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] The inflammasome functions as a central signaling hub of the innate immune system. It is a multiprotein complex assembled after the 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 the inflammasome can be formed by nucleotide-binding oligomeric 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 pro-inflammatory cytokines and promotes a form of inflammatory cell death called pyroptosis, which is induced by gasdelmin 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 in both the innate and adaptive immune systems. Therefore, inflammasome activation is a major regulator of the inflammatory cascade.

[0002] The (NOD)-like receptor protein 3 (NLRP3) inflammasome is the most well-studied of all inflammasomes. NLRP3 can be activated by a number of stimuli, including environmental crystals, pollutants, host-derived DAMPs, and protein aggregates (Tartey S and Kanneganti TD. Immunology, 2019 Apr;156(4):329-338). Risk-associated molecular patterns related to NLRP3 include uric acid and cholesterol crystals that cause gout and arteriosclerosis, amyloid P fibrils that are neurotoxic in Alzheimer's disease, and asbestos particles that cause mesothelioma (Kelley et al., Int J Mol Sci, 2019 Jul 6;20(13)). Furthermore, 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 the 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] NLRP3 responds to sterile inflammatory risk signals PAMP or DAMP by interacting with an adapter protein, an apoptosis-related 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, cleaving gasdelmin D (GSDMD) to produce the N-terminal Gsdmd molecule, which creates a pore in the cell membrane and leads to pyroptosis, a type of lytic cell death. Alternatively, caspase 1 cleaves the inflammatory cytokines pro-IL-IB and pro-IL-18, releasing their physiologically active forms (Kelley et al., 2019 - see above). NLRP3 inflammasome activation releases the inflammatory cytokines IL-1β (interleukin-1β) and IL-18 (interleukin-18), and dysregulation of these cytokines can lead to many diseases.

[0005] Dysregulation of the NLRP3 inflammasome or its downstream mediators is associated with many immune disorders, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases. Activation of the NLRP3 inflammasome is associated with the following diseases and disorders: cryopyrin-associated periodic syndromes; sickle cell disease; systemic lupus erythematosus; allodynia; graft-versus-host disease; liver disorders such as non-alcoholic 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, arthritis, osteoarthritis, and rheumatoid arthritis; other rheumatic diseases such as dermatomyositis, Still's disease, and juvenile idiopathic arthritis; kidney-related diseases such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-associated inflammation, diabetic nephropathy, and diabetic nephropathy; and other inflammatory diseases (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-related disorders, such as brain infections, acute injuries, multiple sclerosis, amyotrophic lateral sclerosis, and other neurodegenerative diseases like Parkinson's disease and Alzheimer's disease, are also associated with NLRP3 inflammasome activation (Sarkar et al., NPJ Parkinsons Dis, 2017 Oct 17;3:30).

[0006] Atherosclerosis, type 1 and type 2 diabetes, diabetic complications such as nephropathy and retinopathy, peripheral artery disease, cardiovascular diseases and metabolic diseases such as acute heart failure and hypertension have been associated with NLRP3 (Ridker et al., CANTOS Trial Group. N Engl J Med, 2017 Sep 21;377(12):1119-1131; and Toldo S and Abbate A Nat Rev Cardiol, 2018 Apr;15(4):203-214). Skin diseases associated with NLRP3 include wound healing and scar formation; and inflammatory skin diseases such as acne, atopic dermatitis, hidradenitis suppurativa and psoriasis (Kelly et al., Br J Dermatol, 2015 Dec;1 73(6)). NLRP3 inflammasome activity has been associated with respiratory symptoms 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 eye 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 syndrome, 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 disorders and inflammatory diseases are typically difficult to diagnose or treat efficiently and effectively. Most treatments involve managing symptoms, slowing disease progression, lifestyle modifications, and 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 is still a need for NLRP3 inhibitors that provide novel treatments for diseases and disorders associated with NLRP3 inflammasome activation and dysregulation. The compounds of the present invention are useful for the treatment and prevention of diseases, disorders, and symptoms mediated by the formation and proliferation of the NLRP3 inflammasome.

[0010] NLRP3 inhibitors are mentioned 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, Disclosed in 104, 8041; Nat. 2006, 440, 9; Immunity. 2006, 24, 317. Several patent applications, including 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, describe NLRP3 inhibitors. [Means for solving the problem]

[0011] This invention relates to a novel compound having the following structural formula I and a pharmaceutically acceptable salt thereof. [ka]

[0012] The compound 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 symptoms such as gout, pseudogout (chondrocalcification), 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, etc.

[0013] The present invention also relates to a pharmaceutical composition comprising the compound of the present invention and a pharmaceutically acceptable carrier.

