methods known in the art by appropriately modifying the methodology disclosed herein. Their absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with reagents containing asymmetric centers of known absolute configuration or sufficient heavy atoms to allow absolute assignment.

[0628] If desired, a racemic mixture of a compound may be separated to isolate a single enantiomer. Separation may be performed by methods well known in the art, such as coupling a racemic mixture of a compound with a pure enantiomer compound to form a diastereomeric mixture, followed by separation of the individual diastereoisomers by standard methods such as fractional crystallization or chromatography. The coupling reaction typically forms salts using an acid or base of the pure enantiomer. The diastereomeric derivatives are then converted to pure enantiomers by cleavage of the added chiral residue. A racemic mixture of a compound may also be directly separated by direct chromatography using chiral stationary phases well known in the art.

[0629] Alternatively, enantiomers of any compound may be stereoselectively synthesized by methods well known in the art using optically pure starting materials or reagents of known configuration.

[0630] Some of the compounds described herein contain olefinic double bonds and unless specified otherwise, are intended to include both E and Z geometric isomers.

[0631] Tautomers are defined as compounds that undergo rapid proton transfer from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of hydrogen attachment. An example of this would be a ketone and its enol form known as keto-enol tautomers. The compounds of Formula I include individual tautomers and mixtures thereof.

[0632] In the compounds of Formula I, the atoms may be present in their natural isotopic abundances, or one or more atoms may be artificially enriched to a specific isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is intended to include all suitable isotopic variants of the compounds of Formula I. For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H) and tritium ( 3H). Protium is the major isotope of hydrogen found in nature. Enrichment with deuterium can provide certain therapeutic advantages, such as increasing the half-life in vivo or reducing dosage requirements, or providing compounds as standards for characterization of biological samples. Tritium is radioactive and can therefore provide radiolabeled compounds as tracers in metabolic or kinetic studies. Isotopically enriched compounds of formula I can be prepared by conventional techniques known to those skilled in the art without excessive experimentation. Alternatively, they can be prepared by processes similar to those described in the processes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0633] In addition, some crystalline forms of the compounds of the present invention may exist in polymorphic forms and are therefore also included in the present invention. In addition, some compounds of the present invention may form solvates with water or common organic solvents. The scope of the present invention includes such solvates.

[0634] The compounds of the present invention are generally preferably administered as pure enantiomer preparations. Racemic mixtures can be separated into their respective enantiomers by any of a variety of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by chromatographic separation or crystallization, and fractional crystallization of diastereomeric salts.

[0635] Salt

[0636] It should be understood that, as used herein, reference to the compounds of the present invention is meant to also include pharmaceutically acceptable salts thereof, as well as non-pharmaceutically acceptable salts thereof when used as precursors of free compounds or pharmaceutically acceptable salts thereof or in other synthetic operations.

[0637] The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic or organic base and an inorganic or organic acid. The basic compounds included in the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of the present invention that are usually prepared by reacting a free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, p-ethanolamidophenylarsonic acid, hexyl metabisphenolate, hybamine salt, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, 2-hydroxyethanesulfonate, Lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthylacetate, nitrate, N-methyl reduced glucosamine ammonium salt, oleate, oxalate, pamoate (enbolate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theochlorate, toluenesulfonate, triethyl iodide, trifluoroacetic acid and valerate. The compounds of the present invention carry an acidic portion, and suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases, including aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, trivalent manganese salts, divalent manganese salts, potassium salts, sodium salts, zinc salts and the like. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts. Other pharmaceutically acceptable non-toxic base salts derived from organic substances include primary, secondary and tertiary amines, cyclic amine basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-diphenylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hybamine, isopropylamine, lysine, methyl reduced glucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0638] In addition, when there is a carboxylic acid (-COOH) or alcohol group in the compound of the present invention, a pharmaceutically acceptable ester of a carboxylic acid derivative such as methyl, ethyl or pivaloyloxymethyl, or an acyl derivative of an alcohol such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl may be used, including esters and acyl groups known in the art for changing the solubility or hydrolysis characteristics of a sustained-release or prodrug formulation.

[0639] The term "prodrug" means a compound that can be rapidly converted in vivo to a parent compound, such as a prodrug of Formula I, or a compound of Formula I or a salt thereof, for example by hydrolysis in the blood; a full discussion is provided in the following: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. The present invention includes novel compounds of the present invention. Solvates, and in particular, the present invention also includes hydrates of compounds of the present invention.

[0640] utility

[0641] The compounds of the present invention are potent inhibitors of NOD-like receptor protein 3 (NLPR3). The compounds and pharmaceutically acceptable salts thereof can effectively treat diseases, disorders and conditions mediated by the inhibition of NOD-like receptor protein 3 (NLPR3).

[0642] The present invention relates to treating or preventing a disease, disorder or condition mediated by NLRP3, such as inflammation, autoimmune disease, cancer, infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a fibrotic disease or fibrosis, a respiratory disease, a renal disease, a liver disease, an ophthalmic or eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, graft-versus-host disease, hyperalgesia, or a related disease in a subject who has been identified as carrying a germline or somatic NLRP3 non-silent mutation.

[0643] Diseases, disorders or conditions mediated by NLRP3 include, but are not limited to, gout, pseudogout, osteoarthritis, familial cold autoinflammatory syndrome, pediatric renal amyloidosis, neonatal-onset multisystem inflammatory disease, diabetes, NASH, sepsis, age-related macular degeneration, diabetic retinopathy, liver fibrosis, renal fibrosis, atherosclerosis, heart failure, peripheral arterial disease, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colon cancer, Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, hidradenitis suppurativa, pericarditis, myocarditis, preeclampsia, dermatomyositis, Still's disease, juvenile idiopathic arthritis, age-related macular degeneration, diabetic retinopathy, acute kidney disease, chronic kidney disease, or rare kidney diseases. Diseases, disorders or conditions mediated by NOD-like receptor protein 3 (NLPR3) also include, but are not limited to, gout, pseudogout, CAPS, NASH, fibrosis, osteoarthritis, atherosclerosis, heart failure, idiopathic pericarditis, myocarditis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease, cancer, Alzheimer's disease, Parkinson's disease, and traumatic brain injury.

[0644] In one embodiment of the invention, the condition, disease or disorder is an inflammatory joint disease such as gout, pseudogout or osteoarthritis.

[0645] In another embodiment, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, pediatric renal amyloidosis, or neonatal-onset multisystem inflammatory disease.

[0646] In another embodiment, the metabolic disease is diabetes.

[0647] In another embodiment, the liver disease is NASH.

[0648] In another embodiment, the infection is sepsis.

[0649] In another embodiment, the ophthalmology or eye disease is age-related macular degeneration or diabetic retinopathy.

[0650] In another embodiment, the fibrotic disease is liver fibrosis or kidney fibrosis.

[0651] In some embodiments, the cardiovascular disease is atherosclerosis, heart failure, heart failure with preserved ejection fraction, or peripheral arterial disease.

[0652] In another embodiment, the cancer is a myeloproliferative neoplasm, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, or colon cancer.

[0653] In another embodiment of the invention, the condition, disease or disorder of the central nervous system is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis or multiple sclerosis.

[0654] In another embodiment, the skin disease is atopic dermatitis or hidradenitis suppurativa (HS).

[0655] In another embodiment, the inflammatory disease is pericarditis or myocarditis.

[0656] In another embodiment, the inflammatory disease is preeclampsia.

[0657] In another embodiment, the rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0658] In another embodiment, the ocular disease is age-related macular degeneration or diabetic retinopathy.

[0659] In another embodiment, the kidney disease is acute kidney disease, chronic kidney disease, or a rare kidney disease.

[0660] One or more of these conditions or diseases may be treated, managed, prevented, alleviated, ameliorated or controlled by administering to a patient in need of treatment a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0661] The compounds of the present invention may also be used to prepare a medicament useful for treating, preventing, managing, alleviating, ameliorating or controlling one or more of these conditions, diseases or disorders including, but not limited to, gout, pseudogout, osteoarthritis, familial cold autoinflammatory syndrome, pediatric renal amyloidosis, neonatal onset multisystem inflammatory disease, diabetes, NASH, sepsis, age-related macular degeneration, diabetic retinopathy, liver fibrosis, renal fibrosis, atherosclerosis, heart failure, peripheral arterial disease, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colon cancer, Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, hidradenitis suppurativa, pericarditis, myocarditis, preeclampsia, dermatomyositis, Still's disease, juvenile idiopathic arthritis, age-related macular degeneration, diabetic retinopathy, acute kidney disease, chronic kidney disease or a rare kidney disease. The compounds of the present invention may also be used to prepare a medicament useful for treating, preventing, managing, alleviating, ameliorating or controlling one or more of these conditions, diseases or disorders including, but not limited to, gout, pseudogout, CAPS, NASH, fibrosis, osteoarthritis, atherosclerosis, heart failure, idiopathic pericarditis, myocarditis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease, cancer, Alzheimer's disease, Parkinson's disease and traumatic brain injury.

[0662] The preferred use of the compound can be to treat one or more of the following diseases by administering a therapeutically effective amount to a patient in need of treatment. The compound can be used to prepare a medicament for treating one or more of these diseases:

[0663] 1) Gout,

[0664] 2) Pseudogout,

[0665] 3) Cryopyrin-associated periodic syndrome,

[0666] 4) Non-alcoholic hepatitis,

[0667] 5) Fibrosis,

[0668] 6) Osteoarthritis,

[0669] 7) Atherosclerosis,

[0670] 8) Atopic dermatitis,

[0671] 9) Hidradenitis suppurativa,

[0672] 10) Alzheimer's disease, and

[0673] 11) Parkinson's disease.

[0674] Treating a disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway refers to administering a compound of the invention to a subject suffering from the disease, disorder or condition.

[0675] One result of treatment may be to alleviate a disease, disorder, or condition mediated by an NLPR3 or NLPR3 inflammasome pathway. Another result of treatment may be to alleviate a disease, disorder, or condition mediated by an NLPR3 or NLPR3 inflammasome pathway. Another result of treatment may be to improve a disease, disorder, or condition mediated by an NLPR3 or NLPR3 inflammasome pathway. Another result of treatment may be to inhibit a disease, disorder, or condition mediated by an NLPR3 or NLPR3 inflammasome pathway. Another result of treatment may be to manage a disease, disorder, or condition mediated by an NLPR3 or NLPR3 inflammasome pathway. Another result of treatment may be to prevent a disease, disorder, or condition mediated by an NLPR3 or NLPR3 inflammasome pathway.

