Phthalazine derivatives useful as inhibitors of nod-like receptor protein 3

Abstract

To provide an NLRP3 inhibitor that is effective in treating and preventing diseases, disorders, and conditions mediated by the formation and proliferation of the NLRP3 inflammasome.SOLUTION: A compound of the formula (I) is provided, where T is independently selected from the group: 1) CR3, and 2) N; provided that zero, one or two of T, U, V and W are N; U is independently selected from the group: 1) CR4, and 2) N; V is independently selected from the group: 1) CR5, and 2) N; W is independently selected from the group: 1) CR6, and 2) N; R1 is selected from -C3-12 cycloalkyl, -C3-12 cycloalkenyl, and -C2-12 heterocyclic alkyl, and R2 is selected from aryl and heteroaryl.SELECTED DRAWING: None

Description

[Background technology]

[0001] Inflammasomes act as central signaling hubs in the innate immune system. They are multiprotein complexes that assemble after activation of intracellular pattern recognition receptors (PRRs) by various pathogen-associated molecular 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 pyrin- and HIN200 domain-containing proteins (Van Opdenbosch N and Lamkanfi M. Immunity, 2019 Jun 18;50(6):1352-1364). Inflammasome activation triggers a cascade of events that release proinflammatory cytokines and promote an inflammatory form of cell death called pyroptosis, which is induced by gasdermin activation. Pyroptosis is a unique form of inflammatory cell death that triggers the release of not only cytokines but also other intracellular components that promote a broader immune response of both the innate and adaptive immune systems. Thus, inflammasome activation is a key regulator of the inflammatory cascade.

[0002] The NOD-like receptor protein 3 (NLRP3) inflammasome is the most well-studied of all inflammasomes. NLRP3 can be activated by many stimuli, including environmental crystals, pollutants, host-derived DAMPs, and protein aggregates (Tartey S and Kanneganti TD. Immunology, 2019 Apr;l56(4):329-338). Danger-associated molecular patterns associated with NLRP3 include uric acid and cholesterol crystals that cause gout and atherosclerosis, neurotoxic amyloid P fibrils in Alzheimer's disease, and asbestos particles that cause mesothelioma (Kelley et al., Int J Mol Sci, 2019 Jul 6;20(13)). In addition, NLRP3 is activated by infectious agents such as Vibrio cholerae, fungal pathogens such as Aspergillus Jumigatus and Candida albicans, adenoviruses, 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 mechanism of NLRP3 activation in humans remains unclear. It has been suggested that the NLRP3 inflammasome requires regulation at both transcriptional and post-transcriptional levels (Yang Yet al., Cell Death Dis, 2019 Feb 12;10(2): 128). NOD-like receptor protein 3 (NLRP3) is a protein-coding gene that encodes a protein consisting of an N-terminal pyrin domain, a nucleotide-binding site domain (NBD), and a C-terminal leucine-rich repeat (LRR) motif (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 adaptor proteins, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and the protease caspase-1 to form the NLRP3 inflammasome. Upon activation, procaspase-1 undergoes autoproteolysis and cleaves gasdermin D (GSDMD) to produce the N-terminal Gsdmd molecule, which leads to the formation of pores in the plasma membrane and a lytic form of cell death called pyroptosis. Alternatively, caspase-1 cleaves the inflammatory cytokines pro-IL-IΒ and pro-IL-18 to release their bioactive forms (Kelley et al., 2019 - see above). NLRP3 inflammasome activation leads to the release of the inflammatory cytokines IL-1β (interleukin-1β) and IL-18 (interleukin-18), which, when dysregulated, can cause a number of diseases.

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

[0006] Cardiovascular and metabolic diseases such as atherosclerosis, type I and type II diabetes, and diabetic complications such as nephropathy and retinopathy, peripheral arterial disease, acute heart failure and hypertension have been linked to 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;l5(4):203-214). Skin diseases associated with NLRP3 include wound healing and scar formation; inflammatory skin diseases such as acne, atopic dermatitis, hidradenitis suppurativa, and psoriasis (Kelly et al., Br J Dermatol, 2015 Dec;l 73(6)). NLRP3 inflammasome activity has also been linked to respiratory conditions such as asthma, sarcoidosis, acute respiratory distress syndrome, and severe acute respiratory syndrome (SARS) (Nieto-Torres et al., Virology, 2015 Nov;485:330-9)); and ocular diseases such as 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 syndromes, myelofibrosis, lung cancer, and colon cancer (Ridker et al., Lancet, 2017 Oct 21;390(10105): 1833-1842; Derangere et al., Cell Death Differ. 2014 Dec;21(12): 1914-24; Basiorka et al., Lancet Haematol, 2018 Sep;5(9): e393-e402, Zhang et al., Hum Immunol, 2018 Jan;79(1):57-62).

[0007] Immune and inflammatory diseases are typically difficult to diagnose or treat efficiently and effectively. Most treatments involve treating symptoms, slowing disease progression, lifestyle changes, and / or surgery. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Van Opdenbosch N and Lamkanfi M. Immunity, 2019 Jun 18;50(6):1352-1364 [Non-Patent Document 2] Tartey S and Kanneganti TD. Immunology, 2019 Apr;l56(4):329-338 [Non-Patent Document 3] Kelley et al., Int J Mol Sci, 2019 Jul 6;20(13) [Non-Patent Document 4] Fung et al. Emerg Microbes Infect, 2020 Mar 14;9(1):558-570 [Non-Patent Document 5] Yang Yet al., Cell Death Dis, 2019 Feb 12;10(2): 128 [Non-Patent Document 6] Inoue et al., Immunology, 2013, 139, 11-18; Sharif et al., Nature, 2019 Jun; 570(7761):338-343 [Non-Patent Document 7] Miyamae T. Paediatr Drugs, 2012 Apr 1, 14(2): 109-17 [Non-Patent Document 8] Szabo G and Petrasek J. Nat Rev Gastroenterol Hepatol, 2015 Jul;12(7):387-400 [Non-Patent Document 9] Zhen Y and Zhang H. Front Immunol, 2019 Feb 28;10:276

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[0009] There remains a need for NLRP3 inhibitors that provide new treatments for diseases and disorders associated with NLRP3 inflammasome activation and dysregulation.The compounds of the present invention are useful for treating and preventing diseases, disorders and conditions mediated by the formation and proliferation of the NLRP3 inflammasome.

[0010] NLRP3 inhibitors have been reported 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. NLRP3 inhibitors have been described in several patent applications, such as WO2021 / 239885, WO2021 / 209552, WO2021 / 209539, WO2021 / 193897, WO2020 / 018975, WO2020 / 037116, WO2020 / 021447, WO2020 / 010143, WO2019 / 079119, WO2019 / 0166621, WO2019 / 121691, US11,319,319, and US2020 / 0361898. [Means for solving the problem]

[0011] The present invention relates to novel compounds of structural formula I below and pharma- ceutically acceptable salts thereof: [ka]

[0012] The compounds of structural formula I, and embodiments thereof, are inhibitors of NOD-like receptor protein 3 (NLRP3) and may be useful in the treatment and prevention of NLRP3-mediated diseases, disorders and conditions, including, but not limited to, gout, pseudogout (chondrocalcinosis), cryopyrin-associated periodic syndromes (CAPS), NASH, fibrosis, heart failure, idiopathic pericarditis, atopic dermatitis, inflammatory bowel disease, Alzheimer's disease, Parkinson's disease and traumatic brain injury.

[0013] The present invention also relates to pharmaceutical compositions comprising a compound of the present invention and a pharma- ceutically acceptable carrier.

[0014] The present invention also relates to methods for treating, managing, preventing, mitigating, ameliorating, suppressing or controlling disorders, diseases and conditions that may respond to inhibition of the NLRP3 receptor in a subject in need of such treatment by administering the compounds and pharmaceutical compositions of the present invention.

[0015] The present invention also relates to the use of the compounds of the present invention for the manufacture of a medicament useful for the treatment of diseases, disorders and conditions that may respond to inhibition of the NLRP3 receptor.

[0016] The present invention also relates to treating or preventing diseases, disorders and conditions by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent that may be useful in treating these diseases, disorders and conditions. The present invention further relates to methods of making the compounds of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The present invention relates to novel compounds of structural formula I: [ka] During the ceremony T independently represents the group: 1) CR 3 , and 2) N Selected from; provided that 0, 1 or 2 of T, U, V and W are N; U is an independent group: 1) CR 4 , and 2) N Selected from; V independently represents the group: 1) CR 5 , and 2) N Selected from; W is independently the group: 1) CR 6 , and 2) N Selected from; R 1 is a group: 1)-C 3-12 Cycloalkyl, 2)-C 3-12 Cycloalkenyl, and 3)-C 2-12 Heterocyclic alkyl is selected from R 1 is either unsubstituted or R a and is substituted by 1 to 6 substituents selected from; R 2 is a group: 1) aryl, and 2) Heteroaryl is selected from R 2 is either unsubstituted or R b and is substituted by 1 to 5 substituents selected from; R 3 is a 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 Heterocyclic alkyl, 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 is selected from R 3 is either unsubstituted or R d and is substituted by 1 to 5 substituents selected from; R 4 is a 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 Heterocyclic alkyl, 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 is selected from R 4 is either unsubstituted or R e and is substituted by 1 to 5 substituents selected from; R 5 is a 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 Heterocyclic alkyl, 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(Ri )2, 20)-(CH2) t N(R j )S(O) m N(R i )2, and 21)-(CH2) t N(R i )2 is selected from R 5 is either unsubstituted or R f and is substituted by 1 to 5 substituents selected from; R 6 is a 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 Heterocyclic alkyl, 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(Ri )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 is selected from R 6 is either unsubstituted or R g and is substituted by 1 to 5 substituents selected from; Each R a are independently grouped as: 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 Heterocyclic alkyl, 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 Heterocyclic alkyl, 18)-C 2-6 Alkenyl-C 3-6 Cycloalkyl, 19)-C 2-6 Alkenyl-C 2-6 Heterocyclic alkyl, 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 Heterocyclic alkyl, 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 Heterocyclic alkyl, 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 Heterocyclic alkyl, 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 is selected from Each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 substituted by 1 to 6 substituents selected from alkyl; Each R b are independently grouped as: 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 Heterocyclic alkyl, 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 Heterocyclic alkyl, 15)-(CH2) q -OC 1-6 Alkyl, 16)-(CH2) q -OC 3-6 Cycloalkyl, 17)-(CH2) q -OC 2-6 Heterocyclic alkyl, 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 Heterocyclic alkyl, 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 is selected from Each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 substituted by 1 to 6 substituents selected from alkyl; Each R d are independently grouped as: 1) CF3, 2) halogens, and 3)-C 1-6 Alkyl is selected from Alkyl is unsubstituted or substituted with CF3, halogen, OH and -OC. 1-6 substituted by 1 to 3 substituents selected from alkyl; Each R e are independently grouped as: 1) CF3, 2) halogens, and 3)-C 1-6 Alkyl is selected from Alkyl is unsubstituted or substituted with CF3, halogen, OH and -OC. 1-6 substituted by 1 to 3 substituents selected from alkyl; Each R f are independently grouped as: 1) CF3, 2) halogens, and 3)-C 1-6 Alkyl, is selected from Alkyl is unsubstituted or substituted with CF3, halogen, OH and -OC. 1-6 substituted by 1 to 3 substituents selected from alkyl; Each R g are independently grouped as: 1) CF3, 2) halogens, and 3)-C 1-6 Alkyl, is selected from Alkyl is unsubstituted or substituted with CF3, halogen, OH and -OC. 1-6 substituted by 1 to 3 substituents selected from alkyl; Each R h are independently grouped as: 1) Hydrogen, 2)-C 1-6 Alkyl, 3)-C 3-6 Cycloalkyl, and 4)-C 2-6 Heterocyclic alkyl is selected from Alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 substituted by 1 to 3 substituents selected from alkyl; Each R i are independently grouped as: 1) Hydrogen, 2)-C 1-6 Alkyl, 3)-C 3-6 Cycloalkyl, and 4)-C 2-6 Heterocyclic alkyl is selected from Alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with CF3, halogen, OH and -OC. 1-6 substituted by 1 to 3 substituents selected from alkyl; Each R j are independently grouped as: 1) Hydrogen, 2)-C 1-6 Alkyl, 3)-C 3-6 Cycloalkyl, and 4)-C 2-6 Heterocyclic alkyl is selected from Alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with CF3, halogen, OH and -OC. 1-6 substituted by 1 to 3 substituents selected from alkyl; Each R k are independently grouped as: 1)-C 1-6 Alkyl, 2)-C 3-6 Cycloalkyl, and 3)-C 2-6 Heterocyclic alkyl is selected from Alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with -CF3, halogen, OH, and -OC. 1-6 substituted by 1 to 3 substituents selected from alkyl; Each R L are independently grouped as: 1) Hydrogen, 2)-C 1-6 Alkyl, 3)-C 3-6 Cycloalkyl, and 4)-C 2-6 Heterocyclic alkyl is selected from Alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with -CF3, halogen, OH, and -OC. 1-6substituted by 1 to 3 substituents selected from alkyl; Each R m are independently grouped as: 1)-C 1-6 Alkyl, 2)-C 3-6 Cycloalkyl, and 3)-C 2-6 Heterocyclic alkyl Selected from; Alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 substituted by 1 to 3 substituents selected from alkyl; Each R n are independently grouped as: 1) Hydrogen, 2) C 1-6 Alkyl, 3)-C 3-6 Cycloalkyl, and 4)-C 2-6 Heterocyclic alkyl is selected from Alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with -CF3, halogen, OH, and -OC. 1-6 substituted by 1 to 3 substituents selected from alkyl; Each R o are independently grouped as: 1) OH, 2)-C 1-6 Alkyl, 3)-C 3-6 Cycloalkyl, and 4)-C 2-6 Heterocyclic alkyl is selected from Alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 substituted by 1 to 3 substituents selected from alkyl; 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; q is 0, 1, 2, 3, 4, 5 or 6.

[0018] The present invention has many embodiments, which are summarized below: The present invention includes the compounds shown, including the individual diastereomers, enantiomers and epimers of the compounds, as well as mixtures of diastereomers and / or enantiomers thereof, including racemic mixtures.

[0019] In one embodiment of the invention, T is independently CR 3 and N, with the proviso that 0, 1 or 2 of T, U, V and W are N. In another embodiment of the invention, T is selected from the group of CR 3 with the proviso that 0, 1 or 2 of T, U, V and W are N. In another embodiment of the invention, T is CR 3 In another embodiment of the invention, T is N, with the proviso that 0, 1 or 2 of U, V and W are N. In another embodiment of the invention, T is N.

[0020] In another embodiment of the present invention, T is independently selected from the group: CR 3 and N, with the proviso that one or two of T, U, V and W is N.

[0021] In another embodiment of the invention, U is selected from the group: CR 4 and N.

[0022] In another embodiment of the invention, U is CR 4 In another embodiment of the invention, U is N.

[0023] In another embodiment of the invention, V is selected from the group: CR 5 and N.

[0024] In another embodiment of the invention, V is CR5 In another embodiment of the invention, V is N.

[0025] In another embodiment of the invention, W is selected from the group: CR 6 and N. In another embodiment of the invention, W is selected from CR 6 In another embodiment of the invention, W is N.