[0014] The present invention also relates to methods for treating, managing, preventing, alleviating, improving, suppressing or controlling disorders, diseases and symptoms that may respond to inhibition of the NLRP3 receptor in subjects requiring 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 pharmaceuticals useful for treating diseases, disorders, and symptoms that may respond to inhibition of the NLRP3 receptor.

[0016] The present invention also relates to treating or preventing diseases, disorders, and symptoms by administering the compounds of the present invention in combination with another therapeutically effective amount of an agent that may be useful in treating these diseases, disorders, and symptoms. The present invention further relates to a method for producing the compounds of the present invention. [Modes for carrying out the invention]

[0017] This invention relates to a novel compound of the following structural formula I or a pharmaceutically acceptable salt thereof; [ka] During the ceremony T is an independent group: 1) CR 3 , and 2) N selected from; provided that zero, one or two of T, U, V and W are N; U is independently selected from the group: 1) CR 4 and 2) N selected from; V is independently selected from the group: 1) CR 5 and 2) N selected from; W is independently selected from the group: 1) CR 6 and 2) N selected from; R 1 is selected from the group: 1) -C 3-12 cycloalkyl, 2) -C 3-12 cycloalkenyl, and 3) -C 2-12 heterocycloalkyl selected from, R 1 is unsubstituted or substituted by 1 to 6 substituents selected from R a ; R 2 is selected from the group: 1) aryl, and 2) heteroaryl selected from, R 2 is unsubstituted or substituted by 1 to 5 substituents selected from R b ; R 3 is selected from the group: 1) hydrogen, 2) OH, 3) CN, 4) CF3, 5) CF2H, 6) -C 1-6 alkyl, 7) -O-C 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 Selected from, R 3 It is either not substituted or R d Substituted by 1 to 5 substituents selected from; R 4 is, 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 selected from R 4 is unsubstituted or substituted by 1 to 5 substituents selected from R e ;[[ID=​7]] R 5 is a group: 1) hydrogen, 2) OH, 3) CN, 4) CF3, 5) CF2H, 6) -C 1-6 alkyl, 7) -O-C 1-6 alkyl, 8) halogen, 9) -C 3-6 cycloalkyl, 10) -C 2-6 heterocycloalkyl, 11) -C 1-6 alkyl-O-C 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 Selected from, R 5 It is either not substituted or R f Substituted by 1 to 5 substituents selected from; R 6 is, 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 Selected from, R 6 It is either not substituted or R g Substituted by 1 to 5 substituents selected from; Each R a They are groups that are independent: 1) CN, 2) Oxo, 3)-OH, 4) Halogen, 5)-C 1-6 Alkyl, 6)-OC 1-6 Alkyl, 7)-C 2-6 Alkenil, 8)-C 2-6 Alkinil, 9)-C 3-6 Cycloalkyl, 10)-C 2-6 Heterocyclic alkyl, 11) Ariel, 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 Alkenil-C 3-6 Cycloalkyl, 19)-C 2-6 Alkenil-C 2-6 Heterocyclic alkyl, 20)-C 2-6 Alkenyl-aryl, 21)-C 2-6 Alkenyl heteroaryl, 22)-C 2-6 Alkinyl-C 3-6 Cycloalkyl, 23)-C 2-6 Alkinyl C 2-6 Heterocyclic alkyl, 24)-C 2-6 Alkinyl-aryl, 25)-C 2-6 Alkinyl heteroaryl, 26)-(CH2) p -OC 1-6 Alkyl, 27)-(CH2) p -OC 2-6 Alkenil, 28)-(CH2) p -OC 2-6 Alkinil, 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 Selected from, Each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 Substituted by 1 to 6 substituents selected from alkyl groups; Each R b They are groups that are independent: 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) Ariel, 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 Selected from, Each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 Substituted by 1 to 6 substituents selected from alkyl groups; Each R d They are groups that are independent: 1) CF3, 2) Halogens, and 