[0676] Prevention of diseases, disorders or conditions mediated by NLPR3 or NLPR3 inflammasome pathways refers to the administration of the compounds of the invention to subjects at risk of suffering from the disease, disorder or condition. One result of prevention may be to reduce the disease, disorder or condition mediated by NLPR3 or NLPR3 inflammasome pathways of subjects at risk of suffering from the disease, disorder or condition. Another result of prevention may be to inhibit the disease, disorder or condition mediated by NLPR3 or NLPR3 inflammasome pathways of subjects at risk of suffering from the disease, disorder or condition. Another result of prevention may be to improve the disease, disorder or condition mediated by NLPR3 or NLPR3 inflammasome pathways of subjects at risk of suffering from the disease, disorder or condition. Another result of prevention may be to alleviate the disease, disorder or condition mediated by NLPR3 or NLPR3 inflammasome pathways of subjects at risk of suffering from the disease, disorder or condition. Another result of prevention may be to manage the disease, disorder or condition mediated by NLPR3 or NLPR3 inflammasome pathways of subjects at risk of suffering from the disease, disorder or condition.

[0677] The term "administration of" and or "administering" a compound is understood to mean providing a compound of the invention or a prodrug of a compound of the invention to a subject or mammal in need of treatment.

[0678] Administration of a compound of formula I to practice the treatment methods of the present invention is to administer an effective amount of a compound of formula I to a mammal in need of such treatment or prevention. The need for prevention and treatment administration according to the methods of the present invention is determined by using well-known risk factors. The effective amount of an individual compound is determined by the physician or veterinarian in charge of the case in the final analysis, but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions suffered by the patient, other drugs that the patient may need at the same time, the route of administration selected for the treatment, and other factors at the discretion of the physician.

[0679] Animal disease models reported in the literature may demonstrate the usefulness of the compounds of the invention in these diseases or conditions.

[0680] Administration and Dosage Range

[0681] Any suitable route of administration can be used to provide an effective dose of the compounds of the present invention to a mammal, especially a human. For example, oral, intravenous, infusion, subcutaneous, transdermal, intramuscular, intradermal, mucosal, intramucosal, rectal, topical, parenteral, ocular, pulmonary, nasal and the like can be used. Dosage forms include tablets, lozenges, dispersants, suspensions, solutions, capsules, creams, ointments, aerosols and the like. Preferably, the compounds of the present invention are administered orally.

[0682] In the treatment or prevention of disorders, diseases and / or conditions requiring inhibition of NLRP3, suitable dosage levels will generally be about 0.0001 to 500 mg / kg patient weight / day, which can be administered by single or multiple doses. In one embodiment, a suitable dosage level may be about 0.001 to 500 mg / kg patient weight / day. In another embodiment, a suitable dosage level may be about 0.001 to about 250 mg / kg / day. In another embodiment, a suitable dosage level may be about 0.01 to about 250 mg / kg / day. In another embodiment, a suitable dosage level may be about 0.1 to about 100 mg / kg / day. In another embodiment, a suitable dosage level may be about 0.05 to 100 mg / kg / day. In another embodiment, a suitable dosage level may be about 0.1 to 50 mg / kg / day. In another embodiment, a suitable dosage level may be about 0.05 to 0.5 mg / kg / day. In another embodiment, a suitable dosage level may be about 0.5 to 5 mg / kg / day. In another embodiment, a suitable dosage level may be about 5 to 50 mg / kg / day. For oral administration, the composition is preferably provided in the form of a tablet containing 0.01 to 1000 mg of active ingredient, especially 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of active ingredient, the dosage being adjusted according to the symptoms of the patient to be treated. The compound can be administered 1 to 8 times per day; preferably, 1 to 4 times per day; more preferably, once or twice per day, even more preferably, once per day. The dosage regimen can be adjusted to provide the optimal therapeutic response.

[0683] It is to be understood, however, that the specific dosage level and frequency of dosing for any particular patient may vary and depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and duration of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host being treated.

[0684] The compounds of the present invention can be used in pharmaceutical compositions comprising (a) a compound or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier. The compounds of the present invention can be used in pharmaceutical compositions in which the compounds of the present invention or a pharmaceutically acceptable salt thereof is the sole active ingredient. The compounds of the present invention can also be used in pharmaceutical compositions comprising one or more other active pharmaceutical ingredients.

[0685] The term "composition" as in the pharmaceutical composition is intended to include a product consisting of one or more active ingredients, and one or more inert ingredients constituting a carrier, as well as any product produced directly or indirectly by the combination, complexation or aggregation of any two or more ingredients, or by the dissociation of one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical composition of the present invention includes any composition prepared by mixing the compound of the present invention with a pharmaceutically acceptable carrier.

[0686] The compounds of the present invention can be used in combination with other drugs that can also be used to treat or improve the diseases or conditions for which the compounds of the present invention are applicable. These other drugs can be administered simultaneously or sequentially with the compounds of the present invention by commonly used routes and dosages. When treating patients with chronic inflammation, more than one drug can be administered. The compounds of the present invention can generally be administered to patients who have already taken one or more other drugs to treat these conditions. The compounds are generally administered to patients who have already taken one or more anti-pain compounds when the patient's pain is not adequately responsive to treatment.

[0687] Combination therapy also includes therapy with the compounds of the present invention and one or more other drugs on different overlapping schedules. It should be carefully considered that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can be used at lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compounds of the present invention.

[0688] Examples of other active ingredients that can be administered in combination with the compounds of the present invention, and administered separately or in the same pharmaceutical composition, include, but are not limited to:

[0689] (i) anti-fat degeneration agents;

[0690] (ii) anti-inflammatory agents;

[0691] (iii) tumor immunotherapy agents;

[0692] (iv) lipid-lowering agents;

[0693] (v) cholesterol-lowering agents;

[0694] (vi) hypoglycemic agents, including SGLT2 inhibitors;

[0695] (vii) anti-angiogenic agents;

[0696] (viii) nonsteroidal anti-inflammatory drugs ("NSAIDs");

[0697] (ix) acetylsalicylic acid (ASA) drugs including aspirin; paracetamol;

[0698] (x) regenerative therapy treatment;

[0699] (xi) Checkpoint inhibitors including anti-PD1 and anti-PDL1 inhibitors;

[0700] (xii) chemotherapy procedures;

[0701] (xiii) radiotherapy;

[0702] (xiv) surgical procedures;

[0703] (xv) uric acid lowering therapy;

[0704] (xvi) anabolic agents and cartilage regeneration therapies;

[0705] (xvii) anti-fibrotic agents;

[0706] (xviii) JAK inhibitors;

[0707] (xix) TNF-α inhibitors;

[0708] (xx) antihypertensive agents; and

[0709] (xxi) STING / cGAS antagonists

[0710] or pharmaceutically acceptable salts thereof.

[0711] In another embodiment of the present invention, the pharmaceutical composition comprises:

[0712] 1) The compound of claim 1, or a pharmaceutically acceptable salt thereof;

[0713] 2) one or more compounds, or pharmaceutically acceptable salts thereof, selected from the following group:

[0714] (i) anti-fat degeneration agents;

[0715] (ii) anti-inflammatory agents;

[0716] (iii) tumor immunotherapy agents;

[0717] (iv) lipid-lowering agents;

[0718] (v) cholesterol-lowering agents;

[0719] (vi) hypoglycemic agents, including SGLT2 inhibitors;

[0720] (vii) anti-angiogenic agents;

[0721] (viii) nonsteroidal anti-inflammatory drugs ("NSAIDs");

[0722] (ix) acetylsalicylic acid (ASA) drugs including aspirin; paracetamol;

[0723] (x) regenerative therapy treatment;

[0724] (xi) checkpoint inhibitors, including anti-PD1 and anti-PDL1 inhibitors;

[0725] (xii) chemotherapy procedures;

[0726] (xiii) radiotherapy;

[0727] (xiv) surgical procedures;

[0728] (xv) uric acid lowering therapy;

[0729] (xvi) anabolic agents and cartilage regeneration therapies;

[0730] (xvii) anti-fibrotic agents;

[0731] (xviii) JAK inhibitors;

[0732] (xix) TNF-α inhibitors;

[0733] (xx) antihypertensive agents; and

[0734] (xxi) STING / cGAS antagonists; and

[0735] Pharmaceutically acceptable salts thereof; and

[0736] 3) Pharmaceutically acceptable carrier.

[0737] Particular compounds for combination with the compounds of the present invention include anti-steatosis agents, including but not limited to DGAT2 inhibitors.

[0738] Suitable anti-inflammatory agents include, but are not limited to, TNFα inhibitors, JAK inhibitors, and NSAIDs.

[0739] Suitable lipid-lowering agents include, but are not limited to, statins and PCSK9.

[0740] Suitable tumor immunotherapy agents include, but are not limited to, PD-L1 inhibitors, PD-1 inhibitors, and STING antagonists.

[0741] Suitable hypoglycemic agents include, but are not limited to, insulin, SGLT2 inhibitors, metformin, GLP1-agonists.

[0742] Suitable anti-neovascular agents include, but are not limited to, anti-VEG-F therapy.

[0743] Suitable NSAIDs or nonsteroidal anti-inflammatory drugs include, but are not limited to, aspirin, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, meloxicam, naproxen, naproxen sodium, oxaprozin, piroxicam, sulindac and tolmetin.

[0744] Suitable analgesics include, but are not limited to, acetaminophen and duloxetine.

[0745] The above combination includes not only another active compound of the compound of the present invention, but also a combination of two or more active compounds. Non-limiting examples include two or more active compounds selected from: anti-fat degeneration agents, anti-inflammatory agents, lipid-lowering agents, anti-fibrosis agents, tumor immunity agents, hypoglycemic agents and anti-neovascular agents, NSAIDs (non-steroidal anti-inflammatory drugs), and analgesic compound combinations.

[0746] The present invention also provides methods for treating or preventing a disease, disorder or condition mediated by NLRP3, the method comprising administering to a patient in need of such treatment or at risk of developing a disease mediated by NLRP3 a therapeutically effective amount of a NLRP3 inhibitor and an amount of one or more active ingredients such that together they provide effective relief.