[0026] In another embodiment of the invention, T is CR 3 and U is CR 4 and V is CR 5 ;W is CR 6 In another embodiment of the invention, T is N; U is CR 4 and V is CR 5 and W is CR 6 In another embodiment of the invention, T is CR 3 and U is CR 4 V is N; W is CR 6 In another embodiment of the invention, T is CR 3 ;U is CR 4 and V is CR 5 and W is N. In another embodiment of the invention, T and U are N; V is CR 5 ;W is CR 6 In another embodiment of the invention, T and V are N; U is CR 4 ;W is CR 6 In another embodiment of the invention, T and W are N; U is CR 4 and V is CR 5 In another embodiment of the invention, U and V are N; T is CR 3 ;W is CR 6 In another embodiment of the invention, U and W are N; T is CR 3 and V is CR 5 In another embodiment of the invention, V and W are N; T is CR 3 ;U is CR 4 In another embodiment of the invention, T is CR3 ;U is N;V is CR 5 ;W is CR 6 It is.

[0027] In another embodiment of the present invention, R 1 Group:-C 3-12 Cycloalkyl, -C 3-12 Cycloalkenyl, and -C 2-12 heterocyclic alkyl; R 1 is either unsubstituted or R a In one class of this embodiment, R 1 is either unsubstituted or R a In another class of this embodiment, R 1 is either unsubstituted or R a It is substituted with 1 to 4 substituents selected from:

[0028] In another embodiment of the present invention, R 1 -C 3-12 cycloalkenyl, R 1 is either unsubstituted or R a In one class of this embodiment, R 1 is either unsubstituted or R a In another class of this embodiment, R 1 is either unsubstituted or R a It is substituted with 1 to 4 substituents selected from:

[0029] In another embodiment of the present invention, R 1 Group:-C 3-12 Cycloalkyl and -C 2-12 heterocyclic alkyl; R 1 is either unsubstituted or R a In one class of this embodiment, R 1is either unsubstituted or R a In another class of this embodiment, R 1 is either unsubstituted or R a It is substituted with 1 to 4 substituents selected from:

[0030] In another embodiment of the present invention, R 1 -C 3-12 cycloalkyl, R 1 is either unsubstituted or R a In one class of this embodiment, R 1 is either unsubstituted or R a In another class of this embodiment, R 1 is either unsubstituted or R a It is substituted with 1 to 4 substituents selected from:

[0031] In another embodiment of the present invention, R 1 is C 2-12 Heterocyclic alkyl, R 1 is either unsubstituted or R a In one class of this embodiment, R 1 is either unsubstituted or R a In another class of this embodiment, R 1 is either unsubstituted or R a It is substituted with 1 to 4 substituents selected from:

[0032] In another embodiment, R 1is selected from the group: 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; R 1 is either unsubstituted or R a In one class of this embodiment, R 1 is either unsubstituted or R a In another class of this embodiment, R 1 is either unsubstituted or R a It is substituted with 1 to 4 substituents selected from:

[0033] In another embodiment, R 1 is selected from the group: 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; R 1 is either unsubstituted or R a In one class of this embodiment, R 1 is either unsubstituted or Ra It is substituted by 1 to 5 substituents selected from:

[0034] In another class of this embodiment, R 1 is either unsubstituted or R a It is substituted with 1 to 4 substituents selected from:

[0035] In another embodiment of the present invention, R 1 is selected from the group: morpholine, piperidine, pyrrolidine, tetrahydropyran, octahydro-1H-pyrrolo[2,3-c]pyridine; R 1 is either unsubstituted or R a In one class of this embodiment, R 1 is either unsubstituted or R a In another class of this embodiment, R 1 is either unsubstituted or R a It is substituted with 1 to 4 substituents selected from:

[0036] In another embodiment of the present invention, R 1 is selected from the group: morpholine, pyrrolidine, tetrahydropyran, octahydro-1H-pyrrolo[2,3-c]pyridine, R 1 is either unsubstituted or R a In one class of this embodiment, R 1 is either unsubstituted or R a In another class of this embodiment, R 1 is either unsubstituted or R a It is substituted with 1 to 4 substituents selected from:

[0037] In another embodiment of the present invention, R 1 is pyrrolidine, R 1 is either unsubstituted or R aIn one class of this embodiment, R 1 is either unsubstituted or R a In another class of this embodiment, R 1 is either unsubstituted or R a It is substituted with 1 to 4 substituents selected from:

[0038] In another embodiment of the present invention, R 2 is selected from the group: aryl and heteroaryl; R 2 is either unsubstituted or R b It is substituted by 1 to 5 substituents selected from:

[0039] In one class of this embodiment, R 2 is either unsubstituted or R b In another class of this embodiment, R 2 is either unsubstituted or R b In another class of this embodiment, R 2 is either unsubstituted or R b It is substituted by 1 to 2 substituents selected from:

[0040] In another embodiment, R 2 is heteroaryl, and R 2 is either unsubstituted or R b In another class of this embodiment, R 2 is either unsubstituted or R b In another class of this embodiment, R 2 is either unsubstituted or R b In another class of this embodiment, R 2 is either unsubstituted or R bIt is substituted by 1 to 2 substituents selected from:

[0041] In another embodiment, R 2 is pyridine or benzofuran, R 2 is either unsubstituted or R b In one class of this embodiment, R 2 is either unsubstituted or R b In another class of this embodiment, R 2 is either unsubstituted or R b In another class of this embodiment, R 2 is either unsubstituted or R b It is substituted by 1 to 2 substituents selected from:

[0042] In another embodiment, R 2 is pyridine and R 2 is either unsubstituted or R b In a subclass of this class, R 2 is either unsubstituted or R b In another subclass of this class, R 2 is either unsubstituted or R b In another subclass of this class, R 2 is either unsubstituted or R b It is substituted by 1 to 2 substituents selected from:

[0043] In another embodiment, R 2 is benzofuran and R 2 is either unsubstituted or R b In a subclass of this class, R 2 is either unsubstituted or Rb In another subclass of this class, R 2 is either unsubstituted or R b In another subclass of this class, R 2 is either unsubstituted or R b It is substituted by 1 to 2 substituents selected from:

[0044] In another embodiment, R 2 is aryl, and R 2 is either unsubstituted or R b In one class of this embodiment, R 2 is either unsubstituted or R b In another class of this embodiment, R 2 is either unsubstituted or R b In another class of this embodiment, R 2 is either unsubstituted or R b In another class of this embodiment, R 2 is phenyl, and R 2 is either unsubstituted or R b In a subclass of this class, R 2 is either unsubstituted or R b In another subclass of this class, R 2 is either unsubstituted or R b In another subclass of this class, R 2 is either unsubstituted or R b It is substituted by 1 to 2 substituents selected from:

[0045] In another embodiment of the present invention, R 3 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, -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, and R 3 is either unsubstituted or R d It is substituted by 1 to 5 substituents selected from:

[0046] In another embodiment of the present invention, R 3 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, and -C 1-6 Alkyl-OC 1-6alkyl; R 3 is either unsubstituted or R d It is substituted by 1 to 5 substituents selected from:

[0047] In another embodiment of the present invention, R 3 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 alkyl, and halogen; R 3 is either unsubstituted or R d It is substituted by 1 to 5 substituents selected from:

[0048] In another embodiment of the present invention, R 3 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl and -OC 1-6 alkyl; R 3 is either unsubstituted or R d It is substituted by 1 to 5 substituents selected from:

[0049] In another embodiment of the present invention, R 3 Groups: Hydrogen, OH, CF3, CF2H, -C 1-6 Alkyl and -OC 1-6 alkyl; R 3 is either unsubstituted or R d It is substituted by 1 to 5 substituents selected from:

[0050] In another embodiment of the present invention, R 3 Group: Hydrogen, -C 1-6 Alkyl and -OC 1-6 alkyl; R 3 is either unsubstituted or R d In one class of this embodiment, R 3 is selected from the group: hydrogen, -CH3, and -OCH3.

[0051] In another embodiment of the present invention, R 3 are the groups: hydrogen, OH, CN, CF3, CF2H, and -C 1-6 alkyl; R 3 is either unsubstituted or R d It is substituted by 1 to 5 substituents selected from:

[0052] In another embodiment of the present invention, R 3 is selected from the group: hydrogen, OH, CN, CF3, CF2H, and -CH3; R 3 is either unsubstituted or R d It is substituted by 1 to 5 substituents selected from:

[0053] In another embodiment of the present invention, R 3 is selected from the group: hydrogen, OH, CF, CFH, and -CH; R 3 is either unsubstituted or R d It is substituted by 1 to 5 substituents selected from:

[0054] In another embodiment of the present invention, R 3 Groups: hydrogen, CF3, CF2H, and -C 1-6 alkyl; R 3 is either unsubstituted or R d It is substituted by 1 to 5 substituents selected from:

[0055] In another embodiment of the present invention, R 3 is selected from the group: hydrogen, CF, CFH, and -CH; R 3 is either unsubstituted or R d It is substituted by 1 to 5 substituents selected from:

[0056] In another embodiment of the present invention, R 3 Groups: Hydrogen, CF3, and -C 1-6 alkyl; R 3 is either unsubstituted or R d It is substituted by 1 to 5 substituents selected from:

[0057] In another embodiment of the present invention, R 3 Group: Hydrogen and -C 1-6 alkyl; R 3 is either unsubstituted or R d In one class of this embodiment, R 3 is hydrogen or CH3.

[0058] In another embodiment of the present invention, R 3 -C 1-6 is alkyl, R 3 is either unsubstituted or R d In one class of this embodiment, R 3 is -CH3. In another embodiment of the present invention, R 3 is hydrogen. In another embodiment of the present invention, R 3 is -CF3.

[0059] In another embodiment of the present invention, R 4 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -(CH2) s C(O)R h , -(CH2) s C(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(Ri )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, and R 4 is either unsubstituted or R e It is substituted by 1 to 5 substituents selected from:

[0060] In another embodiment of the present invention, R 4 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, and -C 1-6 Alkyl-OC 1-6 alkyl; R 4 is either unsubstituted or R e It is substituted by 1 to 5 substituents selected from:

[0061] In another embodiment of the present invention, R 4 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, and -C 1-6 Alkyl-OC 1-6 alkyl; R 4 is either unsubstituted or R e It is substituted by 1 to 5 substituents selected from:

[0062] In another embodiment of the present invention, R 4 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6Alkyl, -OC 1-6 alkyl, and halogen; R 4 is either unsubstituted or R e It is substituted by 1 to 5 substituents selected from:

[0063] In another embodiment of the present invention, R 4 Groups: Hydrogen, CN, CF3, CF2H, -C 1-6 alkyl, and halogen; R 4 is either unsubstituted or R e It is substituted by 1 to 5 substituents selected from:

[0064] In another embodiment of the present invention, R 4 Group: Hydrogen, CF3, CF2H, -C 1-6 alkyl, and halogen; R 4 is either unsubstituted or R e It is substituted by 1 to 5 substituents selected from:

[0065] In another embodiment of the present invention, R 4 Groups: Hydrogen, CF3, and -C 1-6 alkyl; R 4 is either unsubstituted or R e It is substituted by 1 to 5 substituents selected from:

[0066] In another embodiment of the present invention, R 4 Group: Hydrogen and -C 1-6 alkyl; R 4 is either unsubstituted or R e In one class of this embodiment of the invention, R 4 is selected from the group: hydrogen, -CH3, -CF3, and -CHF3. In another class of this embodiment of the invention, R 4 is selected from the group: hydrogen and -CH3; R 4 is either unsubstituted or R eIt is substituted by 1 to 5 substituents selected from:

[0067] In another embodiment of the present invention, R 4 is hydrogen.

[0068] In another embodiment of the present invention, R 4 -C 1-6 is alkyl, R 4 is either unsubstituted or R e In one class of this embodiment, R 4 is -CH3.

[0069] In another embodiment of the present invention, R 5 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, -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(Rj )S(O) m N(R i )2, and -(CH2) t N(R i )2, and R 5 is either unsubstituted or R f It is substituted by 1 to 5 substituents selected from:

[0070] In another embodiment of the present invention, R 5 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, and -C 1-6 Alkyl-OC 1-6 alkyl; R 5 is either unsubstituted or R f It is substituted by 1 to 5 substituents selected from:

[0071] In another embodiment of the present invention, R 5 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, and -C 1-6 Alkyl-OC 1-6 alkyl; R 5 is either unsubstituted or R f In another embodiment of the present invention, R 5 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 alkyl, and halogen; R 5 is either unsubstituted or R f In another embodiment of the present invention, R 5 Groups: Hydrogen, CN, CF3, CF2H, -C 1-6 alkyl, and halogen; R 5 is either unsubstituted or Rf In another embodiment of the present invention, R 5 Group: Hydrogen, CF3, CF2H, -C 1-6 alkyl, and halogen; R 5 is either unsubstituted or R f It is substituted by 1 to 5 substituents selected from:

[0072] In another embodiment of the present invention, R 5 Group: Hydrogen, -C 1-6 alkyl, and halogen; R 5 is either unsubstituted or R f In one class of this embodiment, R 5 is selected from the group: hydrogen, —CH3, CHF3, and F. In another class of this embodiment, R 5 is selected from the group: hydrogen, -CH3, and CHF3. In another class of this embodiment, R 5 is selected from the group: hydrogen, -CH, and F. In another embodiment of the present invention, R 5 Group: Hydrogen and -C 1-6 alkyl; R 5 is either unsubstituted or R f In one class of this embodiment, R 5 is selected from the group: hydrogen, CHF3 and -CH3. In another embodiment of the present invention, R 5 -C 1-6 is alkyl, R 5 is either unsubstituted or R f In one class of this embodiment, R 5 is -CH3. In another embodiment of the present invention, R 5 is hydrogen. In another embodiment, R 5 is F. In another embodiment, R 5 is CHF3.

[0073] In another embodiment of the present invention, R 6 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, -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(R i )2, and -(CH2) u N(R i )2, and R 6 is either unsubstituted or R g It is substituted by 1 to 5 substituents selected from:

[0074] In another embodiment of the present invention, R 6 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, -C 3-6 Cycloalkyl, -C2-6 Heterocyclic alkyl, and -C 1-6 Alkyl-OC 1-6 alkyl; R 6 is either unsubstituted or R g It is substituted by 1 to 5 substituents selected from:

[0075] In another embodiment of the present invention, R 6 Groups: Hydrogen, OH, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 Alkyl, halogen, and -C 1-6 Alkyl-OC 1-6 alkyl; R 6 is either unsubstituted or R g It is substituted by 1 to 5 substituents selected from:

[0076] In another embodiment of the present invention, R 6 Groups: Hydrogen, CN, CF3, CF2H, -C 1-6 Alkyl, -OC 1-6 alkyl, and halogen; R 6 is either unsubstituted or R g It is substituted by 1 to 5 substituents selected from:

[0077] In another embodiment of the present invention, R 6 Group: Hydrogen, CF3, CF2H, -C 1-6 Alkyl and -OC 1-6 alkyl; R 6 is either unsubstituted or R g It is substituted by 1 to 5 substituents selected from:

[0078] In another embodiment of the present invention, R 6 Group: Hydrogen, CF3, -C 1-6 Alkyl and -OC 1-6 alkyl; R 6 is either unsubstituted or R gIn one class of this embodiment, R 6 is selected from the group: hydrogen, CF3, -CH3, and -OCH3.