3)-C 1-6 Alkyl Selected from, Alkyl groups are either unsubstituted, CF3, halogens, OH, and -OC. 1-6 Substituted by 1 to 3 substituents selected from alkyl groups; Each R e They are groups that are independent: 1) CF3, 2) Halogens, and 3)-C 1-6 Alkyl Selected from, Alkyl groups are either unsubstituted, CF3, halogens, OH, and -OC. 1-6 Substituted by 1 to 3 substituents selected from alkyl groups; Each R f They are groups that are independent: 1) CF3, 2) Halogens, and 3)-C 1-6 Alkyl, Selected from, Alkyl groups are either unsubstituted, CF3, halogens, OH, and -OC. 1-6 Substituted by 1 to 3 substituents selected from alkyl groups; Each R g They are groups that are independent: 1) CF3, 2) Halogens, and 3)-C 1-6 Alkyl, Selected from, Alkyl groups are either unsubstituted, CF3, halogens, OH, and -OC. 1-6 Substituted by 1 to 3 substituents selected from alkyl groups; Each R h They are groups that are independent: 1) Hydrogen, 2)-C 1-6 Alkyl, 3)-C 3-6 Cycloalkyl, and 4)-C 2-6 Heterocyclic alkyl Selected from, Alkyl, cycloalkyl, and heterocyclic alkyl groups are either unsubstituted or contain -CF3, halogens, OH, and -OC. 1-6 Substituted by 1 to 3 substituents selected from alkyl groups; Each R i They are groups that are independent: 1) Hydrogen, 2)-C 1-6 Alkyl, 3)-C 3-6 Cycloalkyl, and 4)-C 2-6 Heterocyclic alkyl Selected from, Alkyl, cycloalkyl, and heterocyclic alkyl groups are either unsubstituted or contain CF3, halogens, OH, and -OC. 1-6 Substituted by 1 to 3 substituents selected from alkyl groups; Each R j They are groups that are independent: 1) Hydrogen, 2)-C 1-6 Alkyl, 3)-C 3-6 Cycloalkyl, and 4)-C 2-6 Heterocyclic alkyl Selected from, Alkyl, cycloalkyl, and heterocyclic alkyl groups are either unsubstituted or contain CF3, halogens, OH, and -OC. 1-6 Substituted by 1 to 3 substituents selected from alkyl groups; Each R k They are groups that are independent: 1)-C 1-6 Alkyl, 2)-C 3-6 Cycloalkyl, and 3)-C 2-6 Heterocyclic alkyl Selected from, Alkyl, cycloalkyl, and heterocyclic alkyl groups are either unsubstituted or contain -CF3, halogens, OH, and -OC. 1-6 Substituted by 1 to 3 substituents selected from alkyl groups; Each R L They are groups that are independent: 1) Hydrogen, 2)-C 1-6 Alkyl, 3)-C 3-6 Cycloalkyl, and 4)-C 2-6 Heterocyclic alkyl Selected from, Alkyl, cycloalkyl, and heterocyclic alkyl groups are either unsubstituted or contain -CF3, halogens, OH, and -OC. 1-6Substituted by 1 to 3 substituents selected from alkyl groups; Each R m They are groups that are independent: 1)-C 1-6 Alkyl, 2)-C 3-6 Cycloalkyl, and 3)-C 2-6 Heterocyclic alkyl Selected from; Alkyl, cycloalkyl, and heterocyclic alkyl groups are either unsubstituted or contain -CF3, halogens, OH, and -OC. 1-6 Substituted by 1 to 3 substituents selected from alkyl groups; Each R n They are groups that are independent: 1) Hydrogen, 2) C 1-6 Alkyl, 3)-C 3-6 Cycloalkyl, and 4)-C 2-6 Heterocyclic alkyl Selected from, Alkyl, cycloalkyl, and heterocyclic alkyl groups are either unsubstituted or contain -CF3, halogens, OH, and -OC. 1-6 Substituted by 1 to 3 substituents selected from alkyl groups; Each R o They are groups that are independent: 1) OH, 2)-C 1-6 Alkyl, 3)-C 3-6 Cycloalkyl, and 4)-C 2-6 Heterocyclic alkyl Selected from, Alkyl, cycloalkyl, and heterocyclic alkyl groups are either unsubstituted or contain -CF3, halogens, OH, and -OC. 1-6 Substituted by 1 to 3 substituents selected from alkyl groups; r is 0, 1, 2, 3, 4, 5, or 6; s is 0, 1, 2, 3, 4, 5, or 6; t is 0, 1, 2, 3, 4, 5, or 6; u is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, 3, 4, 5, or 6; 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, and also includes individual diastereomers, enantiomers and epimers of the compounds, as well as mixtures of the diastereomers and / or enantiomers thereof, including racemic mixtures.