[0747] In another aspect of the present invention, a pharmaceutical composition comprising a NLRP3 inhibitor and one or more active ingredients and at least one pharmaceutically acceptable carrier or excipient is provided.

[0748] Therefore, according to another aspect of the present invention, there is provided a use of a NLRP3 inhibitor and one or more active ingredients for the preparation of a medicament for treating or preventing a disease, disorder or condition mediated by NLRP3. In another or alternative aspect of the present invention, there is provided a product comprising a NLRP3 inhibitor and one or more active ingredients as a combined preparation for treating or preventing a disease, disorder or condition mediated by NLRP3 simultaneously, separately or sequentially. This combined preparation can be, for example, in a double package form.

[0749] It will be appreciated that for the treatment or prevention of cardiometabolic diseases, neurodegenerative diseases and inflammatory joint diseases, fibrosis and cancer, the compounds of the invention may be used in combination with another agent that is effective in treating the disease, disorder or condition.

[0750] The invention also provides a method of treating or preventing a chronic inflammatory condition, which method comprises administering to a patient in need of such treatment an amount of a compound of the invention and an amount of another agent effective for treating the disorder, disease or condition such that they together provide effective relief.

[0751] The invention also provides a method of treating or preventing chronic inflammatory conditions, which method comprises administering to a patient in need of such treatment an amount of a compound of the invention and an amount of another agent useful for treating the disorder, disease or condition such that they together provide effective relief.

[0752] The term "therapeutically effective amount" refers to an amount of a compound of formula I that will elicit the biological or medical response of a cell, tissue, system, animal or human being that is being sought by a researcher, veterinarian, medical doctor or other clinician, including relief of symptoms of the condition being treated. The novel treatment methods of the present invention are applicable to conditions known to those skilled in the art. The term "mammal" includes humans and companion animals such as dogs and cats.

[0753] The weight ratio of the compound of formula I to the second active ingredient can be varied and will depend on the effective doses of the individual ingredients. Typically, an effective dose of each will be used. Thus, for example, when the compound of formula I is used in combination with an anti-fat degeneration agent, the weight ratio of the compound of formula I will typically range from about 1000:1 to about 1:1000, preferably from about 200:1 to about 1:200. The combination of the compound of formula I and other active ingredients will typically be within the aforementioned ranges, but in each case, an effective dose of each active ingredient should be used.

[0754] Synthesis method

[0755] The following reaction schemes and examples illustrate methods that can be used to synthesize compounds of formula I described herein. These reaction schemes and examples are provided to illustrate the present invention and should not be construed as limiting the present invention in any way. Unless otherwise indicated, all substituents are as defined above. Several strategies based on synthetic transformations known in the organic synthesis literature can be used to prepare compounds of formula I. The scope of the present invention is defined by the appended claims. Compound names were generated by Chemdraw 21.0.0.28 version.

[0756] instrument

[0757] Reverse phase chromatography was performed on a Waters 150 using a column selected from the following: Phenomenex Synergi C18 (250 mm x 30 mm x 4 μm), Phenomenex Luna C18 (250 mm x 21 mm x 5 μm), Agilent Zorbax Bonus-RP (150 mm x 21 mm x 5 μm), Waters X-Select CSH C18 (150 mm x 19 mm x 5 microns). Conditions included high pH (0-100% acetonitrile / water eluent, containing 0.1% v / v NH4OH) or low pH (0-100% acetonitrile / water eluent, containing 0.1% v / v TFA or formic acid) and some examples are indicated. SFC chiral analysis was performed on a Waters Thar 80SFC or Berger MG II preparative SFC system using the following conditions: Chiral method A: ColumnTek Enantiocel A5-5 column, 20% EtOH / CO2; Chiral method B: ChiralPak ID column, 35% MeOH / CO2; Chiral method C: OJ-H column, 20% iPrOH / CO2; Chiral method D: ChiralPak ID column, 5-60% MeOH / CO2; Chiral method E: Daicel ChiralpakAD column, 25% iPrOH / CO2; Chiral method F: ChiralPak ID column, 30% MeOH / CO2; Chiral method G: ChiralPakIB-N column, 15% MeOH / CO2.

[0758] LC / MS measurements were performed on a Waters ACQUITY UPLC using DAD and QDa MS detectors using the following conditions: Waters ACQUITY UPLC BEH C18 1.7 mm 2.1 x 50 mm column, using a mobile phase containing A: 0.1% TFA in water and B: 0.1% TFA in acetonitrile, a gradient of 10% B to 90% B for 2.0 min and 90% B for 0.4 min, and a flow rate of 0.5 mL / min. Unless otherwise stated, proton or 1 H NMR was acquired on a Bruker 500 MHz NEO NMR spectrometer with a 5 mm iProbe and spectral analysis results were reported according to standard analytical techniques. Chemical shift (δ) values ​​are reported in (δ) units, parts per million (ppm). 1H NMR spectra chemical shifts are given as residual undeuterated solvent signals (CDCl3 referenced at δ 7.26 ppm; DMSO d-6 referenced at δ 2.50 ppm and CD3OD referenced at δ 3.31 ppm). Multiplets are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet or overlap of non-equivalent resonances. Coupling constants (J) are reported in Hertz (Hz).

[0759] The general preparative conditions for separation of diastereomers or mixtures of enantiomers of a compound using chiral SGC are as follows:

[0760]

[0761] abbreviation:

[0762] In the molecule, "*" indicates the stereoisomer center; Ac is acetyl; OAc is acetate; AcOH is acetic acid; aq. is aqueous; B2pin2 is bis(pinacolyl)diboron; BPin ester is boric acid pinacol ester; Boc or boc is tert-butyloxycarbonyl; br is broad peak; Bu or nBU is N-butyl; Bz is benzoyl; ℃ is degrees Celsius; Calc'd is calculated value; CDI is 1,1′-carbonyl-diimidazole, δ is chemical shift; d is doublet; conc. is concentrated; DFMS is bis(((difluoromethyl)sulfinyl)oxy)zinc; DIC is N,N′-diisopropyl-carbodiimide; DAST is diethylaminosulfur trifluoride; DCE is dichloroethane; DCM is dichloromethane; dd is doublet; dq d is a doublet of four doublets; DEA is diethanolamine; DIEA is N,N-diisopropylethylamine; DMA is dimethylformamide; DME is dimethoxyethane; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; dtbbpy is 4,4′-di-tert-butyl-2,2′-dipyridyl; dppf is 1,1′-bis(diphenyl)-ferrocene; EDC is 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide; ESI is electrospray ionization; Et is ethyl; Et2O is diethyl ether; EtOAc is ethyl acetate; EtOH is ethanol; equiv is equivalent; g is gram; h or hr(s) is hour; HOAt is 1-hydroxy-7-azabenzotriazole; HPLC is high performance liquid chromatography; Hz is hertz; i Pr is isopropyl; iPrOH or IPA is isopropanol; iPrMgCl is isopropylmagnesium chloride; J is coupling constant; L is liter; LAH is lithium aluminum hydride; LC is liquid chromatography; LCMS is liquid chromatography / mass spectrometry; LRMS is low resolution mass spectrometry; m is multiplet; M is molar concentration; Me is methyl; MeOH is ethanol; MeCN is acetonitrile; mg is milligrams; min is minutes; mL is milliliters; mM is nanomolar concentration; mmol is millimole; MHz is megahertz; μL is microliter; MS is mass spectrometry; nM is nanomolar concentration; NHPI is N-hydroxyphthalimide; NaHMDS is sodium bis(trimethylsilyl)amide; NH4OAc is ammonium acetate, NMO is 4-Methylmorpholine N-oxy compound; NMP is N-methylpyrrolidone; PCC is pyridinium chlorochromate; Pd / C is palladium / carbon; Pd(dppf)Cl2 is [1,1′-bis-(diphenyl)-ferrocene]dichloropalladium(II); Pd(PPh3)4 is tetrakis(triphenyl-phosphine)palladium(0); Pd(tBu3P)2 is bis(tri-tert-butylphosphine)-palladium(0); PE is petroleum ether; PG is a protecting group; ph is phenyl; pr is propyl; prep is preparation; q is a quartet; rac is a racemic mixture; rt or RT is room temperature; s is a singlet; sat. or satd is saturated; SFC is supercritical fluid chromatography; SnAr is nucleophilic aromatic substitution; t is a triplet; TBHP is tert-butyl hydroperoxide; t Bu is tert-butyl; t BuOH is tert-butyl alcohol; tert is tert-butyl; TBAF is tetrabutylammonium fluoride; TEA is triethylamine; TFA is trifluoroacetic acid; THF is tetrahydrofuran; Ti(OEt)4 is tetraethyl titanate(IV); Ti(OiPr)4 is tetraisopropyl titanate(IV); TLC is thin layer chromatography; TMHD is 2,2,6,6-tetramethyl-3,5-heptanedione; TMS-diazomethane is trimethylsilyl-diazomethane; tt is three triplets; XPhos Pd G3 is (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonic acid; and UV is ultraviolet light.

[0763] Process A

[0764]

[0765] Scheme A illustrates the synthesis of aryl and heteroaryl boronates such as A-2 from aryl halides (Cl, Br or I) such as A-1. Aryl boronates A-2 are prepared by palladium-catalyzed Suzuki-Miyaura borylation of aryl halides such as A-1 with B2pin2 in the presence of a suitable base.

[0766] Process B

[0767]

[0768] Flow chart B illustrates a synthetic sequence for preparing a phthalazine derivative of formula B-4. A heteroaryl diacid of formula B-1 is treated with an acid such as H2SO4 in a suitable alcohol solvent (ROH) such as MeOH to give a diester of formula B-2. The diester of formula B-2 is condensed with hydrazine and then treated with aq.HCl to give a pyridazine-1,4-dione of formula B-3. The pyridazine-1,4-dione of B-3 is reacted with a suitable deoxychlorinating agent (such as POCl3) to give a dichlorophthalazine derivative of formula B-4.