[0079] In another embodiment of the present invention, R 6 Group: Hydrogen, -C 1-6 Alkyl and -OC 1-6 alkyl; R 6 is either unsubstituted or R g In one class of this embodiment, R 6 is selected from the group: hydrogen, -CH3, and -OCH3.

[0080] In another embodiment of the present invention, R 6 Group: Hydrogen and -C 1-6 alkyl; R 6 is either unsubstituted or R g In one class of this embodiment, R 6 is selected from the group: hydrogen and CH. In another embodiment of the present invention, R 6 -C 1-6 is alkyl, R 6 is either unsubstituted or R g In one class of this embodiment, R 6 is -CH3. In another embodiment of the present invention, R 6 is hydrogen.

[0081] In another embodiment of the present invention, each R a are independently selected from the groups: 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 Heterocyclic alkyl, aryl, heteroaryl, -C(O)C1-6 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 Heterocyclic alkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Heterocyclic alkyl, -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 Heterocyclic alkyl, -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 Heterocyclic alkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocyclic alkyl, -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, and each R ais unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0082] In another embodiment of the present invention, each R a are independently selected from the groups: 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 Heterocyclic alkyl, 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 Heterocyclic alkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Heterocyclic alkyl, -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 Heterocyclic alkyl, -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 Heterocyclic alkyl, -(CH2) p-O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocyclic alkyl, -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, and each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0083] In another embodiment of the present invention, each R a are independently selected from the groups: 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 Heterocyclic alkyl, 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, and each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0084] In another embodiment of the present invention, each Ra are independently selected from the groups: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, 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, and each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0085] In another embodiment of the present invention, each R a independently represents the group: 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, and each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 In one class of this embodiment, each R a is independently selected from the group: oxo, -OH, F, -CH, -CHCH, -CFH, -CF, -CHOH, -C(CH)OH, cyclopropyl, phenyl, -C(O)CH, and -CHN(CH); each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0086] In another embodiment of the present invention, each R a independently represents the group: 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, and each R a is unsubstituted or is 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: oxo, -OH, F, -CH, -CHCH, -CFH, -CF, -CHOH, -C(CH)OH, cyclopropyl, phenyl, -C(O)CH, and -CHN(CH); each R a is unsubstituted or is F, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0087] In another embodiment of the present invention, each R a independently represents the groups: -OH and -C 1-6 alkyl, each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 In one class of this embodiment of the invention, each R a independently represents the groups: -OH and -C 1-6 alkyl, and each R a is unsubstituted or is F, CF3, OH, C 1-6 Alkyl and -OC 1-6 In another class of this embodiment of the invention, each R is substituted with 1 to 6 substituents selected from alkyl, ais independently selected from the group: -OH, -CH, -CHCH, -CFH, -CF, -CHOH, and -C(CH)OH. In another class of this embodiment of the invention, each R a is independently selected from the group: -OH and -CH3.

[0088] In another embodiment of the present invention, each R a are independently selected from the groups: 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 Heterocyclic alkyl, 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 Heterocyclic alkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Heterocyclic alkyl, -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 Heterocyclic alkyl, -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 -OC2-6 Heterocyclic alkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocyclic alkyl, -OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, -(CH2) p -S(O) r R k , and -(CH2) p -N(R L )2, and each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0089] In another embodiment of the present invention, each R a are independently selected from the groups: 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 Heterocyclic alkyl, 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 Heterocyclic alkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Heterocyclic alkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl-heteroaryl, -C 2-6 Alkynyl-C 3-6Cycloalkyl, -C 2-6 Alkynyl C 2-6 Heterocyclic alkyl, -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 Heterocyclic alkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocyclic alkyl, -OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, -(CH2) p -S(O) r R k , and -(CH2) p -N(R L )2, and each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0090] In another embodiment of the present invention, each R a are independently selected from the groups: 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 Heterocyclic alkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, and -(CH2) p-N(R L )2, and each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0091] In another embodiment of the present invention, each R a are independently selected from the groups: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl, and -(CH2) p -N(R L )2, and each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0092] In another embodiment of the present invention, each R a are independently selected from the groups: 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 Heterocyclic alkyl, 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 Heterocyclic alkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Heterocyclic alkyl, -C 2-6Alkenyl-aryl, -C 2-6 Alkenyl-heteroaryl, -C 2-6 Alkynyl-C 3-6 Cycloalkyl, -C 2-6 Alkynyl C 2-6 Heterocyclic alkyl, -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 Heterocyclic alkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocyclic alkyl, -OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, and -(CH2) p -S(O) r R k Each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0093] In another embodiment of the present invention, each R a are independently selected from the groups: 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 Heterocyclic alkyl, aryl, heteroaryl, -C(O)C1-6 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 Heterocyclic alkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Heterocyclic alkyl, -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 Heterocyclic alkyl, -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 Heterocyclic alkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocyclic alkyl, -OC 1-6 Alkyl-aryl and -OC 1-6 alkyl-heteroaryl, each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0094] In another embodiment of the present invention, each R a are independently selected from the groups: 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 Heterocyclic alkyl, 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 Heterocyclic alkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Heterocyclic alkyl, -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 Heterocyclic alkyl, -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 Heterocyclic alkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocyclic alkyl, -OC1-6 Alkyl-aryl, -OC 1-6 Alkyl-heteroaryl, and -(CH2) p -S(O) r R k Each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0095] In another embodiment of the present invention, each R a are independently selected from the groups: 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 Heterocyclic alkyl, 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 Heterocyclic alkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Heterocyclic alkyl, -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 Heterocyclic alkyl, -C 2-6 Alkynyl-aryl, -C 2-6 Alkynyl-heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC2-6 Alkynyl, -(CH2) p -OC 3-6 Cycloalkyl, -(CH2) p -OC 2-6 Heterocyclic alkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocyclic alkyl, -OC 1-6 Alkyl-aryl and -OC 1-6 alkyl-heteroaryl, each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0096] In another embodiment of the present invention, each R a are independently selected from the groups: 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 Heterocyclic alkyl, aryl, heteroaryl, and -C(O)C 1-6 alkyl, and each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0097] In another embodiment of the present invention, each R a are independently selected from the groups: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, aryl, heteroaryl, and -C(O)C1-6 alkyl, and each R a is unsubstituted or is halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0098] In another embodiment of the present invention, each R b are independently selected from the groups: CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, 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 Heterocyclic alkyl, -(CH2) q -OC 1-6 Alkyl, -(CH2) q -OC 3-6 Cycloalkyl, -(CH2) q -OC 2-6 Heterocyclic alkyl, -(CH2) q -O-aryl, -(CH2) q -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocyclic alkyl, -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 Each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0099] In another embodiment of the present invention, each R b independently represent the groups: CN, -OH, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, 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 Heterocyclic alkyl, -(CH2) q -OC 1-6 Alkyl, -(CH2) q -OC 3-6 Cycloalkyl, -(CH2) q -OC 2-6 Heterocyclic alkyl, -(CH2) q -O-aryl, -(CH2) q -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocyclic alkyl, -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 Each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another embodiment of the present invention, each Rb independently represents the group: CN, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, 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 Heterocyclic alkyl, -(CH2) q -OC 1-6 Alkyl, -(CH2) q -OC 3-6 Cycloalkyl, -(CH2) q -OC 2-6 Heterocyclic alkyl, -(CH2) q -O-aryl, -(CH2) q -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocyclic alkyl, -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 Each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0100] In another embodiment of the present invention, each R b are independently selected from the groups: CN, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, aryl, heteroaryl, -(CH2) q -S(O) r R m , -(CH2) q N(R n )2, -C(O)R o , and -C(O)NR n Each R b is unsubstituted or 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: CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, aryl, heteroaryl, -(CH2) q -S(O) r R m , -(CH2) q N(R n )2, -C(O)R o , and -C(O)NR n Each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0101] In another embodiment of the present invention, each R b are independently selected from the groups: CN, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, aryl, heteroaryl, -(CH2) q -S(O) r R m , -(CH2) qN(R n )2, -C(O)R o , and -C(O)NR n Each R b is unsubstituted or 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 groups: CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, aryl, heteroaryl, -(CH2) q -S(O) r R m , -(CH2) q N(R n )2, -C(O)R o , and -C(O)NR n Each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0102] In another embodiment of the present invention, each R b are independently selected from the groups: CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, aryl, heteroaryl, -(CH2) q -S(O) r R m , -(CH2) q N(R n )2, -C(O)R o , and -C(O)NR n Each R bis unsubstituted or 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 the groups: CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, aryl, heteroaryl, -(CH2) q -S(O) r R m , -(CH2) q N(R n )2, -C(O)R o , and -C(O)NR n Each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0103] In another embodiment of the present invention, each R b are independently selected from the groups: CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, -(CH2) q -S(O) r R m , -(CH2) q N(R n )2, -C(O)R o , and -C(O)NR n Each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In one class of this embodiment, each R bis independently selected from the group: OH, Cl, F, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane; b is unsubstituted or 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: CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, -(CH2) q -S(O) r R m , -(CH2) q N(R n )2, -C(O)R o , and -C(O)NR n Each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In one class of this embodiment, each R b is independently selected from the group: Cl, F, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane; b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0104] In another embodiment of the present invention, each R b are independently selected from the groups: CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, -(CH2) q -S(O)r R m , -(CH2) q N(R n )2, -C(O)R o , and -C(O)NR n Each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In one class of this embodiment, each R b is independently selected from the group: OH, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane; b is unsubstituted or 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 the groups: CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, -(CH2) q -S(O) r R m , -(CH2) q N(R n )2, -C(O)R o , and -C(O)NR n Each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In one class of this embodiment, each R b is independently selected from the group: -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane; b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0105] In another embodiment of the present invention, each R b is independently selected from the group: CN, -OH, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane; b is unsubstituted or 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 is independently selected from the group: CN, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane; b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0106] In another embodiment of the present invention, each R b are independently selected from the groups: CN, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 heterocyclic alkyl, each R b is unsubstituted or 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 groups: CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 heterocyclic alkyl, each R bis unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0107] In another embodiment of the present invention, each R b are independently selected from the groups: CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 heterocyclic alkyl, each R b is unsubstituted or 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 the groups: CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 heterocyclic alkyl, each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0108] In another embodiment of the present invention, each R b Groups: CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, and -C 3-6 cycloalkyl, each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6In another embodiment of the present invention, each R b Groups: CN, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, and -C 3-6 cycloalkyl, each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0109] In another embodiment of the present invention, each R b independently represent the groups: CN, -OH, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl, and -C 3-6 cycloalkyl, each R b is unsubstituted or 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 represents the group: CN, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl, and -C 3-6 cycloalkyl, each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0110] In another embodiment of the present invention, each R b Groups: -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, and -C 3-6 cycloalkyl, each R bis unsubstituted or 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 Group: halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, and -C 3-6 cycloalkyl, each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0111] In another embodiment of the present invention, each R b are independently selected from the groups: -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, and -C 3-6 cycloalkyl, each R b is unsubstituted or 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 grouped as:-C 1-6 Alkyl, -OC 1-6 Alkyl, and -C 3-6 cycloalkyl, each R b is unsubstituted or halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted by 1 to 6 substituents selected from alkyl.

[0112] In another embodiment of the present invention, each R b are independently selected from the groups: -OH, -C 1-6 Alkyl and -OC1-6 alkyl, and each R b is unsubstituted or 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 groups: -OH, -C 1-6 Alkyl and -OC 1-6 alkyl, and each R b is unsubstituted or is F, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another class of this embodiment, each R is substituted with 1 to 6 substituents selected from alkyl, b is independently OH, -CH3, -CF3, -CF2H, or -OCF2H. b are independently grouped as:-C 1-6 Alkyl and -OC 1-6 alkyl, and each R b is unsubstituted or 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 grouped as:-C 1-6 Alkyl and -OC 1-6 alkyl, and each R b is unsubstituted or is F, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 In another class of this embodiment, each R is substituted with 1 to 6 substituents selected from alkyl, b are independently -CH3, -CF3, -CF2H, or -OCF2H.

[0113] In another class of this embodiment, each R b is independently selected from the group: -OH, -CH3, -CF3, and -OCF2H. In another class of this embodiment, each R b is independently selected from the group: -OH, -CF, and -OCFH. b is independently selected from the group: -OH, -CH3, -CF3, -OCF2H, and cyclopropane. In another class of this embodiment, each R b is independently selected from the group: -CH3, -CF3, and -OCF2H. In another class of this embodiment, each R b is independently selected from the group: -CF, and -OCFH. b is independently selected from the group: -OH, -CH3, -CF3, -OCF2H, and cyclopropane.

[0114] In another embodiment, each R b is independently selected from the group: -OH, and -CF. In another embodiment, each R b is CF3.

[0115] In another embodiment of the present invention, each R c independently represents the group: hydrogen, halogen, and -C 1-6 alkyl, where alkyl is unsubstituted or selected from CF3, halogen, OH and -OC 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0116] In another embodiment, each R c independently represents the group: hydrogen, and -C 1-6 alkyl, where alkyl is unsubstituted or selected from CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R c is -CH3. In another embodiment, R c is hydrogen.

[0117] In another embodiment, R c -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with CF3, halogen, OH and -OC. 1-6 In one class of this embodiment, each R c is -CH3.

[0118] In another embodiment of the present invention, each R d independently represents the group: CF3, halogen, and -C 1-6 alkyl, where alkyl is unsubstituted or selected from CF3, halogen, OH and -OC 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0119] In another embodiment of the present invention, each R d independently represents the group: halogen and -C 1-6 alkyl, where alkyl is unsubstituted or selected from CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R d is independently selected from the group: halogen and -CH. In another embodiment of the present invention, each R d is a halogen.

[0120] In another embodiment of the present invention, each R d -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with CF3, halogen, OH and -OC. 1-6 In one class of this embodiment, each R d is -CH3.

[0121] In another embodiment of the present invention, each R e independently represents the group: CF3, halogen, and -C 1-6 alkyl, where alkyl is unsubstituted or selected from CF3, halogen, OH and -OC 1-6It is substituted by 1 to 3 substituents selected from alkyl.

[0122] In another embodiment of the present invention, each R e independently represents the group: halogen and -C 1-6 alkyl, where alkyl is unsubstituted or selected from CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R e is independently selected from the group: halogen and -CH. In another embodiment of the present invention, each R e is a halogen.

[0123] In another embodiment of the present invention, each R e -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with CF3, halogen, OH and -OC. 1-6 In one class of this embodiment, each R e is -CH3.

[0124] In another embodiment of the present invention, each R f independently represents the group: CF3, halogen, and -C 1-6 alkyl, where alkyl is unsubstituted or selected from CF3, halogen, OH and -OC 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0125] In another embodiment of the present invention, each R f independently represents the group: halogen and -C 1-6 alkyl, where alkyl is unsubstituted or selected from CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R f is independently selected from the group: halogen and -CH. In another embodiment of the present invention, each R f is a halogen.

[0126] In another embodiment of the present invention, each R f -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with CF3, halogen, OH and -OC. 1-6 In one class of this embodiment, each R f is -CH3.

[0127] In another embodiment of the present invention, each R g independently represents the group: CF3, halogen, and -C 1-6 alkyl, where alkyl is unsubstituted or selected from CF3, halogen, OH and -OC 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0128] In another embodiment of the present invention, each R g independently represents the group: halogen and -C 1-6 alkyl, where alkyl is unsubstituted or selected from CF3, halogen, OH and -OC 1-6 In one class of this embodiment, each R g is independently selected from the group: halogen and -CH. In another embodiment of the present invention, each R g is a halogen.