[0019] In one embodiment of the present invention, T independently controls CR 3 Selected from the group and N, wherein 0, 1 or 2 of T, U, V, and W are N. In another embodiment of the present invention, T is CR 3 The case is such that 0, 1, or 2 of T, U, V, and W are N. In another embodiment of the present invention, T is CR 3 In another embodiment of the present invention, T is N, where zero, one, or two of U, V, and W are N. In another embodiment of the present invention, T is N.

[0020] In another embodiment of the present invention, T is independently of group CR 3 Selected from and N, where one or two of T, U, V, and W are N.

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

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

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

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

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

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

[0027] In another embodiment of the present invention, R 1 is group:-C 3-12 Cycloalkyl, -C 3-12 Cycloalkenyl, and -C 2-12 Selected from heterocyclic alkyl groups, R 1 It is either not substituted or R a It is substituted by 1 to 6 substituents selected from. In one class of this embodiment, R 1 It is either not substituted or R a It is substituted by 1 to 5 substituents selected from. In another class of this embodiment, R 1 It is either not substituted or R a It is substituted with 1 to 4 substituents selected from the following.

[0028] In another embodiment of the present invention, R 1 is -C 3-12 It is a cycloalkenyl, and R 1 It is either not substituted or R a It is substituted by 1 to 6 substituents selected from. In one class of this embodiment, R 1 It is either not substituted or R a It is substituted by 1 to 5 substituents selected from. In another class of this embodiment, R 1 It is either not substituted or R a It is substituted with 1 to 4 substituents selected from the following.

[0029] In another embodiment of the present invention, R 1 is group:-C 3-12 Cycloalkyl and -C 2-12 Selected from heterocyclic alkyl groups, R 1 It is either not substituted or R a It is substituted by 1 to 6 substituents selected from. In one class of this embodiment, R 1It is either not substituted or R a It is substituted by 1 to 5 substituents selected from. In another class of this embodiment, R 1 It is either not substituted or R a It is substituted with 1 to 4 substituents selected from the following.

[0030] In another embodiment of the present invention, R 1 is -C 3-12 It is cycloalkyl, R 1 It is either not substituted or R a It is substituted by 1 to 6 substituents selected from. In one class of this embodiment, R 1 It is either not substituted or R a It is substituted by 1 to 5 substituents selected from. In another class of this embodiment, R 1 It is either not substituted or R a It is substituted with 1 to 4 substituents selected from the following.

[0031] In another embodiment of the present invention, R 1 is C 2-12 It is a heterocyclic alkyl group, R 1 It is either not substituted or R a It is substituted by 1 to 6 substituents selected from. In one class of this embodiment, R 1 It is either not substituted or R a It is substituted by 1 to 5 substituents selected from. In another class of this embodiment, R 1 It is either not substituted or R a It is substituted with 1 to 4 substituents selected from the following.

[0032] In another embodiment, R 1The group 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, R 1 It is either not substituted or R a It is substituted by 1 to 6 substituents selected from. In one class of this embodiment, R 1 It is either not substituted or R a It is substituted by 1 to 5 substituents selected from. In another class of this embodiment, R 1 It is either not substituted or R a It is substituted with 1 to 4 substituents selected from the following.

[0033] In another embodiment, R 1 The group is selected from: 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 It is either not substituted or R a It is substituted by 1 to 6 substituents selected from. In one class of this embodiment, R 1 It is either not substituted or Ra It is substituted with 1 to 5 substituents selected from the following.

[0034] In another class of this embodiment, R 1 It is either not substituted or R a It is substituted with 1 to 4 substituents selected from the following.

[0035] In another embodiment of the present invention, R 1 The group is selected from: morpholine, piperidine, pyrrolidine, tetrahydropyran, and octahydro-1H-pyrrolo[2,3-c]pyridine, R 1 It is either not substituted or R a It is substituted by 1 to 6 substituents selected from. In one class of this embodiment, R 1 It is either not substituted or R a It is substituted by 1 to 5 substituents selected from. In another class of this embodiment, R 1 It is either not substituted or R a It is substituted with 1 to 4 substituents selected from the following.

[0036] In another embodiment of the present invention, R 1 The group is selected from: morpholine, pyrrolidine, tetrahydropyran, octahydro-1H-pyrrolo[2,3-c]pyridine, R 1 It is either not substituted or R a It is substituted by 1 to 6 substituents selected from. In one class of this embodiment, R 1 It is either not substituted or R a It is substituted by 1 to 5 substituents selected from. In another class of this embodiment, R 1 It is either not substituted or R a It is substituted with 1 to 4 substituents selected from the following.

[0037] In another embodiment of the present invention, R 1 It is pyrrolidine, and R 1 It is either not substituted or R aIt is substituted by 1 to 6 substituents selected from. In one class of this embodiment, R 1 It is either not substituted or R a It is substituted by 1 to 5 substituents selected from. In another class of this embodiment, R 1 It is either not substituted or R a It is substituted with 1 to 4 substituents selected from the following.

[0038] In another embodiment of the present invention, R 2 The group is selected from aryl and heteroaryl, and R 2 It is either not substituted or R b It is substituted with 1 to 5 substituents selected from the following.

[0039] In one class of this embodiment, R 2 It is either not substituted or R b It is substituted with 1 to 4 substituents selected from. In another class of this embodiment, R 2 It is either not substituted or R b It is replaced by 1 to 3 substituents selected from. In another class of this embodiment, R 2 It is either not substituted or R b It is substituted with one or two substituents selected from the following.

[0040] In another embodiment, R 2 It is a heteroaryl, and R 2 It is either not substituted or R b It is substituted by 1 to 5 substituents selected from. In another class of this embodiment, R 2 It is either not substituted or R b It is substituted with 1 to 4 substituents selected from. In another class of this embodiment, R 2 It is either not substituted or R b It is replaced by 1 to 3 substituents selected from. In another class of this embodiment, R 2 It is either not substituted or R bIt is substituted with one or two substituents selected from the following.