[0769] Process C

[0770]

[0771] Scheme C illustrates a synthetic sequence for preparing phthalazine derivatives such as C-2a and C-2b from precursors of formula B-4. Nucleophilic aromatic substitution (SnAr) using various secondary amines in the presence of a base such as K2CO3 provides tertiary amines of formula C-1a and C-1b. Cross-coupling using an appropriate nucleophile such as an aryl boronic acid aryl and a palladium catalyst provides a bi-aryl product, which is deprotected in situ to provide compounds of formula C-2a and C-2b, as appropriate. If regioisomers are present, they are separated by chromatography, preferably by reverse phase HPLC or SFC.

[0772] Process D

[0773]

[0774] Scheme D illustrates a synthetic sequence for preparing phthalazine derivatives such as C-2a from precursors of formula B-4. Suzuki cross-coupling using an appropriate aromatic nucleophile such as an aromatic boronic acid and a palladium catalyst provides the biaryl product of formula D-1; if regioisomers are present, they are separated by chromatography, preferably silica gel chromatography. Subsequent nucleophilic aromatic substitution (SnAr) with various secondary amines in the presence of a base such as K2CO3 provides the tertiary amine of formula C-2a.

[0775] Process E

[0776]

[0777] Scheme E schematically illustrates the preparation of alkylated compounds of formula E-1 from the corresponding bis-aryl chloride D-1 and an appropriate alkyl electrophilic reagent such as an alkyl halide or N-hydroxyphthalimide (NHPI) ester. Cross-electrophic coupling under nickel catalysis provides the alkylated compounds of formula E-1.

[0778] Process F

[0779]

[0780] Scheme F schematically illustrates the preparation of a tertiary alcohol compound of formula F-2 from the corresponding bisaryl chloride D-1 and an appropriate olefin nucleophile such as pinacol borate, followed by palladium catalyzed cross coupling to give a bisaryl olefin of formula F-1. The olefin is then hydrated using Mukaiyama-Magnus conditions to give a tertiary alcohol of formula F-2.

[0781] Process G

[0782]

[0783] Scheme G illustrates the preparation of alkylated pyridopyridazines of formula G-2a by introducing a Minisci-type free radical into G-1 using a suitable free radical precursor such as zinc sulfinate. The reaction is carried out in the presence of an oxidant such as TBHP to give a mixture of substituted pyridopyridazines of formula G-2a and G-2b, which are subsequently separated by SFC.

[0784] Intermediate 1

[0785] 2-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborin Pentane

[0786]

[0787] A solution of 1-bromo-2-(difluoromethoxy)-4-(trifluoromethyl)benzene (Enamine, 60 mg, 0.2 mmol) in 1,4-dioxane (1.0 mL) was added with B2pin2 (56 mg, 0.22 mmol), KOAc (60 mg, 0.6 mmol) and PdCl2(dppf) (15 mg, 0.2 mmol). The mixture was degassed with N2 and then stirred at 105°C for 12 h. The reaction mixture was then cooled to room temperature, filtered, and the solvent was removed under vacuum. The resulting crude mixture was used directly without further purification. 1 H NMR (500MHz, CDCl3) δ7.88 (br d, J = 7.6Hz, 1H), 7.51 (br d, J = 7.7Hz, 1H), 7.41 (s, 1H), 6.26-6.82 (t, J = 74.4Hz, 1H), 1.37ppm (s, 12H).

[0788] Intermediate 2

[0789] 1,4-Dichloropyridazino[4,5-d]pyridazine

[0790]

[0791] Step 1: Dimethyl pyridazine-4,5-dicarboxylate:A solution of pyridazine-4,5-dicarboxylic acid (Combi-Blocks, 2.0 g, 11.9 mmol) in MeOH (40 mL) was treated with concentrated H2SO4 (0.64 mL, 11.9 mmol). The mixture was heated to reflux for 48 h, then cooled to room temperature and partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (EtOAc:hexanes) to give the title compound. LCMS [M+H] + =197.1 (calculated value 197.1).

[0792] Step 2: 2,3-Dihydropyridazino[4,5-d]pyridazine-1,4-dione: A solution of dimethyl pyridazine-4,5-dicarboxylate (578 mg, 2.95 mmol) in MeOH (7.3 mL) was treated with hydrazine hydrate (0.44 mL, 8.84 mmol) at room temperature, and then heated to reflux for 1 h with vigorous stirring. The mixture was cooled to room temperature and filtered. The filtered solid was transferred to a vial containing H2O (9 mL) and heated to 85°C; the mixture was then acidified to pH 3 with concentrated aqueous HCl and stirred for 20 min. The mixture was cooled to room temperature, filtered, and the resulting solid was dried under reduced pressure to give the title compound. LCMS [M+H] + =165.0 (calculated value 165.0).

[0793] Step 3: 1,4-Dichloropyridazino[4,5-d]pyridazine: A solution of 2,3-dihydropyridazino[4,5-d]pyridazine-1,4-dione (100 mg, 0.61 mmol) and PCl5 (Sigma Aldrich, 254 mg, 1.22 mmol) in POCl3 (Sigma Aldrich, 1.4 mL, 15.2 mmol) was heated to 110 °C overnight. The mixture was cooled to room temperature and poured into ice. The suspension was adjusted to pH 7 with saturated aq. NaHCO3 and then diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (x2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (EtOAc:hexanes) to give the title compound. LCMS [M+H] + =201.0 (calculated value 201.0).

[0794] Table 1. The following compounds were prepared using a procedure similar to that described for Intermediate 2 using appropriate starting materials.

[0795]

[0796] Intermediate 6

[0797] (3aR,7aR)-6-Methyloctahydro-1H-pyrrolo[2,3-c]pyridine

[0798]

[0799] Step 1: (3aS,7aR)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester : Racemic (cis)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (Synthonix, 15 g, 66.3 mmol) was separated by chiral SFC (method A) to give the corresponding enantiomers. Peak 1: (3aR, 7aS)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (6.8 g, 30.0 mmol), and Peak 2: (3aS, 7aR)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (5.7 g, 25.2 mmol).

[0800] Step 2: (3aS, 7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester: To a solution of (3aS,7aR)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (1 g, 4.42 mmol) in MeOH (8.8 mL) was added 37% aq. formaldehyde (1.65 mL, 22.1 mmol) and NaBH3CN (0.56 g, 8.84 mmol) at 0°C. The mixture was warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure and the crude residue containing the title compound was used directly in the next step. LCMS [M+H] + =241.1 (calculated value 241.2).

[0801] Step 3: (3aR, 7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridine: HCl (4M in 1,4-dioxane, 5.5 ml, 22.0 mmol) was added to a solution of crude (3aS,7aR)-6-methyl-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (1.06 g, 4.4 mmol) in 1,4-dioxane (6 mL) and MeOH (3 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude residue containing the title compound was used directly in the next step. LCMS [M+H] + =141.1 (calculated value 141.1).

[0802] Intermediate 7

[0803] Shun -2,6-Dimethyltetrahydro-2H-pyran-4-carboxylic acid 1,3-dioxoisoindolin-2-yl ester

[0804]

[0805] Cis-2,6-dimethyltetrahydro-2H-pyran-4-carboxylic acid (Enamine, 100 mg, 0.63 mmol), N-hydroxyphthalamide (113 mg, 0.7 mmol), and DMAP (3.9 mg, 0.03 mmol) were suspended in DCM (3.1 mL). DIC (1 M in DCM, 0.7 mL, 0.7 mmol) stock solution was added, and the mixture was stirred at room temperature overnight. The reaction was filtered, the solvent was removed under reduced pressure, and the crude residue was purified by silica gel chromatography (EtOAc: hexanes) to give the title compound.

[0806] Examples 1 and 2

[0807] (S)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrole Alkan-3-ol (Example 1); and

[0808] (S)-1-(1-(2-Hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]-pyridazin-4-yl)-3-methylpyrrole Alkane-3-ol (Example 2)

[0809]

[0810] Step 1: (S)-1-(4-chloropyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrolidin-3-ol and (S)-1-(1- Chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpyrrolidin-3-ol: 1,4-Dichloropyrido[3,4-d]pyridazine (Ambeed, 300 mg, 1.5 mmol), K2CO3 (415 mg, 3.0 mmol), and (S)-3-methylpyrrolidin-3-ol hydrochloride (PharmaBlock, 206 mg, 1.5 mmol) were suspended in NMP (6 mL). The mixture was heated to 80 °C overnight. The reaction was then cooled to room temperature, diluted with EtOAc, washed with water, the aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue containing the title compound was a mixture of regioisomers and was used directly in the next step. LCMS [M+H] + =265.0 (calculated value 265.1).

[0811] Step 2: (S)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3-methyl Pyrrolidin-3-ol and (S)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-3-methyl Pyrrolidin-3-ol:Regioisomer mixture (S)-1-(4-chloropyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrolidin-3-ol and (S)-1-(1-chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpyrrolidin-3-ol (555 mg, 2.10 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (PharmaBlock, 734 mg, 3.56 mmol), and XPhosPd G3 (Sigma, 177 mg, 0.21 mmol) were suspended in 1,4-dioxane (10 mL) and K3PO4 (3M aqueous solution, 1.54 mL, 4.61 mmol) stock solution. The mixture was degassed by purging with Ar for 10 min, then sealed and heated to 100° C. and stirred for 3 h. After cooling to room temperature, the crude mixture was dry loaded onto silica gel and purified by silica gel chromatography (MeOH:DCM) to afford the title compound as a mixture of regioisomers. The regioisomers were separated by chiral SFC (Method B). The faster eluting regioisomer was obtained (Example 1). 1 H NMR (500MHz, DMSO-d6) δ8.87(d,J=5.9Hz,1H),8.83(s,1H),8.18(d,J=5.9Hz,1H),7.63(d,J=7.8Hz,1H),7.35(d,J=7.9Hz,1 H),7.30(s,1H),4.94(s,1H),4.20-4.11(m,1H),3.96-3.85(m,2H),3.72(d,J=10.8Hz,1H),2.04-1.91(m,2H),1.42(s,3H). LCMS[M+H] + = 391.0 (calculated 391.1). Slower eluting regioisomer obtained (Example 2). 1 H NMR (500MHz, DMSO-d6) δ10.52(s,1H),9.65(s,1H),8.82(d,J=5.6Hz,1H),7.58(d,J=7.7Hz,1H),7.33-7.27(m,3H),4.92(s,1H), 4.19(td,J=10.1,7.1Hz,1H),3.98(d,J=11.1Hz,1H),3.97-3.91(m,1H),3.76(d,J=11.2Hz,1H),2.06-1.92(m,2H),1.43(s,3H). LCMS[M+H] + =391.0 (calculated value 391.1).