[0129] In another embodiment of the present invention, each R g -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with CF3, halogen, OH and -OC. 1-6 In one class of this embodiment, each R g is -CH3.

[0130] In another embodiment of the present invention, each R h independently represents the group: hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C2-6 Heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or selected from -CF3, halogen, OH and -OC. 1-6 In one class of this embodiment, R h -C 2-6 Heterocycloalkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0131] In another embodiment of the present invention, each R h independently represents the group: hydrogen, -C 1-6 Alkyl, and -C 3-6 cycloalkyl, where alkyl and cycloalkyl are unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R h -C 3-6 Cycloalkyl, where cycloalkyl is unsubstituted or substituted with -CF3, halogen, OH, and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0132] In another embodiment of the present invention, each R h independently represents the group: hydrogen and -C 1-6 alkyl, wherein alkyl is unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In another embodiment of the present invention, R h is hydrogen. In another embodiment of the present invention, R h -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0133] In another embodiment of the present invention, each R i independently represents the group: hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or selected from CF3, halogen, OH and -OC. 1-6 In one class of this embodiment, R i -C 2-6 Heterocycloalkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0134] In another embodiment of the present invention, each R i independently represents the group: hydrogen, -C 1-6 Alkyl, and -C 3-6 cycloalkyl, where alkyl and cycloalkyl are unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R i -C 3-6 Cycloalkyl, where cycloalkyl is unsubstituted or substituted with -CF3, halogen, OH, and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0135] In another embodiment of the present invention, each R i independently represents the group: hydrogen and -C 1-6 alkyl, wherein alkyl is unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In another embodiment of the present invention, R i is hydrogen. In another embodiment of the present invention, R i -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC.1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0136] In another embodiment of the present invention, each R j independently represents the group: hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or selected from CF3, halogen, OH and -OC. 1-6 In one class of this embodiment, R j -C 2-6 Heterocycloalkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0137] In another embodiment of the present invention, each R j independently represents the group: hydrogen, -C 1-6 Alkyl, and -C 3-6 cycloalkyl, where alkyl and cycloalkyl are unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R j -C 3-6 Cycloalkyl, where cycloalkyl is unsubstituted or substituted with -CF3, halogen, OH, and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0138] In another embodiment of the present invention, each R j independently represents the group: hydrogen and -C 1-6 alkyl, wherein alkyl is unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In another embodiment of the present invention, R jis hydrogen. In another embodiment of the present invention, R j -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0139] In another embodiment of the present invention, each R k are independently grouped as:-C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or selected from -CF3, halogen, OH, and -OC. 1-6 In one class of this embodiment, R k -C 2-6 Heterocycloalkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0140] In another embodiment of the present invention, each R k are independently grouped as:-C 1-6 Alkyl and -C 3-6 cycloalkyl, where alkyl and cycloalkyl are unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R k -C 3-6 Cycloalkyl, where cycloalkyl is unsubstituted or substituted with -CF3, halogen, OH, and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0141] In another embodiment of the present invention, R k -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6It is substituted by 1 to 3 substituents selected from alkyl.

[0142] In another embodiment of the present invention, each R L independently represents the group: hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or selected from -CF3, halogen, OH, and -OC. 1-6 In one class of this embodiment, R L -C 2-6 Heterocycloalkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0143] In another embodiment of the present invention, each R L independently represents the group: hydrogen, -C 1-6 Alkyl, and -C 3-6 cycloalkyl, where alkyl and cycloalkyl are unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R L -C 3-6 Cycloalkyl, where cycloalkyl is unsubstituted or substituted with -CF3, halogen, OH, and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0144] In another embodiment of the present invention, each R L independently represents the group: hydrogen and -C 1-6 alkyl, wherein alkyl is unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In another embodiment of the present invention, R L is hydrogen. In another embodiment of the present invention, RL -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 In one class of this embodiment, R L is -CH3.

[0145] In another embodiment of the present invention, each R m are independently grouped as:-C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or selected from -CF3, halogen, OH and -OC. 1-6 In one class of this embodiment, R m -C 2-6 Heterocycloalkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0146] In another embodiment of the present invention, each R m are independently grouped as:-C 1-6 Alkyl and -C 3-6 cycloalkyl, where alkyl and cycloalkyl are unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R m -C 3-6 Cycloalkyl, where cycloalkyl is unsubstituted or substituted with -CF3, halogen, OH, and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0147] In another embodiment of the present invention, R m -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC.1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0148] In another embodiment of the present invention, each R n are independently selected from the group: hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or selected from -CF3, halogen, OH, and -OC. 1-6 In one class of this embodiment, R n -C 2-6 Heterocycloalkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0149] In another embodiment of the present invention, each R n independently represents the group: hydrogen, -C 1-6 Alkyl, and -C 3-6 cycloalkyl, where alkyl and cycloalkyl are unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In one class of this embodiment, R n -C 3-6 Cycloalkyl, where cycloalkyl is unsubstituted or substituted with -CF3, halogen, OH, and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0150] In another embodiment of the present invention, each R n independently represents the group: hydrogen and C 1-6 alkyl, wherein alkyl is unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In another embodiment of the present invention, each R nis hydrogen. In another embodiment of the present invention, each R n -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0151] In another embodiment of the present invention, each R o are independently represented by the groups: OH, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or selected from -CF3, halogen, OH and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0152] In another embodiment of the present invention, each R o independently represents the groups: OH and -C 1-6 alkyl, wherein alkyl is unsubstituted or selected from -CF3, halogen, OH and -OC 1-6 In another embodiment of the present invention, each R o is OH. In another embodiment of the present invention, each R o -C 1-6 Alkyl, where the alkyl is unsubstituted or substituted with -CF3, halogen, OH and -OC. 1-6 It is substituted by 1 to 3 substituents selected from alkyl.

[0153] 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 0, 1 or 2. In another embodiment, r is 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.

[0154] 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 0, 1 or 2. In another embodiment, s is 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.

[0155] 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 0, 1 or 2. In another embodiment, t is 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.

[0156] In another embodiment of the 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 0, 1 or 2. In another embodiment, u is 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.

[0157] 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 0, 1 or 2. In another embodiment, p is 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.

[0158] 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 0, 1 or 2. In another embodiment, q is 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.

[0159] In another embodiment, the present invention relates to a compound of formula Ia: or a pharma- ceutically acceptable salt thereof. [ka]

[0160] In another embodiment, the present invention relates to a compound of formula Ib: or a pharma- ceutically acceptable salt thereof: [ka]

[0161] In another embodiment, the present invention relates to a compound of formula Ic: or a pharma- ceutically acceptable salt thereof. [ka]

[0162] In another embodiment, the present invention relates to a compound of formula Id: or a pharma- ceutically acceptable salt thereof. [ka]

[0163] In another embodiment, the present invention relates to a compound of formula Ie: or a pharma- ceutically acceptable salt thereof. [ka]

[0164] In another embodiment, the present invention relates to a compound of formula If: or a pharma- ceutically acceptable salt thereof. [ka]

[0165] In another embodiment, the invention relates to a compound of formula Ig, or a pharma- ceutically acceptable salt thereof: [ka]

[0166] In another embodiment, the invention relates to a compound of formula Ih: or a pharma- ceutically acceptable salt thereof. [ka]

[0167] In another embodiment, the present invention relates to a compound of formula Ii, or a pharma- ceutically acceptable salt thereof: [ka]

[0168] In another embodiment, the invention relates to compounds of formula Ij: or a pharma- ceutically acceptable salt thereof. [ka]

[0169] In another embodiment, the present invention relates to a compound of formula Ik: [ka]

[0170] Compounds of formula I include compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, and Ik, and pharma- ceutically acceptable salts, hydrates, and solvates thereof.

[0171] Another embodiment of the present invention comprises: R 1 C 2-12 Heterocyclic alkyl, R 1 is not substituted or R a and is substituted by 1 to 6 substituents selected from; R 2 is heteroaryl, and R 2 is not substituted or R b and is substituted by 1 to 5 substituents selected from; R3 But, group: 1) Hydrogen, and 2)-C 1-6 Alkyl Selected from; R 3 is not substituted or R d and is substituted by 1 to 5 substituents selected from; R 4 But, group: 1) Hydrogen, 2) OH, 3) CN, 4) CF3, 5) CF2H, 6)-C 1-6 Alkyl, 7)-OC 1-6 Alkyl, 8) Halogens, and 9)-C 1-6 Alkyl-OC 1-6 Alkyl is selected from R 4 is not substituted or R e and is substituted by 1 to 5 substituents selected from; R 5 But, group: 1) Hydrogen, 2) OH, 3) CN, 4) CF3, 5) CF2H, 6)-C 1-6 Alkyl, 7)-OC 1-6 Alkyl, 8) Halogens, and 9)-C 1-6 Alkyl-OC 1-6 Alkyl Selected from; R 5 is not substituted or R f and is substituted by 1 to 5 substituents selected from; R 6 But, group: 1) Hydrogen, 2)-C 1-6 Alkyl, and 3)-OC 1-6 Alkyl is selected from R 6 is not substituted or R g and is substituted by 1 to 5 substituents selected from; The present invention relates to a compound of structural formula I, or a pharma- ceutically acceptable salt thereof, wherein the other substituents are as defined above.

[0172] Another embodiment of the present invention comprises: W is CR 6 and; R 1 But, 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 is selected from R 1 is not substituted or R a and is substituted by 1 to 6 substituents selected from; R 2 is aryl, and R2 is not substituted or R b and is substituted by 1 to 5 substituents selected from; R 3 is hydrogen; R 4 But, group: 1) Hydrogen, and 2)-C 1-6 Alkyl is selected from R 4 is not substituted or R e and is substituted by 1 to 5 substituents selected from; R 5 But, group: 1) Hydrogen, 2)-C 1-6 Alkyl, and 3) Halogen is selected from R 5 is not substituted or R f and R 6 is hydrogen; The present invention relates to a compound of structural formula I, or a pharma- ceutically acceptable salt thereof, wherein the other substituents are as defined above.

[0173] Illustrative (but non-limiting) examples of compounds of the present invention that are useful as inhibitors of NLRP3 include the following compounds: 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-dimethylmorpholino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5) 2-(1-((cis)-2,6-dimethylmorpholino)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol; 6) 2-(5-((cis)-2,6-dimethylmorpholino)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-dimethylmorpholino)pyridazino[4,5-c]pyridazin-5-yl)-5-(trifluoromethyl)-phenol; 9) 2-(4-((cis)-2,6-dimethylmorpholino)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-dimethylmorpholino)-5-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol; 15) 2-(4-((cis)-2,6-dimethylmorpholino)-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-dimethylmorpholino)-6-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol; 21) 2-(4-((cis)-2,6-dimethylmorpholino)-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]decan-8-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 34) 2-(8-(2-oxa-8-azaspiro[4.5]decan-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]decan-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]decan-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]decan-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]hexan-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-methylmorpholino)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 62) 2-(8-((2S,6S)-2-(hydroxymethyl)-6-methylmorpholino)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 63) 2-(8-((2S,6S)-2-(hydroxymethyl)-6-methylmorpholino)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 64) 2-(8-((2R,6R)-2-(hydroxymethyl)-6-methylmorpholino)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 pharma- ceutically acceptable salt thereof.

[0174] Further illustrative (but non-limiting) examples of compounds of the present invention that are useful as inhibitors of NLRP3 include the following compounds: 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-dimethylmorpholino)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 pharma- ceutically acceptable salt thereof.

[0175] While the specific stereochemistry depicted above is preferred, other stereoisomers, including diastereomers, enantiomers, epimers, and mixtures thereof, may be useful in treating NLRP3-mediated diseases.

[0176] Methods for synthesizing the compounds are disclosed in the following examples. Where no synthetic details are provided in the examples, the compounds are readily prepared by those skilled in the art of medicinal chemistry or synthetic organic chemistry by applying the synthetic information provided herein. Where a stereochemical center is not defined, the structure represents a mixture of stereoisomers at that center. For such compounds, the individual stereoisomers, including enantiomers, diastereomers, and mixtures thereof, are also compounds of the present invention.

[0177] Definition: "Ac" is acetyl, or CH3C(=O)-.

[0178] "Alkyl" means saturated carbon chains which can be linear or branched or combinations thereof, unless the carbon chain is otherwise defined. Other groups having the prefix "alk", such as alkoxy and alkanoyl, can also be linear or branched or combinations thereof, unless the carbon chain is otherwise defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

[0179] "Alkenyl," unless otherwise defined, means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

[0180] "Alkenyl," unless otherwise defined, means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like.

[0181] "Cycloalkyl" means a saturated monocyclic, bicyclic, spirocyclic or bridged carbocyclic ring having the 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 In another embodiment of the present invention, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In another embodiment, cycloalkyl is cyclopropyl.

[0182] "Cycloalkenyl" means a monocyclic, bicyclic, spirocyclic, fused or bridged carbocyclic ring having the specified number of carbon atoms with at least one double bond. Examples of cycloalkenyl include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and the like. In one embodiment, cycloalkenyl is -C 3-12 It is a cycloalkenyl.

[0183] "Heterocycloalkyl" refers to a saturated monocyclic, bicyclic, spirocyclic, fused or bridged ring or ring system having the specified number of carbon atoms and containing at least one ring heteroatom selected from N, NH, S (including SO and SO2) and O. Heterocycloalkyl rings may be substituted on the ring carbons and / or on the ring nitrogen or sulfur. Examples of heterocycloalkyl include tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, azetidinyl, piperazinyl, piperidinyl, morpholinyl, oxetanyl and tetrahydropyranyl. In one embodiment of the invention, heterocycloalkyl is C 2-12 Heterocycle alkyl. In another embodiment, the heterocycle alkyl is selected from 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.

[0184] "Heterocyclic alkenyl" means 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), and O. Examples of heterocyclic alkenyls include dihydropyran and dihydrofuran.

[0185] "Aryl" means a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or ring system containing 6 to 14 carbon atoms, where at least one of the rings is aromatic. Examples of aryl include phenyl and naphthyl. In one embodiment, aryl is phenyl.

[0186] "Heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring or ring system containing 5 to 14 carbon atoms and at least one ring heteroatom selected from N, NH, S (including SO and SO2), and O, where at least one of the heteroatom-containing rings is aromatic. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and the like. In one embodiment, heteroaryl is pyridine or benzofuran. In another embodiment, heteroaryl is pyridine. In another embodiment, heteroaryl is benzofuran.

[0187] "Halogen" includes fluorine, chlorine, bromine, and iodine. In one embodiment, the halogen is fluorine, chlorine, or bromine. In another embodiment, the halogen is fluorine or chlorine. In another embodiment, the halogen is chlorine or bromine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is chlorine. In another embodiment, the halogen is bromine.

[0188] "Me" stands for methyl.

[0189] "Oxo" stands for =O.

[0190] "Saturated" means containing only single bonds.

[0191] "Unsaturated" means containing at least one double 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.

[0192] In any constituent or in formula I, any variable (e.g., R 1 , R a When a variable occurs more than once, its definition at each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A wavy line across a bond in a substituent variable indicates the point of attachment.

[0193] Under 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 The alkyl substituents are equivalent to the following: [ka]

[0194] In selecting the compounds of the present invention, various substituents, i.e., R 1 , R 2 It will be apparent to one skilled in the art that the etc. should be selected according to well-known principles of accessibility and stability of chemical structures.