[0041] In another embodiment, R 2 is pyridine or benzofuran, R 2 It is either not substituted or R b It is substituted by 1 to 5 substituents selected from. In one class of this embodiment, R 2 It is either not substituted or R b It is substituted with 1 to 4 substituents selected from. In another class of this embodiment, R 2 It is either not substituted or R b It is replaced by 1 to 3 substituents selected from. In another class of this embodiment, R 2 It is either not substituted or R b It is substituted with one or two substituents selected from the following.

[0042] In another embodiment, R 2 It is pyridine, and R 2 It is either not substituted or R b It is substituted by 1 to 5 substituents selected from. In one subclass of this class, R 2 It is either not substituted or R b It is replaced by 1 to 4 substituents selected from. In another subclass of this class, R 2 It is either not substituted or R b It is replaced by 1 to 3 substituents selected from. In another subclass of this class, R 2 It is either not substituted or R b It is substituted with one or two substituents selected from the following.

[0043] In another embodiment, R 2 is a benzofuran, and R 2 It is either not substituted or R b It is substituted by 1 to 5 substituents selected from. In one subclass of this class, R 2 It is either not substituted or Rb It is replaced by 1 to 4 substituents selected from. In another subclass of this class, R 2 It is either not substituted or R b It is replaced by 1 to 3 substituents selected from. In another subclass of this class, R 2 It is either not substituted or R b It is substituted with one or two substituents selected from the following.

[0044] In another embodiment, R 2 is an aryl, and R 2 It is either not substituted or R b It is substituted by 1 to 5 substituents selected from. In one class of this embodiment, R 2 It is either not substituted or R b It is substituted with 1 to 4 substituents selected from. In another class of this embodiment, R 2 It is either not substituted or R b It is replaced by 1 to 3 substituents selected from. In another class of this embodiment, R 2 It is either not substituted or R b It is replaced by one or two substituents selected from. In another class of this embodiment, R 2 is phenyl, and R 2 It is either not substituted or R b It is substituted by 1 to 5 substituents selected from. In one subclass of this class, R 2 It is either not substituted or R b It is replaced by 1 to 4 substituents selected from. In another subclass of this class, R 2 It is either not substituted or R b It is replaced by 1 to 3 substituents selected from. In another subclass of this class, R 2 It is either not substituted or R b It is substituted with one or two substituents selected from the following.

[0045] In another embodiment of the present invention, R 3 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -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 ) Selected from 2, R 3 It is either not substituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0046] In another embodiment of the present invention, R 3 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -C. 1-6 Alkyl, -OC 1-6 Alkyl, halogen, and -C 1-6 Alkyl-OC 1-6Selected from alkyl, R 3 It is either not substituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0047] In another embodiment of the present invention, R 3 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -C. 1-6 Alkyl, -OC 1-6 Selected from alkyl and halogen, R 3 It is either not substituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0048] In another embodiment of the present invention, R 3 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -C. 1-6 Alkyl and -OC 1-6 Selected from alkyl, R 3 It is either not substituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0049] In another embodiment of the present invention, R 3 The group consists of: hydrogen, OH, CF3, CF2H, and -C. 1-6 Alkyl and -OC 1-6 Selected from alkyl, R 3 It is either not substituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0050] In another embodiment of the present invention, R 3 The group is: hydrogen, -C 1-6 Alkyl and -OC 1-6 Selected from alkyl, R 3 It is either not substituted or R d It is substituted by 1 to 5 substituents selected from. In one class of this embodiment, R 3 The group is selected from hydrogen, -CH3, and -OCH3.

[0051] In another embodiment of the present invention, R 3 The groups are: hydrogen, OH, CN, CF3, CF2H, and -C 1-6 Selected from alkyl, R 3 It is either not substituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0052] In another embodiment of the present invention, R 3 The group is selected from hydrogen, OH, CN, CF3, CF2H, and -CH3, R 3 It is either not substituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0053] In another embodiment of the present invention, R 3 The group is selected from hydrogen, OH, CF3, CF2H, and -CH3, R 3 It is either not substituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0054] In another embodiment of the present invention, R 3 The group consists of: hydrogen, CF3, CF2H, and -C 1-6 Selected from alkyl, R 3 It is either not substituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0055] In another embodiment of the present invention, R 3 The group is selected from hydrogen, CF3, CF2H, and -CH3, and R 3 It is either not substituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0056] In another embodiment of the present invention, R 3 The group consists of: hydrogen, CF3, and -C 1-6 Selected from alkyl, R 3 It is either not substituted or R d It is substituted with 1 to 5 substituents selected from the following.