[0812] Table 2. The following compounds were prepared using appropriate starting materials using procedures similar to those described in Examples 1 and 2. Regioisomers, if present, were separated by silica gel chromatography after step 1 or by reverse phase HPLC after step 2.

[0813]

[0814]

[0815]

[0816]

[0817] Table 3. The following compounds were prepared using procedures similar to those described in Examples 1 and 2 using appropriate starting materials. The regioisomeric products were separated using the chiral SFC methods specified in the table after step 2. For pairs of regioisomers, the faster eluting isomer is listed first.

[0818]

[0819]

[0820] Embodiment 22

[0821] (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-3-methylpyrrole Alkane-3-ol

[0822]

[0823] Step 1: 2-(8-chloropyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol: A solution of (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (PharmaBlock, 2.47 g, 12.0 mmol), 5,8-dichloropyrido[2,3-d]pyridazine (Ambeed, 2 g, 10.0 mmol), K2CO3 (2.07 g, 15.0 mmol), and Pd(dppf)Cl2 (0.48 g, 0.65 mmol) in 1,4-dioxane (30 mL) and H2O (10 mL) was degassed by sparging with Ar for 10 min. The vial was heated to 85 °C and stirred for 2 h. The reaction was then cooled to room temperature, diluted with EtOAc and dry loaded onto silica gel. Purification by silica gel chromatography (EtOAc:hexanes) gave the title compound. LCMS [M+H] + =326.0 (calculated value 326.0).

[0824] Step 2: (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methyl Pyrrolidin-3-ol:K2CO3 (151 mg, 1.09 mmol) and (S)-3-methylpyrrolidin-3-ol hydrochloride (PharmaBlock, 88 mg, 0.64 mmol) were added to a solution of 2-(8-chloropyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol (148 mg, 0.45 mmol) in NMP (1.5 ml). The mixture was heated to 80°C and stirred for 2 h. The reaction was then cooled to room temperature and directly purified by reverse phase preparative HPLC (C18 stationary phase, MeCN / H2O+0.05% FA) to give the title compound. 1 HNMR(500MHz,DMSO-d6)δ10.51(s,1H),9.09(dd,J=4.2,1.5Hz,1H),7.85(dd,J=8.4,1.5Hz,1H),7.78(dd,J=8.4,4.2Hz,1H),7.58(d,J=7 .8Hz,1H),7.32(d,J=8.0Hz,1H),7.29(s,1H),4.82(s,1H),4.11(s,3H),3.95(s,1H),2.02-1.96(m,1H),1.96-1.87(m,1H),1.42(s,3H). LCMS[M+H] + =391.2 (calculated value 391.1).

[0825] Table 4. The following compounds were prepared using a similar procedure as described in Example 22 using appropriate starting materials.

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832] Table 5. The following compounds were prepared by a procedure analogous to that described in Example 22 using appropriate starting materials. The enantiomeric products were separated by the chiral SFC method listed in the table. For a pair of enantiomers, the faster eluting isomer is listed first.

[0833]

[0834]

[0835] Embodiment 53

[0836] 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-methyl-4-(trifluoromethyl)benzene Phthaloazine

[0837]

[0838] Step 1: 1-Chloro-4-(2-methyl-4-(trifluoromethyl)phenyl)phthalazine: A solution of (2-methyl-4-(trifluoromethyl)phenyl)boronic acid (Combi-Blocks, 510 mg, 2.5 mmol) in 1,4-dioxane (16.7 mL) and H2O (8.3 mL) was added with 1,4-dichlorophthalazine (Combi-Blocks, 498 mg, 2.5 mmol), K2CO3 (1.38 g, 10.0 mmol) and PdCl2(dppf) (183 mg, 0.25 mmol). The mixture was degassed with N2 and then stirred at 100°C for 2 h. After cooling to room temperature, the mixture was quenched with saturated aqueous NaHCO3 and partitioned between H2O and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The crude residue obtained was purified by silica gel chromatography (EtOAc: hexane) followed by HPLC (C18 stationary phase, MeCN / H2O + 0.1% TFA). The combined product fractions were quenched with saturated aqueous NaHCO3 and diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (x3). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Repurification by silica gel chromatography (EtOAc: hexane) gave the title compound. LCMS [M+H] + =323.1 (calculated value 323.1).

[0839] Step 2: 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-methyl-4-(trifluoro-methyl)- Phthaloazine: A catalyst solution of dtbbpy (14 mg, 0.05 mmol) and Ni(DME)Br2 (16 mg, 0.05 mmol) in DMA (0.7 mL) was degassed with Ar for 10 min. In a separate vial, cis-2,6-dimethyltetrahydro-2H-pyran-4-carboxylic acid 1,3-dioxyisoindolin-2-yl ester (78 mg, 0.26 mmol), 1-chloro-4-(2-methyl-4-(trifluoromethyl)phenyl)-phthalazine (55 mg, 0.17 mmol), and zinc powder (Strem, 22 mg, 0.34 mmol) were added under Ar, and the catalyst solution (0.7 mL) was added. The vial was sealed and heated to 50°C with vigorous stirring (>1000 rpm) overnight. The reaction mixture was cooled to room temperature, filtered and directly purified by reverse phase preparative HPLC (C18 stationary phase, MeCN / H2O+0.05% FA) to give the title compound. 1HNMR(500MHz,CD3CN)δ8.40(d,J=8.4Hz,1H),7.99(ddd,J=8.3,7.1,1.2Hz,1H), 7.86(td,J=7.6,7.1,1.0Hz,1H),7.77(s,1H),7.70(d,J=7.9Hz,1H),7.53(dd,J= 8.0,4.5Hz,2H),4.00(tt,J=12.0,3.6Hz,1H),3.82(dqd,J=12.4,6.2,1.8Hz,2H ), 2.11 (s, 3H), 2.02 (d, J = 11.5Hz, 2H), 1.83-1.71 (m, 2H), 1.24 (d, J = 6.2Hz, 6H). LCMS [M+H] + =401.2 (calculated value 401.2).

[0840] Embodiments 54 and 55

[0841] (2R,4s,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-2, 6-dimethyltetrahydro-2H-pyran-4-ol (Example 54); and

[0842] (2R,4r,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-2, 6-Dimethyltetrahydro-2H-pyran-4-ol (Example 55)

[0843]

[0844] Step 1: 2-(8-((2R,6S and 2S,6R)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyrido[2, 3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol: A solution of 2-(8-chloropyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol (300 mg, 0.92 mmol) and XPhos Pd G3 (78 mg, 0.09 mmol) was added to a solution of 2-((2R,6S and 2S,6R)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (J&W Pharmlab, 373 mg, 1.57 mmol) in 1,4-dioxane (7.4 mL). The reaction mixture was degassed by purging with Ar for 10 min, and then 1M aq. K3PO4 (2.0 mL, 2.03 mmol) was added. The reaction mixture was heated to 100°C and stirred for 2 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc, dry loaded onto silica gel, and purified by silica gel chromatography (EtOAc: hexanes) to give the title compound. LCMS [M+H] + =402.1 (calculated value 401.1).

[0845] Step 2: (2R,4s,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazine-8-yl)- (2R,4r,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)-phenyl)pyran-4-ol Imido[2,3-d]pyridazin-8-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol:2-(8-((2R,6S and 2S,6R)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol (54 mg, 0.135 mmol) and Mn(TMHD)3 (98 mg, 0.16 mmol) were suspended in i PrOH (1.4 mL). The mixture was charged with O2 for 5 min, followed by the addition of PhSiH3 (33 μL, 0.27 mmol). The mixture was sealed under an O2 atmosphere, heated to 60 °C, and stirred for 2 h. The reaction mixture was then cooled to room temperature, quenched with excess P(OMe)3 and stirred for 5 min. The mixture was diluted with H2O, then 1M aq.HCl, and EtOAc. The layers were separated, and the aqueous layer was neutralized to pH 7, stripped with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc: hexane) to give the title compound as two separated diastereomers. The faster eluting diastereomer obtained (Example 54). 1 H NMR(500MHz,CD3CN)δ9.23(dd,J=4.2,1.4Hz,1H),8.38(dd,J=8.6,1.4Hz,1H),7.91(dd,J=8.5,4.3Hz,1H),7.71(d,J=7.7Hz,1H) ,7.43-7.34(m,2H),6.59(s,1H),4.17(dq,J=11.0,6.3Hz,2H),2.08(d,J=13.0Hz,2H),1.82-1.79(m,2H),1.21(d,J=6.2Hz,6H). LCMS[M+H] + = 420.1 (calculated 420.2). The slower eluting isomer of the title compound was obtained (Example 55). 1 H NMR(500MHz,CD3CN)δ9.25-9.20(m,1H),8.40(dd,J=8.6,1.1Hz,1H),7.91(dd,J=8.5,4.3Hz,1H),7.72(d,J=7.8Hz,1H),7.4 2-7.39(m,2H),6.36(s,1H),3.86(dq,J=11.4,6.3Hz,2H),2.75(d,J=13.1Hz,2H),1.71-1.62(m,2H),1.14(d,J=6.2Hz,6H). LCMS[M+H] + =420.1 (calculated value 420.2).

[0846] Embodiment 56 and 57

[0847] (S)-1-(2-(difluoromethyl)-5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazine-8- 1-Methyl-2-pyrrolidin-3-ol (Example 56); and

[0848] (S)-1-(3-(difluoromethyl)-5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazine-8- 1-Methyl-2-pyrrolidin-3-ol (Example 57)

[0849]

[0850] (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidin-3-ol (Example 22, 60 mg, 0.15 mmol) and DFMS (136 mg, 0.46 mmol) were suspended in a mixture of CHCl3 (0.53 mL) and H2O (0.23 mL). TBHP (70 wt.% in H2O, 85 μL, 0.62 mmol) was then added dropwise with stirring, and the mixture was heated to 50°C for 3 h. DFMS (91 mg, 0.307 mmol) and TBHP (70 wt.% in H2O, 50 μL, 0.38 mmol) solutions were then added, and the mixture was stirred at 50°C overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The crude residue obtained was purified by reverse phase HPLC (C18 stationary phase, MeCN / H2O + 0.05% FA) to afford the title compound as a mixture of regioisomers which were subsequently analyzed by chiral SFC (Method G). The faster eluting isomer was obtained (Example 56). 1 H NMR (500MHz, CD3CN) δ8.35(d,J=8.6Hz,1H),7.94(d,J=8.7Hz,1H),7.63(d,J=7.9Hz,1H),7.25-7. 19(m,2H),6.91(t,J=54.9Hz,1H),4.33-4.08(m,3H),3.95(s,1H),2.06-1.97(m,2H),1.48(s,3H). LCMS[M+H] + = 441.0 (calculated 441.1). The slower eluting diastereomer obtained (Example 57). 1 H NMR(500MHz,CD3CN)δ9.18(s,1H),8.31(s,1H),7.63(d,J=7.8Hz,1H),7.22(d,J=8.0Hz,2H),7. 00(t,J=55.0Hz,1H),4.28-4.09(m,3H),3.96(d,J=11.1Hz,1H),2.05-1.99(m,2H),1.48(s,3H). LCMS[M+H] + =441.0 (calculated value 441.1).