[0195] The term "substituted" is intended to mean substituted to multiple degrees by a named substituent. Where multiple substituent moieties are disclosed or claimed, a substituted compound may be singly or multiply substituted, independently, with one or more of the disclosed or claimed substituent moieties. Independently substituted means that the (two or more) substituents may be the same or different.

[0196] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, salts, and / or dosage forms that are safe and suitable for administration to human beings or animals, based on sound medical judgment and in accordance with all applicable government regulations.

[0197] The compounds of formula I may contain one or more asymmetric centers and therefore may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers, and the present invention is meant to encompass all such isomeric forms of the compounds of formula I.

[0198] The independent syntheses of enantiomers and diastereoisomers or their chromatographic separations may be achieved according to methods known in the art by appropriate modification of the methods disclosed herein. Their absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with an asymmetric center of known absolute configuration, or with a reagent containing an atom sufficiently heavy to make an absolute assignment.

[0199] If desired, the individual enantiomers can be isolated by separating a racemic mixture of the compounds. This separation can be carried out by methods known in the art, such as coupling a racemic mixture of the compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of a salt with an enantiomerically pure acid or base. The diastereomeric derivative can then be converted to the pure enantiomer by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, known in the art.

[0200] Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods known in the art.

[0201] Some of the compounds described herein contain olefinic double bonds, and unless otherwise specified, are meant to include both E and Z geometric isomers.

[0202] 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 attachment of hydrogen. Such examples may include a ketone and its enol form, known as keto-enol tautomers. Individual tautomers as well as mixtures thereof are encompassed by the compounds of formula I.

[0203] In the compounds of general formula I, atoms may be present in their natural isotopic abundance or one or more atoms may be artificially enriched with a particular isotope having the same atomic number but a different atomic mass or mass number than that found predominantly in nature. The present invention is intended to encompass all suitable isotopic variations of the compounds of structural formula I. For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Protium is the predominant hydrogen isotope found in nature. Enrichment with deuterium may provide certain therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, or may provide compounds useful as standards for characterization of biological samples. Tritium is radioactive, and thus may provide radiolabeled compounds useful as tracers in metabolic or kinetic studies. Isotopically enriched compounds encompassed by structural formula I may be prepared without undue experimentation by routine procedures well known to those skilled in the art, or by methods similar to those described in the schemes and examples herein, using appropriate isotopically enriched reagents and / or intermediates.

[0204] Additionally, some of the crystalline forms of the compounds of the present invention may exist as polymorphs, which are also intended to be included in the present invention. Additionally, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the present invention.

[0205] It is generally preferred to administer the compounds of the present invention as enantiomerically pure preparations.Racemic mixtures can be separated into their individual enantiomers by any of many conventional methods.These methods include chiral chromatography, derivatization with chiral auxiliaries followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.

[0206] salt It will be understood that, as used herein, references to the compounds of the invention are meant to include pharma- ceutically acceptable salts as well as salts that are not pharma- ceutically acceptable when used as precursors to the free compounds or their pharma- ceutical acceptable salts or in other synthetic procedures.

[0207] The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. The salts of basic compounds encompassed by the term "pharmaceutically acceptable salts" generally refer to non-toxic salts of the compounds of the present invention prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of the present invention include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, formate, fumarate, gluceptate, gluconate, glutamate, glycollylars-anilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothioate, lact ... Examples of suitable pharmaceutically acceptable salts include, but are not limited to, tobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, trifluoroacetate, and valerate. When the compound of the present invention contains an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.Salts derived from pharma- ceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0208] Additionally, when a carboxylic acid (-COOH) or alcohol group is present in the compounds of the invention, pharma- ceutically acceptable esters of the carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of the alcohol, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, can also be used, including ester and acyl groups known in the art for altering the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

[0209] The term "prodrug" refers to a compound that is rapidly converted to the parent compound in vivo, for example by hydrolysis in blood, such as the conversion of a prodrug of formula I to a compound of formula I or to a salt thereof. A detailed description is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium 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 prodrugs of the novel compounds of the present invention. The present invention also includes solvates, particularly hydrates, of the compounds of the present invention.

[0210] Purpose The compounds of the present invention are potent inhibitors of NOD-like receptor protein 3 (NLPR3). The compounds and pharma- ceutically acceptable salts thereof may be useful in the treatment of diseases, disorders, and conditions mediated by inhibition of NOD-like receptor protein 3 (NLPR3).

[0211] The present invention relates to the treatment or prevention of a disease, disorder or condition mediated by NLRP3, such as inflammation, an autoimmune disease, cancer, an infectious disease, 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 ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, graft versus host disease, allodynia, or an NLRP3-associated disease, in a subject determined to have a germline or somatic non-silent mutation in NLRP3.

[0212] Diseases, disorders, or conditions mediated by NLRP3 include, but are not limited to, gout, pseudogout, osteoarthritis, familial common cold autoinflammatory syndrome, Muckle-Wells syndrome, 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 syndromes, 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 disease. Additionally, diseases, disorders, or conditions mediated by NOD-like receptor protein 3 (NLPR3) 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.

[0213] In one embodiment of the invention, the condition, disease or disorder is inflammatory joint disease, such as gout, pseudogout, or osteoarthritis.

[0214] In another embodiment, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal onset multisystem inflammatory disease.

[0215] In another embodiment, the metabolic disease is diabetes.

[0216] In another embodiment, the liver disease is NASH.

[0217] In another embodiment, the infection is sepsis.

[0218] In another embodiment, the ophthalmic or eye disease is age-related macular degeneration or diabetic retinopathy.

[0219] In another embodiment, the fibrotic disease is liver fibrosis or kidney fibrosis.

[0220] In some embodiments, the cardiovascular disease is atherosclerosis, heart failure, heart failure with preserved ejection fraction, or peripheral arterial disease.

[0221] In another embodiment, the cancer is a myeloproliferative neoplasm, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, or colon cancer.

[0222] 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.

[0223] In another embodiment, the skin disorder is atopic dermatitis or hidradenitis suppurativa (HS).

[0224] In another embodiment, the inflammatory disease is pericarditis or myocarditis.

[0225] In another embodiment, the inflammatory disease is pre-eclampsia.

[0226] In another embodiment, the rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0227] In another embodiment, the eye disease is age-related macular degeneration or diabetic retinopathy.

[0228] In another embodiment, the kidney disease is acute kidney disease, chronic kidney disease, or a rare kidney disease.

[0229] One or more of these conditions or diseases can be treated, managed, prevented, alleviated, ameliorated, or suppressed by administering to a patient in need of treatment a therapeutically effective amount of a compound of the present invention, or a pharma- ceutically acceptable salt thereof.

[0230] The compounds of the present invention are useful for the treatment of gout, pseudogout, osteoarthritis, familial common cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease, diabetes, NASH, sepsis, age-related macular degeneration, diabetic retinopathy, liver fibrosis, kidney fibrosis, atherosclerosis, heart failure, peripheral arterial disease, myeloproliferative neoplasms, leukemia, myelodysplastic syndromes, myelofibrosis, lung cancer, colon cancer, Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord cancer, and osteoporosis. In some embodiments, the compounds may be used in the manufacture of a medicament that may be useful in treating, preventing, managing, mitigating, ameliorating or controlling one or more of these conditions, diseases or disorders, including, but not limited to, glaucoma, glaucoma, myocarditis, myocarditis, myocardial infarction ... The compounds of the invention may also be used in the manufacture of a medicament that may be useful in treating, preventing, managing, mitigating, 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.

[0231] A preferred use of the compounds may be for treating one or more of the following diseases by administering a therapeutically effective amount to a patient in need of treatment: The compounds may be used in the manufacture of a medicament for treating one or more of these diseases; 1) Gout, 2) Pseudogout, 3) cryopyrin-associated periodic syndrome, 4) Nonalcoholic fatty liver disease, 5) fibrosis, 6) Osteoarthritis, 7) arteriosclerosis, 8) Atopic dermatitis, 9)Hidradenitis suppurativa, 10) Alzheimer's disease, and 11) Parkinson's disease.

[0232] 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 having the disease, disorder, or condition.

[0233] One outcome of treatment may be alleviating a disease, disorder or condition mediated by the NLPR3 or NLPR3 inflammasome pathway. Another outcome of treatment may be alleviating a disease, disorder or condition mediated by the NLPR3 or NLPR3 inflammasome pathway. Another outcome of treatment may be ameliorating a disease, disorder or condition mediated by the NLPR3 or NLPR3 inflammasome pathway. Another outcome of treatment may be inhibiting a disease, disorder or condition mediated by the NLPR3 or NLPR3 inflammasome pathway. Another outcome of treatment may be managing a disease, disorder or condition mediated by the NLPR3 or NLPR3 inflammasome pathway. Another outcome of treatment may be preventing a disease, disorder or condition mediated by the NLPR3 or NLPR3 inflammasome pathway.

[0234] Prevention of a disease, disorder or condition mediated by NLPR3 or NLPR3 inflammasome pathway refers to administration of a compound of the present invention to a subject at risk of the disease, disorder or condition. One outcome of prevention can be reducing a disease, disorder or condition mediated by NLPR3 or NLPR3 inflammasome pathway in a subject at risk of the disease, disorder or condition. Another outcome of prevention can be suppressing a disease, disorder or condition mediated by NLPR3 or NLPR3 inflammasome pathway in a subject at risk of the disease, disorder or condition. Another outcome of prevention can be improving a disease, disorder or condition mediated by NLPR3 or NLPR3 inflammasome pathway in a subject at risk of the disease, disorder or condition. Another outcome of prevention can be alleviating a disease, disorder or condition mediated by NLPR3 or NLPR3 inflammasome pathway in a subject at risk of the disease, disorder or condition. Another outcome of prevention may be managing a disease, disorder, or condition mediated by NLPR3 or the NLPR3 inflammasome pathway in a subject at risk of the disease, disorder, or condition.

[0235] The terms "administration" and / or "administering" a compound should be understood to mean providing a compound of the invention, or a prodrug of a compound of the invention, to an individual or mammal in need of treatment.

[0236] Administration of the compounds of formula I to practice the therapeutic methods of the present invention is carried out by administering an effective amount of the compound of formula I to a mammal in need of treatment or prophylaxis. The need for prophylactic administration according to the methods of the present invention is determined using known risk factors. The effective amount of each compound will, in the final analysis, be determined by the physician or veterinarian attending to the patient, depending on factors such as the exact disease being treated, the severity of the disease and other diseases or conditions suffered by the patient, the selected route of administration of other drugs and treatments that the patient may require concomitantly, and other factors at the physician's discretion.

[0237] The usefulness of the compounds of the invention in these diseases or disorders may be demonstrated in animal disease models already reported in the literature.

[0238] Administration and Dose Range Any suitable route of administration can be used to administer an effective dose of the compound of the present invention to a mammal, particularly a human. For example, oral, intravenous, infusion, subcutaneous, transdermal, intramuscular, intradermal, transmucosal, intramucosal, rectal, topical, parenteral, ocular, pulmonary, nasal, etc., can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. Preferably, the compound of the present invention is administered orally.

[0239] In the treatment or prevention of disorders, diseases and / or conditions requiring inhibition of NLRP3, a suitable dosage level is usually about 0.0001-500 mg / kg of patient body weight / day, which can be administered in a single dose or multiple doses. In another embodiment, a suitable dosage level can be about 0.001-250 mg / kg / day. In another embodiment, a suitable dosage level can be about 0.01-250 mg / kg / day. In another embodiment, a suitable dosage level can be about 0.1-100 mg / kg / day. In another embodiment, a suitable dosage level can be about 0.05-100 mg / kg / day. In another embodiment, a suitable dosage level can be about 0.1-50 mg / kg / day. In another embodiment, a suitable dosage level can be about 0.05-0.5 mg / kg / day. In another embodiment, a suitable dosage level can be about 0.5-5 mg / kg / day. In another embodiment, a suitable dosage level may be about 5-50 mg / kg / day. For oral administration, the composition is preferably provided in the form of a tablet containing 0.01-1000 mg of active ingredient, in particular 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, for symptomatic adjustment of the dosage to the patient being treated. The compounds may be administered on a regimen of 1 to 8 times per day, preferably 1 to 4 times per day, more preferably once or twice per day, and even more preferably once per day, which can be adjusted to provide the optimal therapeutic response.

[0240] However, it will be understood that the specific dose level and frequency of administration for a particular patient may vary and will depend upon a variety of factors such as the activity of the particular compound used, the metabolic stability and duration of action of that compound, age, body weight, general health, sex, diet, method and time of administration, rate of excretion, coadministered medications, the severity of the particular condition, and the host being treated.

[0241] The compounds of the present invention can be used in pharmaceutical compositions comprising (a) the compound or a pharma- ceutically acceptable salt thereof, and (b) a pharma- ceutically acceptable carrier. The compounds of the present invention can be used in pharmaceutical compositions in which the compound of the present invention or a pharma- ceutically acceptable salt thereof is the only active ingredient. The compounds of the present invention can also be used in pharmaceutical compositions that contain one or more other active pharmaceutical ingredients.

[0242] The term "composition" in pharmaceutical composition includes a product containing an active ingredient and an inactive ingredient that constitutes a carrier, as well as any product that results directly or indirectly from the combination, complexation or aggregation of two or more ingredients, or the dissociation of one or more ingredients, or any other type of reaction or interaction of one or more ingredients. Thus, the pharmaceutical composition of the present invention includes any composition produced by mixing a compound of the present invention with a pharma- ceutically acceptable carrier.

[0243] The compounds of the present invention may be used in combination with other drugs that may also be useful in treating or ameliorating the disease or condition for which the compounds of the present invention are useful. Such other drugs may be administered simultaneously or sequentially with the compounds of the present invention, by a route and in an amount that is normally used. In treating patients suffering from chronic inflammatory conditions, multiple drugs may be administered. The compounds of the present invention may generally be administered to patients who are already taking one or more other drugs for these conditions. In many cases, the compounds are administered to patients who are already being treated with one or more anti-pain compounds when the patient's pain does not respond adequately to treatment.

[0244] Combination therapy also includes therapy in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules.It is also envisioned that when combined with one or more other active ingredients, the compound of the present invention and the other active ingredients can be used in lower doses than when each is used alone.Therefore, the pharmaceutical composition of the present invention also includes those that contain one or more other active ingredients in addition to the compound of the present invention.

[0245] Examples of other active ingredients that may be administered in combination with the compounds of the present invention, either separately or in the same pharmaceutical composition, include, but are not limited to, the following: (i) Antilipolytic agents; (ii) anti-inflammatory agents; (iii) immuno-oncology drugs; (iv) lipid-lowering agents; (v) cholesterol-lowering agents; (vi) Hypoglycemic agents including SGLT2 inhibitors; (vii) antiangiogenic agents; (viii) nonsteroidal anti-inflammatory drugs ("NSAIDs"); (ix) Acetylsalicylic acid drugs (ASA), e.g. aspirin, paracetamol; (x) regenerative therapy treatment; (xi) checkpoint inhibitors, including anti-PD1 inhibitors and anti-PDL1 inhibitors; (xii) chemotherapy procedures; (xiii) Radiation therapy; (xiv) surgery; (xv) uric acid lowering therapy; (xvi) anabolic drugs and cartilage regeneration therapies; (xvii) antifibrotic agents; (xviii) JAK inhibitors; (xix) TNF-α inhibitors; (xx) Antihypertensives; and (xxi) STING / cGAS antagonists and pharma- ceutically acceptable salts thereof.