[0057] In another embodiment of the present invention, R 3 The group consists of: hydrogen and -C 1-6 Selected from alkyl, R 3 It is either not substituted or R d It is substituted by 1 to 5 substituents selected from. In one class of this embodiment, R 3 It is hydrogen or CH3.

[0058] In another embodiment of the present invention, R 3 is -C 1-6 It is alkyl, R 3 It is either not substituted or R d It is substituted by 1 to 5 substituents selected from. 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 It is -CF3.

[0059] In another embodiment of the present invention, R 4 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -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 ) Selected from 2, R 4 It is either not substituted or R e It is substituted with 1 to 5 substituents selected from the following.

[0060] In another embodiment of the present invention, R 4 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -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 Selected from alkyl, R 4 It is either not substituted or R e It is substituted with 1 to 5 substituents selected from the following.

[0061] In another embodiment of the present invention, R 4 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -C. 1-6 Alkyl, -OC 1-6 Alkyl, halogen, and -C 1-6 Alkyl-OC 1-6 Selected from alkyl, R 4 It is either not substituted or R e It is substituted with 1 to 5 substituents selected from the following.

[0062] In another embodiment of the present invention, R 4 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -C. 1-6Alkyl, -OC 1-6 Selected from alkyl and halogen, R 4 It is either not substituted or R e It is substituted with 1 to 5 substituents selected from the following.

[0063] In another embodiment of the present invention, R 4 The group consists of: hydrogen, CN, CF3, CF2H, and -C. 1-6 Selected from alkyl and halogen, R 4 It is either not substituted or R e It is substituted with 1 to 5 substituents selected from the following.

[0064] In another embodiment of the present invention, R 4 The group consists of: hydrogen, CF3, CF2H, and -C. 1-6 Selected from alkyl and halogen, R 4 It is either not substituted or R e It is substituted with 1 to 5 substituents selected from the following.

[0065] In another embodiment of the present invention, R 4 The group consists of: hydrogen, CF3, and -C 1-6 Selected from alkyl, R 4 It is either not substituted or R e It is substituted with 1 to 5 substituents selected from the following.

[0066] In another embodiment of the present invention, R 4 The group consists of: hydrogen and -C 1-6 Selected from alkyl, R 4 It is either not substituted or R e It is substituted with 1 to 5 substituents selected from. In one class of this embodiment of the present invention, R 4 R is selected from the group: hydrogen, -CH3, -CF3, and -CHF3. In another class of this embodiment of the present invention, R 4 The group is selected from hydrogen and -CH3, and R 4 It is either not substituted or R eIt is substituted with 1 to 5 substituents selected from the following.

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

[0068] In another embodiment of the present invention, R 4 is -C 1-6 It is alkyl, R 4 It is either not substituted or R e It is substituted by 1 to 5 substituents selected from. In one class of this embodiment, R 4 It is -CH3.

[0069] In another embodiment of the present invention, R 5 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -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 ) Selected from 2, R 5 It is either not substituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0070] In another embodiment of the present invention, R 5 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -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 Selected from alkyl, R 5 It is either not substituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0071] In another embodiment of the present invention, R 5 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -C. 1-6 Alkyl, -OC 1-6 Alkyl, halogen, and -C 1-6 Alkyl-OC 1-6 Selected from alkyl, R 5 It is either not substituted or R f It is substituted with 1 to 5 substituents selected from. In another embodiment of the present invention, R 5 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -C. 1-6 Alkyl, -OC 1-6 Selected from alkyl and halogen, R 5 It is either not substituted or R f It is substituted with 1 to 5 substituents selected from. In another embodiment of the present invention, R 5 The group consists of: hydrogen, CN, CF3, CF2H, and -C. 1-6 Selected from alkyl and halogen, R 5 It is either not substituted or Rf It is substituted with 1 to 5 substituents selected from. In another embodiment of the present invention, R 5 The group consists of: hydrogen, CF3, CF2H, and -C. 1-6 Selected from alkyl and halogen, R 5 It is either not substituted or R f It is substituted with 1 to 5 substituents selected from the following.

[0072] In another embodiment of the present invention, R 5 The group is: hydrogen, -C 1-6 Selected from alkyl and halogen, R 5 It is either not substituted or R f It is substituted by 1 to 5 substituents selected from. 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 R is selected from the group: hydrogen, -CH3, and CHF3. In another class of this embodiment, R 5 is selected from the group: hydrogen, -CH3, and F. In another embodiment of the present invention, R 5 The group consists of: hydrogen and -C 1-6 Selected from alkyl, R 5 It is either not substituted or R f It is substituted by 1 to 5 substituents selected from. In one class of this embodiment, R 5 R is selected from the group: hydrogen, CHF3, and -CH3. In another embodiment of the present invention, R 5 is -C 1-6 It is alkyl, R 5 It is either not substituted or R f It is substituted by 1 to 5 substituents selected from. 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 In another embodiment, R 5 It is CHF3.