[0851] Pharmaceutical Composition Examples

[0852] As a specific embodiment of the oral pharmaceutical composition, a 100 mg potency tablet is composed of 100 mg of any of the examples, 268 mg of microcrystalline cellulose, 20 mg of cross-linked carboxymethyl cellulose sodium and 4 mg of magnesium stearate. The active ingredients, microcrystalline cellulose, and cross-linked carboxymethyl cellulose are first mixed. The mixture is then lubricated with magnesium stearate and pressed into tablets.

[0853] Biological analysis

[0854] The activation of the typical NLRP3 inflammasome requires two steps, namely priming and activation. Priming signals such as pathogen-activated molecular patterns (PAMPs) or danger-activated molecular patterns (DAMPs) are recognized by Toll-like receptors, leading to nuclear factor κB (NF-KB)-mediated signal transduction. This in turn upregulates the transcription of inflammasome-related components, including inactive NLRP3 and prolL-1β (Bauernfeind et al., J. Immunol. 2009, 183, 787-791; Franchi et al., Nat. Immunol. 2012, 13, 325-332; Franchi et al., J. Immunol. 2014, 193, 4214-4222). The second step is activation, which will induce the oligomerization of NLRP3, followed by the assembly of NLRP3, apoptosis-associated speck-like protein (ASC) containing CARD and apoptotic proteinase procaspase-1 into an inflammasome complex. This triggers the conversion of pro-apoptotic proteinase-1 to pro-apoptotic proteinase-1, and the production and secretion of mature IL-1β and IL-18. (Kim et al., J. Inflamm. 2015, 12, 41; Ozaki et al., J. Inflamm. Res. 2015, 8, 15-27; Rabeony et al., Eur. J. Immunol. 2015, 45, 2847). During the assembly of the inflammasome complex, the oligomerization of NLRP3 triggers the nucleation of ASC, an event often referred to as the formation of "ASC SPECK" because a discrete point is found within the cell after staining and visualization of ASC using common immunocytochemical methods.

[0855] In vitro, the ability of compounds to inhibit NLRP3 inflammasome activation was determined by monitoring the formation of ASC-speckles after stimulation of human monocytic THP-1 cells. THP-1 cells (ATCC catalog #TIB-202) were maintained in complete growth medium containing Roswell Park Memorial Institute RPMI (ATCC catalog #30-2001), 10% heat-inactivated fetal bovine serum, 1X penicillin / streptomycin, and 0.05 mM 2-mercaptoethanol. At the beginning of the assay, undifferentiated THP-1 cells were plated in 384-well plates (poly-D-lysine coated Cell Carrier Ultra microplates, Perkin Elmer catalog #6057500) at a density of 20,000 cells / well in complete growth medium supplemented with 10 ng / ml phorbol 12-tetradecanoate 13-acetate (PMA; Sigma catalog #P8139), and then incubated overnight. The next day, the medium was replaced with assay medium [RPMI (Gibco catalog #11875-093), 0.01% bovine serum albumin (BSA)]. Compounds were serially diluted in DMSO and then 12.5 μg / ml Gramicidin (Enzo Lifescience, catalog #ALX-350-233-M005) was added. All incubations were performed at 37°C (5% CO2 / 95% air). After treatment with Gramicidin for 3 hours, cells were fixed with 4% paraformaldehyde and stored at 4°C until immunofluorescence staining.

[0856] Immunofluorescence staining: Anti-ASC antibody (MBL catalog #D086-3) was desalted and labeled with Alexa 488 antibody labeling kit (Thermo catalog #A20181) before use as described below. After fixation, the following steps were performed at room temperature. First, cells were permeabilized with phosphate buffered saline (PBS) containing 0.3% Triton X-100 for 15 minutes, followed by incubation in blocking buffer containing 5% goat serum, 0.03% tween-20, and 0.03% sodium azide in PBS for 1 hour. Cells were stained with a mixture of ASC-Alexa 488 antibody (1:200 dilution in blocking buffer) and nuclear stain DRAQ5 (1:5000 in blocking buffer, Thermo catalog #62251) in blocking buffer for 1 hour. Subsequently, after washing with PBS containing 0.3% Tween-20, each plate was imaged using the Opera Phenix High Throughput Screening System. The number of DRAQ5-positive cells containing ASC spots in each well was quantified.

[0857] Data analysis: E.C. 50The values ​​were calculated by standard curve fitting analysis using a program developed in-house with TIBCO Spotfire software.

[0858] The compounds of the invention inhibit NLRP3 inflammasome activation in the above bioassays with an EC of less than 5 micromolar 50 The specific EC values ​​of the compounds of Examples 1-57 in the above biological assays are 50 The values ​​are listed in Table I below.

[0859] Table I. Inhibition of NLRP3 inflammasome activation in the above bioassays Example EC 50 Value (nM)

[0860]

[0861]

[0862]

[0863] The scope of the claims should not be limited by the preferred embodiments set forth, but should be given the broadest interpretation consistent with the overall description.

[0864] Although the present invention has been described and illustrated with reference to certain specific embodiments thereof, it will be understood by those skilled in the art that various adjustments, changes, modifications, substitutions, deletions or additions may be made to the procedures and schemes without departing from the scope of the present invention. For example, due to the different responsiveness of mammals to the above-mentioned compounds of the present invention for the treatment of any indication, an effective dose other than the above-mentioned specific dose may be used. The specific pharmacological response observed may vary depending on the specific active compound selected or the presence or absence of a drug carrier and the type of formulation and mode of administration adopted, and such changes or differences in the expected results are contemplated according to the purposes and practice of the present invention.