[0246] In another embodiment of the invention, the pharmaceutical composition comprises: 1) A compound of claim 1 or a pharma- ceutically acceptable salt thereof; 2) The following groups: (i) Antilipolytic agents; (ii) anti-inflammatory agents; (iii) immuno-oncology drugs; (iv) lipid-lowering agents; (v) cholesterol-lowering agents; (vi) Hypoglycemic agents including SGLT2 inhibitors; (vii) antiangiogenic agents; (viii) nonsteroidal anti-inflammatory drugs ("NSAIDs"); (ix) Acetylsalicylic acid drugs (ASA), e.g. aspirin, paracetamol; (x) regenerative therapy treatment; (xi) checkpoint inhibitors, including anti-PD1 inhibitors and anti-PDL1 inhibitors; (xii) chemotherapy procedures; (xiii) Radiation therapy; (xiv) surgery; (xv) uric acid lowering therapy; (xvi) anabolic drugs and cartilage regeneration therapies; (xvii) antifibrotic agents; (xviii) JAK inhibitors; (xix) TNF-α inhibitors; (xx) Antihypertensives; (xxi) STING / cGAS antagonists; and Pharmaceutically acceptable salts thereof or a pharma- ceutically acceptable salt thereof; and 3) Pharmaceutically acceptable carrier Includes.

[0247] Specific compounds that may be used in combination with the compounds of the present invention include anti-lipodegenerative agents, such as, but not limited to, DGAT2 inhibitors.

[0248] Suitable anti-inflammatory agents include, but are not limited to, TNFα inhibitors, JAK inhibitors, and NSAIDs.

[0249] Suitable lipid-lowering agents include, but are not limited to, statins and PCSK9.

[0250] Suitable immuno-oncology agents include, but are not limited to, PD-L1 inhibitors, PD-1 inhibitors, and STING antagonists.

[0251] Suitable hypoglycemic agents include, but are not limited to, insulin, SGLT2 inhibitors, metformin, and GLP1 agonists.

[0252] Suitable anti-angiogenic therapeutics include, but are not limited to, anti-VEG-F therapeutics.

[0253] Suitable NSAIDS or nonsteroidal anti-inflammatory drugs include, but are not limited to, aspirin, diclofenac, diflunisal, etodolac, fenoprofin, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, meloxicam, naproxen, naproxen sodium, oxaprozin, piroxicam, sulindac, and tolmetin.

[0254] Suitable painkillers include, but are not limited to, acetaminophen and duloxetine.

[0255] The above combinations include the combination of the compound of the present invention with not only one other active compound, but also two or more other active compounds.Non-limiting examples include the combination of the compound with two or more active compounds selected from antilipodegenerative agents, anti-inflammatory agents, lipid-lowering agents, antifibrotic agents, immuno-tumor agents, glucose-lowering agents and anti-angiogenic agents, NSAIDs (non-steroidal anti-inflammatory drugs), and analgesics.

[0256] The present invention also provides a method for treating or preventing an NLRP3-mediated disease, disorder, or condition, comprising administering to a patient in need of such treatment or at risk of developing an NLRP3-mediated disease a therapeutically effective amount of an NLRP3 inhibitor and an amount of one or more active ingredients, which together provide effective relief.

[0257] In a further aspect of the present invention, there is provided a pharmaceutical composition comprising an NLRP3 inhibitor and one or more active ingredients, together with at least one pharma- ceutically acceptable carrier or excipient.

[0258] Thus, according to a further aspect of the present invention, there is provided the use of an NLRP3 inhibitor and one or more active ingredients for the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition mediated by NLRP3. Thus, in a further or alternative aspect of the present invention, there is provided a product comprising an NLRP3 inhibitor and one or more active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a disease, disorder or condition mediated by NLRP3. Such a combined preparation may, for example, be in the form of a twin pack.

[0259] It will be appreciated that for the treatment or prevention of cardiometabolic diseases, neurodegenerative diseases and inflammatory joint diseases, fibrosis, cancer, compound q of the present invention can be used in combination with another pharmaceutical agent effective to treat the disease, disorder or condition.

[0260] The present invention also provides a method for treating or preventing chronic inflammatory conditions, comprising administering to a patient in need of such treatment an amount of a compound of the present invention and an amount of another pharmaceutical agent effective to address the disorder, disease or condition, which together provide effective relief.

[0261] The present invention also provides a method for treating or preventing chronic inflammatory conditions, which comprises administering to a patient in need of such treatment an amount of a compound of the present invention and an amount of another pharmaceutical agent useful in treating that particular condition, disorder or disease, which together provide effective relief.

[0262] The term "therapeutically effective amount" refers to that amount of a compound of structural formula I that elicits the physiological or medical response of a cell, tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or other clinical practitioner, including alleviation of the symptoms of the disease being treated. The novel methods of treatment of the present invention are directed to disorders known to those of skill in the art. The term "mammal" includes humans and companion animals such as dogs and cats.

[0263] The weight ratio of the compound of formula I and the second active ingredient can vary and depends on the effective dose of each ingredient. Generally, each effective dose is used. Thus, for example, when the compound of formula I is combined with an antilipid degeneration agent, the weight ratio of the compound of formula I is generally in the range of about 1000:1 to about 1:1000, preferably in the range of about 200:1 to about 1:200. The combination of the compound of formula I and other active ingredients is also generally within the above range, but in each case, the effective dose of each active ingredient should be used.

[0264] Synthesis method The following schemes and examples show methods that can be used to synthesize compounds of formula I according to the present invention. These schemes and examples are provided to illustrate the present invention and should not be construed as limiting the present invention in any manner. Unless otherwise specified, 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 with Chemdraw version 21.0.0.28.

[0265] Device Reverse phase chromatography was performed on a Waters 150 equipped with columns selected from the following: Phenomenex Synergi C18 (250 mm x 30 mm x 4 microns), Phenomenex Luna C18 (250 mm x 21 mm x 5 microns), Agilent Zorbax Bonus-RP (150 mm x 21 mm x 5 microns), Waters X-Select CSH C18 (150 mm x 19 mm x 5 microns). Conditions included high pH (0% to 100% acetonitrile / water eluent with 0.1% NH4OH by volume) or low pH (0% to 100% acetonitrile / water eluent with 0.1% TFA or formic acid by volume) and are shown in some examples. SFC chiral resolution was performed on a Waters Thar 80 SFC 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 Chiralpak AD column, 25% iPrOH / CO2; Chiral Method F: ChiralPak ID column, 30% MeOH / CO2; Chiral Method G: ChiralPak IB-N column, 15% MeOH / CO2.

[0266] LC / MS measurements were performed on a Waters ACQUITY UPLC equipped with a DAD and QDa MS detector under the following conditions: a Waters ACQUITY UPLC BEH C18 1.7 mm 2.1 x 50 mm column containing mobile phase A: 0.1% TFA in water and B: 0.1% TFA / acetonitrile, with a flow rate of 0.5 mL / min, a gradient from 10% B to 90% B over 2.0 min, and a 0.4 min hold at 90% B. 1H NMR was obtained using a Bruker 500 MHz NEO NMR spectrometer equipped with a 500 nm Probe according to standard analytical techniques, and the spectral results are reported unless otherwise specified. Chemical shifts (δ) values ​​are reported in delta (δ) units, parts per million (ppm). 1 Chemical shifts for H NMR spectra are given relative to residual non-deuterated solvent signals (CDCl3 referenced to δ 7.26 ppm; DMSO d-6 referenced to δ 2.50 ppm; CD3OD referenced to δ 3.31 ppm). Multiplicities are reported with the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet or overlap of unequal resonances. Coupling constants (J) are reported in Hertz (Hz).

[0267] General preparative conditions for separating diastereomeric or enantiomeric mixtures of compounds using chiral SFC are as follows: [Table 1]

[0268] Abbreviation: "*" in the molecule indicates a stereocenter. Ac is acetyl. OAc is acetate. AcOH is acetic acid. aq. is aqueous solution. B2pin2 is bis(pinacolato)diboron. BPin ester is boronic acid pinacol ester. Boc or boc is tert-butoxycarbonyl. br is broad. Bu or nBu is n-butyl. Bz is benzoyl. °C is Celsius. Calc'd is calculated. CDI is 1,1'-carbonyldiimidazole. □ is chemical shift. d is doublet. conc. is concentrate. DFMS is bis(((difluoromethyl)sulfinyl)oxy)zinc. DIC is N,N'-diisopropylcarbodiimide. DAST is diethylaminosulfur trifluoride. DCE is dichloroethane. DCM is dichloromethane. dd is doublet of doublet. dqd is a doublet of a quartet of doublets. DEA is diethanolamine. DIEA is N,N-diisopropylethylamine. DMA is dimethylacetamide. DME is dimethoxyethane. DMF is dimethylformamide. DMSO is dimethylsulfoxide. dtbbpy is 4,4′-di-tert-butyl-2,2′-dipyridyl. dppf is 1,1′-bis(diphenylphosphino)-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 equivalents. g is grams. h or hr(s) is hours. HOAt is 1-hydroxy-7-azabenzotriazole. HPLC is high performance liquid chromatography. Hz is hertz. iPr is isopropyl. iPrOH or IPA is isopropyl alcohol. iPrMgCl is isopropyl magnesium chloride. is the binding constant. L is liters. 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 methanol. MeCN is acetonitrile. mg is milligram. min is minute. mL is milliliter. mM is millimolar. mmol is millimole. MHz is megahertz. □L is microliter. MS is mass spectrometry. nM is nanomolar. NHPI is N-hydroxyphthalimide. NaHMDS is sodium bis(trimethylsilyl)amide. NHOAC is ammonium acetate. NMO is 4-methylmorpholine N-oxide. NMP is N-methylpyrrolidone. PCC is pyridinium chlorochromate. Pd / C is palladium on carbon. Pd(DPPF)Cl2 is [1,1′-bis-(diphenylphosphino)-ferrocene]dichloropalladium(II). Pd(PPh3)4 is tetrakis(triphenylphosphine)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 preparative. q is quartet. rac is racemic mixture. rt or RT is room temperature. s is singlet. sat. or satd is saturated. SFC is supercritical fluid chromatography. SnAr is nucleophilic aromatic substitution. t is triplet; TBHP is tert-butyl hydroperoxide. tBu is tert-butyl. tBuOH is tert-butyl alcohol. tert is tertiary. TBAF is tetrabutylammonium fluoride. TEA is triethylamine. TFA is trifluoroacetic acid. THF is tetrahydrofuran. Ti(OEt)4 is titanium(IV) ethoxide. Ti(OiPr)4 is titanium(IV) isopropoxide. TLC is thin layer chromatography. TMHD is 2,2,6,6-tetramethyl-3,5-heptanedione. TMS-Diazomethane is trimethylsilyl-diazomethane. tt is a triplet of triplets.XPhos Pd G3 is (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. UV is ultraviolet light.

[0269] Diagram A [ka]

[0270] Scheme A shows the synthesis of aryl and heteroaryl boronates such as A-2 from aryl halides (Cl, Br, or I) such as A-1. The aryl boronates A-2 are prepared by palladium catalyzed Suzuki-Miyaura borylation of B2pin2 of aryl halides such as A-1 in the presence of a suitable base.

[0271] Diagram B [ka]

[0272] Scheme B shows a synthetic procedure for the preparation of phthalazine derivatives of formula B-4. Heteroaryl diacids of formula B-1 are treated with an acid, such as H2SO4, in a suitable alcoholic solvent (ROH), such as MeOH, to give diesters of formula B-2. The diesters of formula B-2 are condensed with hydrazine, followed by treatment with aqueous HCl to give pyridazine-1,4-diones of formula B-3. Reaction of pyridazine-1,4-diones B-3 with a suitable deoxychlorination reagent, such as POCl3, gives dichlorophthalazine derivatives of formula B-4.

[0273] Diagram C [ka]

[0274] Scheme C shows a synthetic procedure for preparing phthalazine derivatives such as C-2a and C-2b from precursors of formula B-4. Nucleophilic aromatic substitution (SnAr) proceeds using various secondary amines in the presence of a base such as K2CO3 to give tertiary amines of formula C-1a and C-1b. Cross-coupling using appropriate aryl nucleophiles such as arylboronic acids with palladium catalyst gives the biaryl products, which are deprotected in situ, if applicable, to give compounds of formula C-2a and C-2b. Regioisomers, if present, are separated chromatographically, preferably using reversed-phase HPLC or SFC.

[0275] Diagram D [ka]

[0276] Scheme D shows a synthetic procedure for preparing phthalazine derivatives such as C-2a from precursors of formula B-4. Suzuki cross-coupling using an appropriate aryl nucleophile such as an arylboronic acid and a palladium catalyst gives the biaryl products of formula D-1. If regioisomers are present, they are chromatographically separated, preferably using silica gel chromatography. Subsequent nucleophilic aromatic substitution reactions (SnAr) with various secondary amines in the presence of a base such as K2CO3 produce tertiary amines of formula C-2a.

[0277] Diagram E [ka]

[0278] Scheme E illustrates the preparation of alkylated compounds of formula E-1 from the corresponding biaryl chloride D-1 and a suitable alkyl electrophile, such as an alkyl halide or N-hydroxyphthalimide (NHPI) ester. Nickel-catalyzed cross-electrophile coupling proceeds to give the alkylated compounds of formula E-1.

[0279] Diagram F [ka]

[0280] Scheme F illustrates the preparation of tertiary alcohol compounds of formula F-2 from the corresponding biaryl chloride D-1 and an appropriate alkenyl nucleophile such as pinacol boronate ester. Palladium catalyzed cross-coupling affords biaryl alkenes of formula F-1. Subsequent alkene hydration using Mukaiyama-Magnus conditions affords tertiary alcohols of formula F-2.

[0281] Diagram G [ka]

[0282] Scheme G shows how to prepare alkylated pyridopyridazines of formula G-2a and G-2b by Minisci-type radical addition to G-1 using a suitable radical precursor, such as a zinc sulfinate reagent. The reaction proceeds in the presence of an oxidizing agent, such as TBHP, to give a regioisomeric mixture of substituted pyridopyridazines of formula G-2a and G-2b, which are then separated by SFC.

[0283] Intermediate 1 2-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] To 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 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 stirred at 105 °C for 12 h. The reaction mixture was cooled to room temperature, filtered and the solvent was removed under reduced pressure. The resulting crude mixture was carried forward without further purification. 1H NMR (500 MHz, CDCl3) δ 7.88 (br d, J = 7.6 Hz, 1H), 7.51 (br d, J = 7.7 Hz, 1H), 7.41 (s, 1H), 6.26-6.82 (t, J = 74.4 Hz, 1H), 1.37 ppm (s, 12H).

[0284] Intermediate 2 1,4-Dichloropyridazino[4,5-d]pyridazine [ka] Step 1: Dimethylpyridazine-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 provide the title compound. LCMS [M+H] + =197.1(Calculated value:197.1).

[0285] Step 2: 2,3-Dihydropyridazino[4,5-d]pyridazine-1,4-dione: A solution of dimethylpyridazine-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 under vigorous stirring for 1 h. 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, then the mixture was acidified to pH 3 with concentrated aqueous HCl. Stirred for 20 min. The mixture was cooled to room temperature, filtered and the resulting solid was dried in vacuum to give the title compound. LCMS [M+H] + =165.0(Calculated value:165.0).