[0073] In another embodiment of the present invention, R 6 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -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 ) Selected from 2, R 6 It is either not substituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0074] In another embodiment of the present invention, R 6 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -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 Selected from alkyl, R 6 It is either not substituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0075] In another embodiment of the present invention, R 6 The group consists of: hydrogen, OH, CN, CF3, CF2H, and -C. 1-6 Alkyl, -OC 1-6 Alkyl, halogen, and -C 1-6 Alkyl-OC 1-6 Selected from alkyl, R 6 It is either not substituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0076] In another embodiment of the present invention, R 6 The group consists of: hydrogen, CN, CF3, CF2H, and -C. 1-6 Alkyl, -OC 1-6 Selected from alkyl and halogen, R 6 It is either not substituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0077] In another embodiment of the present invention, R 6 The group consists of: hydrogen, CF3, CF2H, and -C. 1-6 Alkyl and -OC 1-6 Selected from alkyl, R 6 It is either not substituted or R g It is substituted with 1 to 5 substituents selected from the following.

[0078] In another embodiment of the present invention, R 6 The group consists of hydrogen, CF3, and -C. 1-6 Alkyl and -OC 1-6 Selected from alkyl, R 6 It is either not substituted or R gIt is substituted by 1 to 5 substituents selected from. In one class of this embodiment, R 6 The group is selected from hydrogen, CF3, -CH3, and -OCH3.

[0079] In another embodiment of the present invention, R 6 The group is: hydrogen, -C 1-6 Alkyl and -OC 1-6 Selected from alkyl, R 6 It is either not substituted or R g It is substituted by 1 to 5 substituents selected from. In one class of this embodiment, R 6 The group is selected from hydrogen, -CH3, and -OCH3.

[0080] In another embodiment of the present invention, R 6 The group consists of: hydrogen and -C 1-6 Selected from alkyl, R 6 It is either not substituted or R g It is substituted by 1 to 5 substituents selected from. In one class of this embodiment, R 6 R is selected from the group: hydrogen and CH3. In another embodiment of the present invention, R 6 is -C 1-6 It is alkyl, R 6 It is either not substituted or R g It is substituted by 1 to 5 substituents selected from. In one class of this embodiment, R 6 is -CH3. In another embodiment of the present invention, R 6 It is hydrogen.

[0081] Another embodiment of the present invention, each R a These are independently grouped as: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -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 Heterocycloalkyl, -C 2-6 Alkenyl-C 3-6 Cycloalkyl, -C 2-6 Alkenyl-C 2-6 Heterocycloalkyl, -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 Heterocycloalkyl, -C 2-6 Alkynyl-aryl, -C 2-6 Alkynyl-heteroaryl, -(CH2) p -O-C 1-6 Alkyl, -(CH2) p -O-C 2-6 Alkenyl, -(CH2) p -O-C 2-6 Alkynyl, -(CH2) p -O-C 3-6 Cycloalkyl, -(CH2) p -O-C 2-6 Heterocycloalkyl, -(CH2) p -O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 Alkyl-C 3-6 Cycloalkyl, -OC 1-6 Alkyl-C 2-6 Heterocycloalkyl, -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 is selected from -(CH2) a each Ris unsubstituted or substituted by 1 to 6 substituents selected from halogen, CF3, OH, C 1-6 alkyl, and -OC 1-6 alkyl.

[0082] In another embodiment of the present invention, each R a is independently selected from the group: CN, oxo, -OH, halogen, -C 1-6 alkyl, -O-C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, -C 2-6 heterocycloalkyl, 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 heterocycloalkyl, -C 2-6 alkenyl-C 3-6 cycloalkyl, -C 2-6 alkenyl-C 2-6 heterocycloalkyl, -C 2-6 alkenyl-aryl, -C 2-6 alkenyl-heteroaryl, -C 2-6 alkynyl-C 3-6 cycloalkyl, -C 2-6 alkynylC 2-6 heterocycloalkyl, -C 2-6 alkynyl-aryl, -C 2-6 0]alkynyl-heteroaryl, -(CH2) p -O-C 1-6 alkyl, -(CH2) p -O-C 2-6 alkenyl, -(CH2) p -O-C 2-6 alkynyl, -(CH2) p -O-C 3-6 cycloalkyl, -(CH2) p -O-C 2-6 heterocycloalkyl, -(CH2) p-O-aryl, -(CH2) p -O-heteroaryl, -OC 1-6 alkyl-C 3-6 cycloalkyl, -OC 1-6 alkyl-C 2-6 heterocycloalkyl, -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 selected from, each R a is unsubstituted or substituted by 1 to 6 substituents selected from halogen, CF3, OH, C 1-6 alkyl, and -OC 1-6 alkyl.