Claims

1. A compound of structural formula I: or a pharmaceutically acceptable salt thereof, wherein T is independently selected from the following group: 1)CR 3 ,and 2)N， Provided that zero, one or two of T, U, V and W are N; U is independently selected from the following group: 1)CR 4 ,and 2)N； V is independently selected from the group consisting of: 1)CR 5 ,and 2)N； W is independently selected from the following group: 1)CR 6 ,and 2)N； R 1 Select from the following group: 1)-C 3-12 Cycloalkyl, 2) -C 3-12 Cycloalkenyl, and 3) -C 2-12 Cycloheteroalkyl, Where R 1 is unsubstituted or substituted with one to six residues selected from R a Substituents are substituted; R 2 Select from the following group: 1) aryl, and 2) heteroaryl, Where R 2 is unsubstituted or substituted with one to five b Substituents are substituted; R 3 Select from the following group: 1) Hydrogen, 2) OH, 3) CN, 4) CF3, 5) CF2H, 6) -C 1-6 alkyl, 7)-OC 1-6 alkyl, 8) Halogen, 9)-C 3-6 Cycloalkyl, 10) -C 2-6 Cycloheteroalkyl, 11) -C 1-6 Alkyl-OC 1-6 alkyl, 12)-(CH2) r C(O)R h , 13)-(CH2) r C(O)N(R i )2, 14)-(CH2) r N(R j )C(O)R h , 15)-(CH2) r N(R j )C(O)OR h , 16)-(CH2) r N(R j )C(O)N(R i )2, 17)-(CH2) r N(R j )C(O)N(R i )2, 18)-(CH2) r N(R j )S(O) m R h , 19)-(CH2) r N(R j )S(O) m N(R i )2, 20)-(CH2) r N(R j )S(O) m N(R i )2, and 21)-(CH2) r N(R i )2, Where R 3 is unsubstituted or substituted with one to five d Substituents are substituted; R 4 Select from the following group: 1) Hydrogen, 2) OH, 3) CN, 4) CF3, 5) CF2H, 6) -C 1-6 alkyl, 7)-OC 1-6 alkyl, 8) Halogen, 9)-C 3-6 Cycloalkyl, 10) -C 2-6 Cycloheteroalkyl, 11) -C 1-6 Alkyl-OC 1-6 alkyl, 12)-(CH2) s C(O)R h , 13)-(CH2) s C(O)N(R i )2, 14)-(CH2) s N(R j )C(O)R h , 15)-(CH2) s N(R j )C(O)OR h , 16)-(CH2) s N(R j )C(O)N(R i )2, 17)-(CH2) s N(R j )C(O)N(R i )2, 18)-(CH2) s N(R j )S(O) m R h , 19)-(CH2) s N(R j )S(O) m N(R i )2, 20)-(CH2) s N(R j )S(O) m N(R i )2, and 21)-(CH2) s N(R i )2, Where R 4 is unsubstituted or substituted with one to five e Substituents are substituted; R 5 Select from the following group: 1) Hydrogen, 2) OH, 3) CN, 4) CF3, 5) CF2H, 6) -C 1-6 alkyl, 7)-OC 1-6 alkyl, 8) Halogen, 9)-C 3-6 Cycloalkyl, 10) -C 2-6 Cycloheteroalkyl, 11) -C 1-6 Alkyl-OC 1-6 alkyl, 12)-(CH2) t C(O)R h , 13)-(CH2) t C(O)N(R i )2, 14)-(CH2) t N(R j )C(O)R h , 15)-(CH2) t N(R j )C(O)OR h , 16)-(CH2) t N(R j )C(O)N(R i )2, 17)-(CH2) t N(R j )C(O)N(R i )2, 18)-(CH2) t N(R j )S(O) m R h , 19)-(CH2) t N(R j )S(O) m N(R i )2, 20)-(CH2) t N(R j )S(O) m N(R i )2, and 21)-(CH2) t N(R i )2, Where R 5 is unsubstituted or substituted with one to five f Substituents are substituted; R 6 Select from the following group: 1) Hydrogen, 2) OH, 3) CN, 4) CF3, 5) CF2H, 6) -C 1-6 alkyl, 7)-OC 1-6 alkyl, 8) Halogen, 9)-C 3-6 Cycloalkyl, 10) -C 2-6 Cycloheteroalkyl, 11) -C 1-6 Alkyl-OC 1-6 alkyl, 12)-(CH2) u C(O)R h , 13)-(CH2) u C(O)N(R i )2, 14)-(CH2) u N(R j )C(O)R h , 15)-(CH2) u N(R j )C(O)OR h , 16)-(CH2) u N(R j )C(O)N(R i )2, 17)-(CH2) u N(R j )C(O)N(R i )2, 18)-(CH2) u N(R j )S(O) m R h , 19)-(CH2) u N(R j )S(O) m N(R i )2, 20)-(CH2) u N(R j )S(O) m N(R i )2, and 21)-(CH2) u N(R i )2, Where R 6 is unsubstituted or substituted with one to five g Substituents are substituted; Each R a Independently selected from the following group: 1) CN, 2) Oxo, 3) -OH, 4) Halogen, 5) -C 1-6 alkyl, 6)-OC 1-6 alkyl, 7)-C 2-6 Alkenyl, 8)-C 2-6 Alkynyl, 9)-C 3-6 Cycloalkyl, 10) -C 2-6 Cycloheteroalkyl, 11) aryl, 12) heteroaryl, 13)-C(O)C 1-6 alkyl, 14) -C 1-6 Alkyl-aryl, 15) -C 1-6 Alkyl-heteroaryl, 16) -C 1-6 Alkyl-C 3-6 Cycloalkyl, 17) -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, 18) -C 2-6 Alkenyl-C 3-6 Cycloalkyl, 19) -C 2-6 Alkenyl-C 2-6 Cycloheteroalkyl, 20)-C 2-6 Alkenyl-aryl, 21)-C 2-6 alkenyl-heteroaryl, 22)-C 2-6 Alkynyl-C 3-6 Cycloalkyl, 23)-C 2-6 Alkynyl C 2-6 Cycloheteroalkyl, 24)-C 2-6 Alkynyl-aryl, 25)-C 2-6 Alkynyl-heteroaryl, 26)-(CH2) p -OC 1-6 alkyl, 27)-(CH2) p -OC 2-6 Alkenyl, 28)-(CH2) p -OC 2-6 Alkynyl, 29)-(CH2) p -OC 3-6 Cycloalkyl, 30)-(CH2) p -OC 2-6 Cycloheteroalkyl, 31)-(CH2) p -O-aryl, 32)-(CH2) p -O-heteroaryl, 33)-OC 1-6 Alkyl-C 3-6 Cycloalkyl, 34)-OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, 35)-OC 1-6 Alkyl-aryl, 36)-OC 1-6 Alkyl-heteroaryl, 37)-(CH2) p -S(O) r R k , 38)-(CH2) p -S(O)N(R L )2, and 39)-(CH2) p -N(R L )2, where each R a is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 Substitution of alkyl groups; Each R b Independently selected from the following group: 1) CN, 2) -OH, 3) Oxo, 4) Halogen, 5) -C 1-6 alkyl, 6)-OC 1-6 alkyl, 7)-C 3-6 Cycloalkyl, 8)-C 2-6 Cycloheteroalkyl, 9) aryl, 10) heteroaryl, 11) -C 1-6 Alkyl-aryl, 12) -C 1-6 Alkyl-heteroaryl, 13) -C 1-6 Alkyl-C 3-6 Cycloalkyl, 14) -C 1-6 Alkyl-C 2-6 Cycloheteroalkyl, 15)-(CH2) q -OC 1-6 alkyl, 16)-(CH2) q -OC 3-6 Cycloalkyl, 17)-(CH2) q -OC 2-6 Cycloheteroalkyl, 18)-(CH2) q -O-aryl, 19)-(CH2) q -O-heteroaryl, 20)-OC 1-6 Alkyl-C 3-6 Cycloalkyl, 21)-OC 1-6 Alkyl-C 2-6 Cycloheteroalkyl, 22)-OC 1-6 Alkyl-aryl, 23)-OC 1-6 Alkyl-heteroaryl, 24)-(CH2) q -S(O) r R m , 25)-(CH2) q N(R n )2, 26)-C(O)R o ,and 27)-C(O)NR n , Among them, each R b is unsubstituted or substituted with one to six substituted radicals selected from halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 The substituents of the alkyl group are substituted; each R d Independently selected from the following group: 1) CF3, 2) halogen, and 3) -C 1-6 alkyl, wherein the alkyl group is unsubstituted or substituted with one to three substituted alkyl groups selected from CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups; Each R e Independently selected from the following group: 1) CF3, 2) halogen, and 3) -C 1-6 alkyl, wherein the alkyl group is unsubstituted or substituted with one to three substituted alkyl groups selected from CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups; Each R f Independently selected from the following group: 1) CF3, 2) halogen, and 3) -C 1-6 alkyl, wherein the alkyl group is unsubstituted or substituted with one to three substituted alkyl groups selected from CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups; Each R g Independently selected from the following group: 1) CF3, 2) halogen, and 3) -C 1-6 alkyl, wherein the alkyl group is unsubstituted or substituted with one to three substituted alkyl groups selected from CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups; Each R h Independently selected from the following group: 1) Hydrogen, 2) -C 1-6 alkyl, 3) -C 3-6 Cycloalkyl, and 4) -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituted alkyl radicals selected from -CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups; Each R i Independently selected from the following group: 1) Hydrogen, 2) -C 1-6 alkyl, 3) -C 3-6 Cycloalkyl, and 4) -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituted alkyl radicals selected from CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups; Each R j Independently selected from the following group: 1) Hydrogen, 2) -C 1-6 alkyl, 3) -C 3-6 Cycloalkyl, and 4) -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituted alkyl radicals selected from CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups; Each R k Independently selected from the following group: 1)-C 1-6 alkyl, 2) -C 3-6 Cycloalkyl, and 3) -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituted alkyl radicals selected from -CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups; Each R L Independently selected from the following group: 1) Hydrogen, 2) -C 1-6 alkyl, 3) -C 3-6 Cycloalkyl, and 4) -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituted alkyl radicals selected from -CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups; Each R m Independently for: 1)-C 1-6 alkyl, 2) -C 3-6 Cycloalkyl, and 3) -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituted alkyl radicals selected from -CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups; Each R n Independently selected from the following group: 1) Hydrogen, 2) C 1-6 alkyl, 3) -C 3-6 Cycloalkyl, and 4) -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituted alkyl radicals selected from -CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups; Each R o Independently selected from the following group: 1) OH, 2) -C 1-6 alkyl, 3) -C 3-6 Cycloalkyl, and 4) -C 2-6 Cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to three substituted alkyl radicals selected from -CF3, halogen, OH and -OC 1-6 Substitution of alkyl groups; r is 0, 1, 2, 3, 4, 5 or 6; s is 0, 1, 2, 3, 4, 5, or 6; t is 0, 1, 2, 3, 4, 5, or 6; u is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5 or 6; and q is 0, 1, 2, 3, 4, 5 or 6.

2. The compound according to claim 1, wherein W is CR 6 ; or a pharmaceutically acceptable salt thereof.

3. The compound as claimed in claim 1, wherein R 1 C 2-12 Cycloheteroalkyl, wherein R 1 is unsubstituted or substituted with one to six substituted a or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein R 1 Select from the following group: 1) Morpholine, 2) Thiomorpholine, 3) piperidine, 4) piperazine, 5) pyrrolidine, 6) Tetrahydropyran, 7) octahydro-1H-pyrrolo[2,3-c]pyridine, 8) 3-azabicyclo[3.1.0]hexane, 9) 5-azaspiro[2.4]heptane, 10) 1-oxa-7-azaspiro[4.4]nonane, 11) 1-oxa-8-azaspiro[4.5]decane, 12) 3-oxa-1,8-diazaspiro[4.5]decane, 13) 2,8-diazaspiro[4.5]decane, 14) 1-oxa-3,8-diazaspiro[4.5]decane, 15) 2-oxa-8-azaspiro[4.5]decane, 16) 1,8-diazaspiro[4.5]decane, and 17) 1-oxa-4,9-diazaspiro[5.5]undecane, Where R 1 is unsubstituted or substituted with one to six residues selected from R a Substituents are substituted; or a pharmaceutically acceptable salt thereof.