[0286] 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 onto ice. The suspension was adjusted to pH 7 with saturated aqueous NaHCO3 and then diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2x). 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).

[0287] Table 1. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for Intermediate 2. [Table 2]

[0288] Intermediate 6 (3aR,7aR)-6-Methyloctahydro-1H-pyrrolo[2,3-c]pyridine [ka] Step 1: tert-Butyl (3aS,7aR)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate Racemic tert-butyl (cis)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (Synthonix, 15 g, 66.3 mmol) was separated by chiral SFC (Method A) to give the corresponding enantiomers: Peak 1: tert-butyl (3aR,7aS)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (6.8 g, 30.0 mmol), and Peak 2: tert-butyl (3aS,7aR)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (5.7 g, 25.2 mmol).

[0289] Step 2: tert-Butyl (3aS,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate:To a solution of tert-butyl (3aS,7aR)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1 g, 4.42 mmol) in MeOH (8.8 mL) at 0° C. was added 37% aqueous formaldehyde (1.65 mL, 22.1 mmol) and NaBH3CN (0.56 g, 8.84 mmol). The mixture was allowed to warm 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).

[0290] 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 tert-butyl (3aS,7aR)-6-methyl-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (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).

[0291] Intermediate 7 Cis-1,3-dioxoisoindolin-2-yl 2,6-dimethyltetrahydro-2H-pyran-4-carboxylate [ka] 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). A stock solution of DIC (1 M in DCM, 0.7 mL, 0.7 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was filtered, the solvent removed under reduced pressure, and the crude residue was purified by silica gel chromatography (EtOAc:Hexanes) to give the title compound.

[0292] Examples 1 and 2 (S)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrolidin-3-ol (Example 1); and (S)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]-pyridazin-4-yl)-3-methylpyrrolidin-3-ol (Example 2) [ka] 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, and 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 compounds as a mixture of regioisomers was used directly in the next step. LCMS [M+H] + =265.0 (calculated value: 265.1).

[0293] Step 2: (S)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrolidin-3-ol and (S)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-3-methylpyrrolidin-3-ol: The mixture of regioisomers (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 XPhos Pd G3 (Sigma, 177 mg, 0.21 mmol) were suspended in 1,4-dioxane (10 mL) and a stock solution of K3PO4 (3 M in water, 1.54 mL, 4.61 mmol). The mixture was degassed by bubbling with Ar for 10 min, then sealed and heated to 100 °C with stirring 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 give the title compounds as a mixture of regioisomers. The regioisomers were separated by chiral SFC (Method B). The faster eluting regioisomer was obtained (Example 1). 1H NMR (500 MHz, DMSO-d6) δ 8.87 (d, J = 5.9 Hz, 1H), 8.83 (s, 1H), 8.18 (d, J = 5.9 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.30 (s, 1H), 4.94 (s, 1H), 4.20 - 4.11 (m, 1H), 3.96 - 3.85 (m, 2H), 3.72 (d, J = 10.8 Hz, 1H), 2.04 - 1.91 (m, 2H), 1.42 (s, 3H).LCMS[M+H] + =391.0 (calculated: 391.1). The later eluting positional isomer was obtained (Example 2). 1 H NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.65 (s, 1H), 8.82 (d, J = 5.6 Hz, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.33 - 7.27 (m, 3H), 4.92 (s, 1H), 4.19 (td, J = 10.1, 7.1 Hz, 1H), 3.98 (d, J = 11.1 Hz, 1H), 3.97 - 3.91 (m, 1H), 3.76 (d, J = 11.2 Hz, 1H), 2.06 - 1.92 (m, 2H), 1.43 (s, 3H).LCMS[M+H] + =391.0 (calculated value: 391.1).

[0294] Table 2. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for Examples 1 and 2. Regioisomers (if present) were separated by silica gel chromatography after step 1 or reverse phase HPLC after step 2. [Table 3] TIFF2025023868000030.tif249168TIFF2025023868000031.tif95167

[0295] Table 3. Using the appropriate starting materials, the following compounds were prepared using procedures similar to those described for Examples 1 and 2. The chiral SFC method specified in the table was used to separate the regioisomeric products after step 2. For pairs of regioisomers, the faster eluting isomer is listed first. [Table 4]

[0296] Example 22 (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-3-methylpyrrolidin-3-ol [ka] 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 bubbling with Ar for 10 min. The vial was heated to 85 °C and stirred for 2 h. The reaction was cooled to room temperature, diluted with EtOAc, and dry loaded onto silica gel. Purification by silica gel chromatography (EtOAc:Hexanes) afforded the title compound. LCMS [M+H] + =326.0(Calculated value:326.0).

[0297] Step 2: (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidin-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 cooled to room temperature and directly purified by preparative reverse phase HPLC (C18 stationary phase, MeCN / H2O+0.05% FA) to give the title compound.1 H NMR (500 MHz, DMSO-d6) δ 10.51 (s, 1H), 9.09 (dd, J = 4.2, 1.5 Hz, 1H), 7.85 (dd, J = 8.4, 1.5 Hz, 1H), 7.78 (dd, J = 8.4, 4.2 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 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).

[0298] Table 4. Using the appropriate starting materials and procedures similar to those described for Example 22, the following compounds were prepared.

[0299] [Table 5] TIFF2025023868000035.tif255169TIFF2025023868000036.tif245170TIFF2025023868000037.tif243170TIFF2025023868000038.tif40168

[0300] Table 5. Using the appropriate starting materials, the following compounds were prepared using a procedure similar to that described for Example 22. The enantiomeric products were separated using the chiral SFC method specified in the table. For pairs of enantiomers, the faster eluting isomer is listed first.

[0301] [Table 6]

[0302] Example 53 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-methyl-4-(trifluoromethyl)phenyl)phthalazine [ka] Step 1: 1-chloro-4-(2-methyl-4-(trifluoromethyl)phenyl)phthalazine: To 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 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 layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (EtOAc:Hexanes) followed by reverse phase 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 layer was extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Further purification by silica gel chromatography (EtOAc:Hexanes) afforded the title compound. LCMS [M+H] + =323.1(Calculated value: 323.1).

[0303] Step 2: 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-methyl-4-(trifluoro-methyl)phenyl)phthalazine: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-1,3-dioxoisoindolin-2-yl 2,6-dimethyltetrahydro-2H-pyran-4-carboxylate (78 mg, 0.26 mmol), 1-chloro-4-(2-methyl-4-(trifluoromethyl)phenyl)-phthalazine (55 mg, 0.17 mmol), and Zn powder (Strem, 22 mg, 0.34 mmol) were placed under Ar and the catalyst solution (0.7 mL) was added. The vial was sealed and heated to 50 °C under high agitation (>1000 rpm) overnight. The reaction mixture was cooled to room temperature, filtered, and directly purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / H2O+0.05% FA) to give the title compound. 1 H NMR (500 MHz, CD3CN) δ 8.40 (d, J = 8.4 Hz, 1H), 7.99 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.86 (td, J = 7.6, 7.1, 1.0 Hz, 1H), 7.77 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.53 (dd, J = 8.0, 4.5 Hz, 2H), 4.00 (tt, J = 12.0, 3.6 Hz, 1H), 3.82 (dqd, J = 12.4, 6.2, 1.8 Hz, 2H), 2.11 (s, 3H), 2.02 (d, J = 11.5 Hz, 2H), 1.83 - 1.71 (m, 2H), 1.24 (d, J = 6.2 Hz, 6H).LCMS[M+H] + =401.2(Calculated value: 401.2).

[0304] Examples 54 and 55 (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 (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) [ka] 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: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) were 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 bubbling with Ar for 10 min, then 1M aqueous K3PO4 solution (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).

[0305] Step 2: (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 (2R,4r,6S)-4-(5-(2-hydroxy-4-(trifluoromethyl)-phenyl)pyrido[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) (98 mg, 0.16 mmol) were added to i The mixture was bubbled with O2 for 5 min, then PhSiH3 (33 μL, 0.27 mmol) was added. 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 diluted with 1M aqueous HCl, and EtOAc. The layers were separated, and the aqueous layer was neutralized to pH 7 and back-extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc:Hexanes) to afford the title compound as two separated diastereomers. The faster eluting diastereomer was obtained (Example 54). 1H NMR (500 MHz, CD3CN) δ 9.23 (dd, J = 4.2, 1.4 Hz, 1H), 8.38 (dd, J = 8.6, 1.4 Hz, 1H), 7.91 (dd, J = 8.5, 4.3 Hz, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.43 - 7.34 (m, 2H), 6.59 (s, 1H), 4.17 (dq, J = 11.0, 6.3 Hz, 2H), 2.08 (d, J = 13.0 Hz, 2H), 1.82 - 1.79 (m, 2H), 1.21 (d, J = 6.2 Hz, 6H).LCMS[M+H] + =420.1 (calculated value: 420.2). After the title compound was dissolved, the opposite form was obtained (Example 55). 1 H NMR (500 MHz, CD3CN) δ 9.25 - 9.20 (m, 1H), 8.40 (dd, J = 8.6, 1.1 Hz, 1H), 7.91 (dd, J = 8.5, 4.3 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.42 - 7.39 (m, 2H), 6.36 (s, 1H), 3.86 (dq, J = 11.4, 6.3 Hz, 2H), 2.75 (d, J = 13.1 Hz, 2H), 1.71 - 1.62 (m, 2H), 1.14 (d, J = 6.2 Hz, 6H).LCMS[M+H] + =420.1 (calculated value: 420.2).

[0306] Examples 56 and 57 (S)-1-(2-(difluoromethyl)-5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidin-3-ol (Example 56); and (S)-1-(3-(difluoromethyl)-5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidin-3-ol (Example 57)

change

[0307] Examples of pharmaceutical compositions As a specific embodiment of the oral pharmaceutical composition, a tablet of 100 mg strength is composed of 100 mg of any of the examples, 268 mg of microcrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg of magnesium stearate. The active ingredient, microcrystalline cellulose, and croscarmellose are first mixed. The mixture is then lubricated with magnesium stearate and compressed into tablets.

[0308] Biological assays Activation of the canonical NLRP3 inflammasome requires two steps: priming and activation. Priming signals, such as pathogen-activating molecular patterns (PAMPs) and danger-activating molecular patterns (DAMPs), are recognized by Toll-like receptors and trigger signaling through nuclear factor-κB (NF-KB), which in turn upregulates the transcription of inactive NLRP3 and inflammasome-associated components, such as proIL-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 induces oligomerization of NLRP3 and subsequent assembly of NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), and pro-caspase 1 into the inflammasome complex. This induces the conversion of pro-caspase 1 to caspase 1 and the production and secretion of mature IL-1β and IL-18 (Kim et al., J. Inflamm. 2015, 12, 41; Ozaki et al., J. Inflamm. Res. 2015, 8, 15 - 27; Rabeony et al., Eur. J. Immunol. 2015, 45, 2847). Upon assembly of the inflammasome complex, oligomerization of NLRP3 induces the nucleation of ASC, an event commonly referred to as "ASC SPECK" formation, as it is identified in cells as distinct specks within cells after staining and visualization of ASC using common immunocytochemical methods.

[0309] The ability of compounds to inhibit NLRP3 inflammasome activation was measured in vitro by monitoring the formation of ASC-SPECK in human monocytic THP-1 cells after stimulation. THP-1 cells (ATCC Catalog No. TIB-202) were maintained in complete growth medium containing Roswell Park Memorial Institute RPMI (ATCC Catalog No. 30-2001), 10% heat-inactivated fetal bovine serum, 1x penicillin / streptomycin, and 0.05 mM 2-mercaptoethanol. At the start of the assay, undifferentiated THP-1 cells were seeded in 384-well plates (Poly-D-lysine coated Cell CarrierUltra microplates, Perkin Elmer Catalog No. 6057500) at a density of 20,000 cells / well in complete growth medium supplemented with 10 ng / mL phorbol 12-myristate 13-acetate (PMA, Sigma Catalog No. P8139) and incubated overnight. The next day, medium was replaced with assay medium [RPMI (Gibco Cat. No. 11875-093), 0.01% bovine serum albumin (BSA)]. Compounds were serially diluted in DMSO and added to the wells, followed 1 h later by the addition of 12.5 μg / mL gramicidin (Enzo Lifescience, Cat. No. ALX-350-233-M005). All incubations were performed at 37°C (5% CO2 / 95% air). After 3 h of treatment with gramicidin, cells were fixed with 4% paraformaldehyde and stored at 4°C until immunofluorescence staining.

[0310] Immunofluorescence staining: Anti-ASC antibody (MBL Catalog No. D086-3) was desalted and labeled with ALEXA488 antibody labeling kit (THERMO Catalog No. A20181) before being used as described below. After fixation, the following procedure was performed at room temperature. Cells were first permeabilized with 0.3% TRITON® X-100 in phosphate-buffered saline (PBS) for 15 min, then incubated for 1 h in blocking buffer containing 5% goat serum, 0.3% tween-20, and 0.03% sodium azide in PBS. Cells were stained with a mixture of ASC-Alexa 488 antibody (diluted 1:200 in blocking buffer) and nuclear stain DRAQ5 (1:5000 in blocking buffer, Thermo Catalog No. 62251) in blocking buffer for 1 h. After washing with 0.3% Tween-20 in PBS, plates were imaged on the Opera Phenix High Content Screening System. The number of DRAQ5-positive cells, including ASC SPECKS, was quantified in each well.

[0311] Data analysis: EC values ​​were determined by standard curve fitting analysis using an in-house developed program in TIBCO Spotfire software. 50 values ​​were calculated.

[0312] The compounds of the present invention inhibit the activation of NLRP3 inflammasome in the above biological assays and inhibit EC 50 The specific EC values ​​of the compounds of Examples 1 to 57 in the above biological assays are less than 5 μM. 50 The values ​​are listed in Table I.

[0313] Table I. EC of examples that inhibit NLRP3 inflammasome activation in the above biological assays 50 Value (nM) [Table 7] TIFF2025023868000044.tif45170

[0314] The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be accorded the broadest interpretation consistent with the description as a whole.

[0315] Although the present invention has been described and illustrated with reference to certain specific embodiments thereof, those skilled in the art will understand that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols can be made without departing from the scope of the present invention. For example, as a result of changes in the responsiveness of a mammal undergoing treatment for any indication with the compounds of the present invention as set forth above, effective dosages other than the specific dosages set forth herein may be applied. The specific pharmacological response observed may vary according to and depending on the presence or absence of the particular active compound or pharmaceutical carrier selected, as well as the type of formulation and method of administration used, and such expected variations or differences in results are contemplated in accordance with the purpose and practice of the present invention.

Claims

1. The present invention relates to a compound of structural formula I: or a pharma- ceutically acceptable salt thereof. [During the ceremony T independently represents the group: CR ３ , and N; provided that one or two of T, U, V, and W are N; U independently represents the group: 1) CR ４ , and 2) N Selected from: V independently represents the group: 1) CR ５ , and 2) N Selected from: W independently represents the group: 1) CR ６ , and 2) N Selected from: R １ is a group: 1) morpholine, 2) thiomorpholine, 3) piperidine, 4) pyrrolidine, 5) tetrahydropyran, 6) octahydro-1H-pyrrolo[2,3-c]pyridine, 7) 3-azabicyclo[3.1.0]hexane, 8) 5-azaspiro[2.4]heptane, 9) 1-oxa-7-azaspiro[4.4]nonane, 10) 1-oxa-8-azaspiro[4.5]decane, 11) 3-oxa-1,8-diazaspiro[4.5]decane, 12) 2,8-diazaspiro[4.5]decane, 13) 1-oxa-3,8-diazaspiro[4.5]decane, 14) 2-oxa-8-azaspiro[4.5]decane, 15) 1,8-diazaspiro[4.5]decane, and 16) 1-Oxa-4,9-diazaspiro[5.5]undecane is selected from Here, R １ is unsubstituted or R ａ Substituted by 1 to 6 substituents selected from: R ２ is a group: 1) aryl, and 2) Heteroaryl is selected from Here, R ２ is unsubstituted or R ｂ Substituted by 1 to 5 substituents selected from: R ３ is a group: 1) Hydrogen, 2) OH, 3) C.N., 4)CF ３ 、 5)CF 2 H、 6) -C １－６ Alkyl, 7) -O-C １－６ Alkyl, 8) halogens, and 9) -C １－６ Alkyl-O-C １－６ Alkyl is selected from Here, R ３ is unsubstituted or R ｄ Substituted by 1 to 5 substituents selected from: R ４ is a group: 1) Hydrogen, 2) OH, 3) C.N., 4)CF ３ 、 5)CF ２ H、 6) -C １－６ Alkyl, 7) -O-C １－６ Alkyl, 8) halogens, 9) -C ３－６ Cycloalkyl, 10) -C ２－６ Heterocyclic alkyl, and 11) -C １－６ Alkyl-O-C １－６ Alkyl is selected from Here, R ４ is unsubstituted or R ｅ Substituted by 1 to 5 substituents selected from: R ５ is a group: 1) Hydrogen, 2) OH, 3) C.N., 4)CF ３ 、 5)CF ２ H、 6) -C １－６ Alkyl, 7) -O-C １－６ Alkyl, 8) halogens, 9) -C ３－６ Cycloalkyl, 10) -C ２－６ Heterocyclic alkyl, and 11) -C １－６ Alkyl-O-C １－６ Alkyl is selected from Here, R ５ is unsubstituted or R ｆ Substituted by 1 to 5 substituents selected from: R ６ is a group: 1) Hydrogen, 2) OH, 3) C.N., 4)CF ３ 、 5)CF ２ H、 6) -C １－６ Alkyl, 7) -O-C １－６ Alkyl, 8) halogens, 9) -C ３－６ Cycloalkyl, 10) -C ２－６ Heterocyclic alkyl, and 11) -C １－６ Alkyl-O-C １－６ Alkyl is selected from Here, R ６ is unsubstituted or R ｇ Substituted by 1 to 5 substituents selected from: Each R ａ are independently the groups: 1) C.N., 2) oxo, 3) -OH, 4) halogens, 5) -C １－６ Alkyl, 6) -O-C １－６ Alkyl, 7) -C ２－６ Alkenyl, 8) -C ２－６ Alkynyl, 9) -C ３－６ Cycloalkyl, 10) -C ２－６ Heterocyclic alkyl, 11) aryl, 12) heteroaryl, and 13) -C(O)C １－６ Alkyl is selected from Here, each R ａ is unsubstituted or substituted with halogen, CF ３ , O.H., C. １－６ Alkyl, and -OC １－６ substituted by 1 to 6 substituents selected from alkyl; Each R ｂ are independently the groups: 1) C.N., 2) -OH, 3)-CH ３ 、 4)-CF ３ 、 5)-CF ２ H、 6) -OCF ２ H, and 7) Cyclopropane is selected from Here, each R ｂ is unsubstituted or substituted with halogen, CF ３ , C.F. ２ H, O.C.F. ３ , C.N., C.H. ２ CF ３ , C.F. ２ CH ３ , -C １－６ Alkyl, and -OC １－６ substituted by 1 to 6 substituents selected from alkyl; Each R ｄ are independently the groups: 1)CF ３ 、 2) halogens, and 3) -C １－６ Alkyl is selected from where alkyl is unsubstituted or CF ３ , halogen, OH and -OC １－６ substituted by 1 to 3 substituents selected from alkyl; Each R ｅ are independently the groups: 1)CF ３ 、 2) halogens, and 3) -C １－６ Alkyl is selected from where alkyl is unsubstituted or CF ３ , halogen, OH and -OC １－６ substituted by 1 to 3 substituents selected from alkyl; Each R ｆ are independently the groups: 1)CF ３ 、 2) halogens, and 3) -C １－６ Alkyl, is selected from where alkyl is unsubstituted or CF ３ , halogen, OH and -OC １－６ substituted by 1 to 3 substituents selected from alkyl; Each R ｇ are independently the groups: 1)CF ３ 、 2) halogens, and 3) -C １－６ Alkyl, is selected from where alkyl is unsubstituted or CF ３ , halogen, OH and -OC １－６ substituted by 1 to 3 substituents selected from alkyl; Each R ｈ are independently the groups: 1) Hydrogen, 2) -C １－６ Alkyl, 3) -C ３－６ Cycloalkyl, and 4) -C ２－６ Heterocyclic alkyl is selected from where alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or -CF ３ , halogen, OH and -OC １－６ substituted by 1 to 3 substituents selected from alkyl; Each R ｉ are independently the groups: 1) Hydrogen, 2) -C １－６ Alkyl, 3) -C ３－６ Cycloalkyl, and 4) -C ２－６ Heterocyclic alkyl, is selected from where alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or CF ３ , halogen, OH and -OC １－６ substituted by 1 to 3 substituents selected from alkyl; Each R ｊ are independently the groups: 1) Hydrogen, 2) -C １－６ Alkyl, 3) -C ３－６ Cycloalkyl, and 4) -C ２－６ Heterocyclic alkyl is selected from where alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or CF ３ , halogen, OH and -OC １－６ substituted by 1 to 3 substituents selected from alkyl; Each R ｋ are independently the groups: 1) -C １－６ Alkyl, 2) -C ３－６ Cycloalkyl, and 3) -C ２－６ Heterocyclic alkyl is selected from where alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or -CF ３ , halogen, OH and -OC １－６ substituted by 1 to 3 substituents selected from alkyl; Each R Ｌ are independently the groups: 1) Hydrogen, 2) -C １－６ Alkyl, 3) -C ３－６ Cycloalkyl, and 4) -C ２－６ Heterocyclic alkyl is selected from where alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or -CF ３ , halogen, OH and -OC １－６ substituted by 1 to 3 substituents selected from alkyl; Each R ｍ is independently 1) -C １－６ Alkyl, 2) -C ３－６ Cycloalkyl, and 3) -C ２－６ Heterocyclic alkyl and where alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or -CF ３ , halogen, OH and -OC １－６ substituted by 1 to 3 substituents selected from alkyl; Each R ｎ are independently the groups: 1) Hydrogen, 2) C １－６ Alkyl, 3) -C ３－６ Cycloalkyl, and 4) -C ２－６ Heterocyclic alkyl is selected from where alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or -CF ３ , halogen, OH and -OC １－６ substituted by 1 to 3 substituents selected from alkyl; Each R ｏ are independently the groups: 1) OH, 2) -C １－６ Alkyl, 3) -C ３－６ Cycloalkyl, and 4) -C ２－６ Heterocyclic alkyl is selected from where alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or -CF ３ , halogen, OH and -OC １－６ substituted by 1 to 3 substituents selected from alkyl; 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. However, the following compounds or pharma- ceutically acceptable salts thereof are excluded: 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-dimethylmorpholino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol; 5) 2-(1-((cis)-2,6-dimethylmorpholino)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol; 6) 2-(5-((cis)-2,6-dimethylmorpholino)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-dimethylmorpholino)pyridazino[4,5-c]pyridazin-5-yl)-5-(trifluoromethyl)-phenol; 9) 2-(4-((cis)-2,6-dimethylmorpholino)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-dimethylmorpholino)-5-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol; 15) 2-(4-((cis)-2,6-dimethylmorpholino)-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-dimethylmorpholino)-6-methylphthalazin-1-yl)-5-(trifluoromethyl)phenol; 21) 2-(4-((cis)-2,6-dimethylmorpholino)-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-oxo-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-oxo-7-azaspiro[4.4]nonan-7-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 32) (S)-2-(8-(1-oxo-7-azaspiro[4.4]nonan-7-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 33) 2-(8-(1-oxo-8-azaspiro[4.5]decan-8-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 34) 2-(8-(2-oxo-8-azaspiro[4.5]decan-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-oxo-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]decan-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]decan-2-yl)ethan-1-one; 39) 8-(5-(2-hydroxy-4-(trifluoro-methyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-3-methyl-1-oxo-3,8-diazaspiro[4.5]decan-2-one; 40) 2-(8-(4,4-dimethyl-1-oxo-8-azaspiro[4.5]decan-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-oxo-3,8-diazaspiro[4.5]decan-2-one; 45) 2-(8-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-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-oxo-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-methylmorpholino)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 62) 2-(8-((2S,6S)-2-(hydroxymethyl)-6-methylmorpholino)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 63) 2-(8-((2S,6S)-2-(hydroxymethyl)-6-methylmorpholino)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 64) 2-(8-((2R,6R)-2-(hydroxymethyl)-6-methylmorpholino)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.

2. W is CR ６ 2. The compound of claim 1, wherein:

3. R １ But, group: 1) morpholine, 2) piperidine, 3) pyrrolidine, 4) tetrahydropyran, and 5) Octahydro-1H-pyrrolo[2,3-c]pyridine where R １ is unsubstituted or R ａ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, substituted by 1 to 6 substituents selected from:

4. R １ But, group: 1) morpholine, 2) piperidine, 3) tetrahydropyran, and 4) octahydro-1H-pyrrolo[2,3-c]pyridine, is selected from Here, R １ is unsubstituted or R ａ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, substituted by 1 to 6 substituents selected from:

5. R ２ is heteroaryl, where the heteroaryl is unsubstituted or ｂ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, substituted by 1 to 5 substituents selected from:

6. R ２ is aryl, where the aryl is R ｂ 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, which is substituted by 2 to 5 substituents selected from:

7. R ３ But, group: 1) hydrogen, and 2) -C １－６ Alkyl is selected from Here, R ３ is unsubstituted or R ｄ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, substituted by 1 to 5 substituents selected from:

8. R ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

9. R ４ But, group: 1) Hydrogen, 2) OH, 3) C.N., 4)CF ３ 、 5)CF ２ H、 6) -C １－６ Alkyl, 7) -O-C １－６ Alkyl, 8) halogens, and 9) -C １－６ Alkyl-O-C １－６ Alkyl is selected from Here, R ４ is unsubstituted or R ｅ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, substituted by 1 to 5 substituents selected from:

10. R ４ But, group: 1) hydrogen, and 2) -C １－６ Alkyl is selected from Here, R ４ is unsubstituted or R ｅ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, substituted by 1 to 5 substituents selected from:

11. R ５ But, group: 1) Hydrogen, 2) OH, 3) C.N., 4)CF ３ 、 5)CF ２ H、 6) -C １－６ Alkyl, 7) -O-C １－６ Alkyl, 8) halogens, and 9) -C １－６ Alkyl-O-C １－６ Alkyl is selected from Here, R ５ is unsubstituted or R ｆ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, substituted by 1 to 5 substituents selected from:

12. R ５ But, group: 1) Hydrogen, 2) -C １－６ Alkyl, and 3) Halogens is selected from Here, R ５ is unsubstituted or R ｆ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, substituted by 1 to 5 substituents selected from:

13. R ６ But, group: 1) Hydrogen, 2) -C １－６ Alkyl, and 3) -O-C １－６ Alkyl is selected from Here, R ６ is unsubstituted or R ｇ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, substituted by 1 to 5 substituents selected from:

14. R ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

15. R ２ is heteroaryl, where R ２ is unsubstituted or R ｂ Substituted by 1 to 5 substituents selected from: R ３ But, group: 1) hydrogen, and 2) -C １－６ Alkyl is selected from Here, R ３ is unsubstituted or R ｄ Substituted by 1 to 5 substituents selected from: R ４ But, group: 1) Hydrogen, 2) OH, 3) C.N., 4)CF ３ 、 5)CF ２ H、 6) -C １－６ Alkyl, 7) -O-C １－６ Alkyl, 8) halogens, and 9) -C １－６ Alkyl-O-C １－６ Alkyl is selected from Here, R ４ is unsubstituted or R ｅ Substituted by 1 to 5 substituents selected from: R ５ But, group: 1) Hydrogen, 2) OH, 3) C.N., 4)CF ３ 、 5)CF ２ H、 6) -C １－６ Alkyl, 7) -O-C １－６ Alkyl, 8) halogens, and 9) -C １－６ Alkyl-O-C １－６ Alkyl is selected from Here, R ５ is unsubstituted or R ｆ and R ６ But, group: 1) Hydrogen, 2) -C １－６ Alkyl, and 3) -O-C １－６ Alkyl is selected from Here, R ６ is unsubstituted or R ｇ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, substituted by 1 to 5 substituents selected from:

16. W is CR ６ and R ２ is aryl, where the aryl is R ｂ and is substituted by 2 to 5 substituents selected from R ３ is hydrogen; R ４ But, group: 1) hydrogen, and 2) -C １－６ Alkyl is selected from Here, R ４ is unsubstituted or R ｅ Substituted by 1 to 5 substituents selected from: R ５ But, group: 1) Hydrogen, 2) -C １－６ Alkyl, and 3) Halogens is selected from Here, R ５ is unsubstituted or R ｆ and R ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

17. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

18. 13. Use of a compound according to claim 1 for the manufacture of a medicament useful for the treatment of a disorder, condition or disease responsive to the inhibition of NLRP3 in a mammal in need of such treatment.

19. 13. Use of a compound according to claim 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment, prevention or control of inflammatory, fibrotic, cardiovascular, metabolic and neurodegenerative disorders.

20. 20. The use according to claim 19, wherein the disorder is an inflammatory disorder.

21. 21. The use according to claim 20, wherein the inflammatory disorder is selected from an autoimmune disorder, an autoinflammatory disorder, an inflammatory joint disorder, an inflammatory skin disorder, and a neuroinflammatory disorder.

22. 20. The use according to claim 19, wherein the disorder is selected from atherosclerosis, non-alcoholic steatohepatitis, Alzheimer's disease and Parkinson's disease.

23. 10. A compound according to claim 1, or a pharma- ceutically acceptable salt thereof, for use in therapy.

24. 18. The pharmaceutical composition of claim 17 for the treatment or prevention of a disorder, condition or disease responsive to inhibition of NLRP3 in a patient in need of such treatment.

25. 25. The pharmaceutical composition of claim 24, wherein the disorder is selected from an inflammatory disorder, a fibrotic disorder, a cardiovascular disorder, a metabolic disorder and a neurodegenerative disorder.

26. 26. The pharmaceutical composition of claim 25, wherein the disorder is an inflammatory disorder.

27. 26. The pharmaceutical composition of claim 25, wherein the inflammatory disorder is selected from an autoimmune disorder, an autoinflammatory disorder, an inflammatory joint disorder, an inflammatory skin disorder, and a neuroinflammatory disorder.

28. 25. The pharmaceutical composition of claim 24, wherein the disorder is selected from atherosclerosis, non-alcoholic steatohepatitis, Alzheimer's disease and Parkinson's disease.

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