5. The compound as claimed in claim 1, wherein R 2 is a heteroaryl group, wherein the heteroaryl group is unsubstituted or substituted with one to five residues selected from R b or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein R 2 is aryl, wherein aryl is unsubstituted or substituted with one to five substituted b Substituents are substituted; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein R 3 Select from the following group: 1) Hydrogen, and 2) -C 1-6 alkyl, Where R 3 is unsubstituted or substituted with one to five d Substituents are substituted; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, wherein R 3 is hydrogen; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, wherein R 4 Select from the following group: 1) Hydrogen, 2) OH, 3) CN, 4) CF3, 5) CF2H, 6) -C 1-6 alkyl, 7)-OC 1-6 alkyl, 8) halogen, and 9)-C 1-6 Alkyl-OC 1-6 alkyl, Where R 4 is unsubstituted or substituted with one to five e or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, wherein R 4 Select from the following group: 1) Hydrogen, and 2) -C 1-6 alkyl, Where R 4 is unsubstituted or substituted with one to five e or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein R 5 Select from the following group: 1) Hydrogen, 2) OH, 3) CN, 4) CF3, 5) CF2H, 6) -C 1-6 alkyl, 7)-OC 1-6 alkyl, 8) halogen, and 9)-C 1-6 Alkyl-OC 1-6 alkyl, Where R 5 is unsubstituted or substituted with one to five f Substituents are substituted; or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, wherein R 5 Select from the following group: 1) Hydrogen, 2) -C 1-6 Alkyl, and 3) Halogen, Where R 5 is unsubstituted or substituted with one to five f Substituents are substituted; or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, wherein R 6 Select from the following group: 1) Hydrogen, 2) -C 1-6 Alkyl, and 3)-OC 1-6 alkyl, Where R 6 is unsubstituted or substituted with one to five g Substituents are substituted; or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, wherein R 6 is hydrogen; or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, wherein R 1 C 2-12 Cycloheteroalkyl, wherein R 1 is unsubstituted or substituted with one to six residues selected from R a Substituents are substituted; R 2 is a heteroaryl group, wherein R 2 is unsubstituted or substituted with one to five b Substituents substituted; R 3 Select from the following group: 1) Hydrogen, and 2) -C 1-6 alkyl, Where R 3 is unsubstituted or substituted with one to five d Substituents are substituted; R 4 Select from the following group: 1) Hydrogen, 2) OH, 3) CN, 4) CF3, 5) CF2H, 6) -C 1-6 alkyl, 7)-OC 1-6 alkyl, 8) halogen, and 9)-C 1-6 Alkyl-OC 1-6 alkyl, Where R 4 is unsubstituted or substituted with one to five e Substituents are substituted; R 5 Select from the following group: 1) Hydrogen, 2) OH, 3) CN, 4) CF3, 5) CF2H, 6) -C 1-6 alkyl, 7)-OC 1-6 alkyl, 8) halogen, and 9)-C 1-6 Alkyl-OC 1-6 alkyl, Where R 5 is unsubstituted or substituted with one to five f substituted by a substituent; and R 6 Select from the following group: 1) Hydrogen, 2) -C 1-6 Alkyl, and 3)-OC 1-6 alkyl, Where R 6 is unsubstituted or substituted with one to five g or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, wherein W is CR 6 ; R 1 Independently selected from the following group: 1) Morpholine, 2) Thiomorpholine, 3) piperidine, 4) piperazine, 5) pyrrolidine, 6) Tetrahydropyran, 7) octahydro-1H-pyrrolo[2,3-c]pyridine, 8) 3-azabicyclo[3.1.0]hexane, 9) 5-azaspiro[2.4]heptane, 10) 1-oxa-7-azaspiro[4.4]nonane, 11) 1-oxa-8-azaspiro[4.5]decane, 12) 3-oxa-1,8-diazaspiro[4.5]decane, 13) 2,8-diazaspiro[4.5]decane, 14) 1-oxa-3,8-diazaspiro[4.5]decane, 15) 2-oxa-8-azaspiro[4.5]decane, 16) 1,8-diazaspiro[4.5]decane, and 17) 1-oxa-4,9-diazaspiro[5.5]undecane, Where R 1 is unsubstituted or substituted with one to six substituted a Substituents are substituted; R 2 is aryl, wherein aryl is unsubstituted or substituted with one to five substituted b Substituents are substituted; R 3 is hydrogen; R 4 Select from the following group: 1) Hydrogen, and 2) -C 1-6 alkyl, Where R 4 is unsubstituted or substituted with one to five e Substituents are substituted; R 5 Select from the following group: 1) Hydrogen, 2) -C 1-6 Alkyl, and 3) Halogen, Where R 5 is unsubstituted or substituted with one to five f substituted with a substituent; and R 6 is hydrogen; or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, selected from: 1)(S)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrolidin-3-ol; 2)(S)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]-pyridazin-4-yl)-3-methylpyrrolidin-3-ol; 3) (cis)-4-(5-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-2,6-dimethylmorpholine; 4) 2-(4-((cis)-2,6-dimethylmorpholinyl)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5) 2-(1-((cis)-2,6-dimethylmorpholinyl)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol; 6) 2-(5-((cis)-2,6-dimethylmorpholinyl)pyrido[2,3-d]pyridazin-8-yl)-5-(trifluoromethyl)phenol; 7) (cis)-4-(1-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-2,6-dimethylmorpholine; 8) 2-(8-((cis)-2,6-dimethylmorpholinyl)pyridazino[4,5-c]pyridazin-5-yl)-5-(trifluoromethyl)-phenol; 9) 2-(4-((cis)-2,6-dimethylmorpholinyl)pyridazino[4,5-d]pyridazin-1-yl)-5-(trifluoromethyl)-phenol; 10) (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methylpyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidin-3-ol; 11) (cis)-4-(1-(benzofuran-5-yl)pyrido[3,4-d]pyridazin-4-yl)-2,6-dimethylmorpholine; 12) (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidin-3-ol; 13) (3S,4s,5R)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazino[4,5-d]pyridazin-1-yl)-3,4,5-trimethylpiperidin-4-ol; 14) 2-(4-((cis)-2,6-dimethylmorpholinyl)-5-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol; 15) 2-(4-((cis)-2,6-dimethylmorpholinyl)-8-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol; 16) (3S,4s,5R)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-3,4,5-trimethylpiperidin-4-ol; 17) (3S,4s,5R)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3,4,5-trimethylpiperidin-4-ol; 18) (3S,4r,5R)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-3,5-dimethylpiperidin-4-ol; 19) (3S,4r,5R)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethylpiperidin-4-ol; 20) 2-(4-((cis)-2,6-dimethylmorpholinyl)-6-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol; 21) 2-(4-((cis)-2,6-dimethylmorpholinyl)-7-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol; 22)(S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-3-methylpyrrolidin-3-ol; 23) 2-(8-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 24)(3S,4s,5R)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3,4,5-trimethylpiperidin-4-ol; 25) 8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-oxa-1,8-diazaspiro[4.5]decan-2-one; 26) (cis)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-2,6-dimethylthiomorpholine 1,1-dioxide; 27) (R)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-(trifluoromethyl)pyrrolidin-3-ol; 28) (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-(trifluoromethyl)pyrrolidin-3-ol; 29) (R)-3-(difluoromethyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol; 30)(S)-3-(difluoromethyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol; 31) (R)-2-(8-(1-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 32) (S)-2-(8-(1-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 33) 2-(8-(1-oxa-8-azaspiro[4.5]dec-8-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 34) 2-(8-(2-oxa-8-azaspiro[4.5]dec-8-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 35) 9-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one; 36) 2-(8-((cis)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 37) 1-(8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1,8-diazaspiro[4.5]dec-1-yl)ethan-1-one; 38) 1-(8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-2,8-diazaspiro[4.5]dec-2-yl)ethan-1-one; 39) 8-(5-(2-hydroxy-4-(trifluoro-methyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 40) 2-(8-(4,4-dimethyl-1-oxa-8-azaspiro[4.5]dec-8-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 41)(R)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-phenylpyrrolidin-3-ol; 42)(S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-phenylpyrrolidin-3-ol; 43) 8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-methyl-1,8-diazaspiro[4.5]decan-2-one; 44) 8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 45) 2-(8-(6,6-difluoro-3-azabicyclo[3.1.0]hex-3-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 46) 8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-oxa-8-azaspiro[4.5]decan-2-one; 47) (R)-4,4-difluoro-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol; 48) (S)-4,4-difluoro-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol; 49) (R)-5-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-5-azaspiro[2.4]heptan-7-ol; 50)(S)-5-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-5-azaspiro[2.4]heptan-7-ol; 51)(R)-3-cyclopropyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol; 52)(S)-3-cyclopropyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol; 53) (R)-3-((dimethylamino)methyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido-[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol; 54)(S)-3-((dimethylamino)methyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido-[2,3-d]pyridazin-8-yl)pyrrolidin-3-ol; 55) (R)-3-ethyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-pyrrolidin-3-ol; 56) (S)-3-ethyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-pyrrolidin-3-ol; 57) (R)-2-(8-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 58) (S)-2-(8-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 59) (R)-2-(8-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 60)(S)-2-(8-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 61) 2-(8-((2R,6R)-2-(hydroxymethyl)-6-methylmorpholinyl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 62) 2-(8-((2S,6S)-2-(hydroxymethyl)-6-methylmorpholinyl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 63) 2-(8-((2S,6S)-2-(hydroxymethyl)-6-methylmorpholinyl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 64) 2-(8-((2R,6R)-2-(hydroxymethyl)-6-methylmorpholinyl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 65) 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-methyl-4(trifluoromethyl)-phenyl)phthalazine; 66)(2R,4s,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol; 67) (2R,4r,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol; 68) (S)-1-(2-(difluoromethyl)-5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidin-3-ol; and 69) (S)-1-(3-(difluoromethyl)-5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidin-3-ol; or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, selected from: 1)(S)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrolidin-3-ol; 2)(S)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]-pyridazin-4-yl)-3-methylpyrrolidin-3-ol; 3) 2-(4-((cis)-2,6-dimethylmorpholinyl)pyridazino[4,5-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 4) (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-3-methylpyrrolidin-3-ol; 5) 2-(8-((3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 6)(2R,4s,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol; and 7)(2R,4r,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-2,6-dimethyltetrahydro-2H-pyran-4-ol; or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament useful for treating a disorder, condition or disease responsive to inhibition of NLRP3 in a mammal in need thereof.

21. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating, preventing or controlling inflammatory disorders, fibrotic disorders, cardiovascular disorders, metabolic disorders and neurodegenerative disorders.

22. The use according to claim 21, wherein the disorder is an inflammatory disorder.

23. The use of claim 22, wherein the inflammatory disorder is selected from the group consisting of an autoimmune disorder, an autoinflammatory disorder, an inflammatory joint disorder, an inflammatory skin disorder, and a neuroinflammatory disorder.

24. The use according to claim 21, wherein the disease is selected from the group consisting of atherosclerosis, non-alcoholic steatohepatitis, Alzheimer's disease and Parkinson's disease.

25. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in therapy.

26. A method of treating or preventing a disorder, condition or disease responsive to inhibition of NLRP3 in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, wherein the disorder is selected from the group consisting of an inflammatory disorder, a fibrotic disorder, a cardiovascular disorder, a metabolic disorder, and a neurodegenerative disorder.

28. The method of claim 27, wherein the disorder is an inflammatory disorder.

29. The method of claim 27, wherein the inflammatory disorder is selected from the group consisting of an autoimmune disorder, an autoinflammatory disorder, an inflammatory joint disorder, an inflammatory skin disorder, and a neuroinflammatory disorder.

30. The method of claim 26, wherein the disorder is selected from the group consisting of atherosclerosis, nonalcoholic steatohepatitis, Alzheimer's disease, and Parkinson's disease.

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