[0083] In another embodiment of the present invention, each R a is independently selected from the group: CN, oxo, -OH, halogen, -C 1-6 alkyl, -O-C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, -C 2-6 heterocycloalkyl, 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 selected from, each R a is unsubstituted or substituted by 1 to 6 substituents selected from halogen, CF3, OH, C 1-6 alkyl, and -OC 1-6 alkyl,

[0084] In another embodiment of the present invention, each Ra These are independently grouped as: 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 ) Selected from 2, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0085] Another embodiment of the present invention, each R a These are independently grouped as: oxo, -OH, halogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, aryl, -C(O)C 1-6 Alkyl and -(CH2) p -N(R L ) Selected from 2, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R a The groups are independently selected from: oxo, -OH, F, -CH3, -CH2CH3, -CF2H, -CF3, -CH2OH, -C(CH3)2OH, cyclopropyl, phenyl, -C(O)CH3, and -CH2N(CH3)2, and each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0086] Another embodiment of the present invention, each R a These are independently grouped as: oxo, -OH, halogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, aryl, -C(O)C 1-6 Alkyl and -(CH2) p -N(R L ) Selected from 2, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment of the present invention, each R a The groups are independently selected from: oxo, -OH, F, -CH3, -CH2CH3, -CF2H, -CF3, -CH2OH, -C(CH3)2OH, cyclopropyl, phenyl, -C(O)CH3, and -CH2N(CH3)2, and each R a It is either not substituted, or F, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0087] Another embodiment of the present invention, each R a These are independently the groups: -OH and -C 1-6 Selected from alkyl groups, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment of the present invention, each R a These are independently the groups: -OH and -C 1-6 Selected from alkyl groups, each R a It is either not substituted, or F, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another class of this embodiment of the present invention, each R aR is independently selected from the groups: -OH, -CH3, -CH2CH3, -CF2H, -CF3, -CH2OH, and -C(CH3)2OH. In another class of this embodiment of the present invention, each R a These are independently selected from the groups -OH and -CH3.

[0088] Another embodiment of the present invention, each R a These are independently grouped as: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -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 Alkenil-C 3-6 Cycloalkyl, -C 2-6 Alkenil-C 2-6 Heterocyclic alkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl heteroaryl, -C 2-6 Alkinyl-C 3-6 Cycloalkyl, -C 2-6 Alkinyl C 2-6 Heterocyclic alkyl, -C 2-6 Alkinyl-aryl, -C 2-6 Alkynyl heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkinyl, -(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 ) Selected from 2, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0089] Another embodiment of the present invention, each R a These are independently grouped as: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -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 Alkenil-C 3-6 Cycloalkyl, -C 2-6 Alkenil-C 2-6 Heterocyclic alkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl heteroaryl, -C 2-6 Alkinyl-C 3-6Cycloalkyl, -C 2-6 Alkinyl C 2-6 Heterocyclic alkyl, -C 2-6 Alkinyl-aryl, -C 2-6 Alkynyl heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkinyl, -(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 ) Selected from 2, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0090] Another embodiment of the present invention, each R a These are independently grouped as: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, aryl, heteroaryl, -C(O)C 1-6 Alkyl and -(CH2) p-N(R L ) Selected from 2, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0091] Another embodiment of the present invention, each R a These are independently grouped as: 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 ) Selected from 2, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0092] Another embodiment of the present invention, each R a These are independently grouped as: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -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 Alkenil-C 3-6 Cycloalkyl, -C 2-6 Alkenil-C 2-6 Heterocyclic alkyl, -C 2-6Alkenyl-aryl, -C 2-6 Alkenyl heteroaryl, -C 2-6 Alkinyl-C 3-6 Cycloalkyl, -C 2-6 Alkinyl C 2-6 Heterocyclic alkyl, -C 2-6 Alkinyl-aryl, -C 2-6 Alkynyl heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkinyl, -(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 Selected from, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0093] Another embodiment of the present invention, each R a These are independently grouped as: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -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 Alkenil-C 3-6 Cycloalkyl, -C 2-6 Alkenil-C 2-6 Heterocyclic alkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl heteroaryl, -C 2-6 Alkinyl-C 3-6 Cycloalkyl, -C 2-6 Alkinyl C 2-6 Heterocyclic alkyl, -C 2-6 Alkinyl-aryl, -C 2-6 Alkynyl heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkinyl, -(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 Selected from alkyl-heteroaryls, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0094] Another embodiment of the present invention, each R a These are independently grouped as: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -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 Alkenil-C 3-6 Cycloalkyl, -C 2-6 Alkenil-C 2-6 Heterocyclic alkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl heteroaryl, -C 2-6 Alkinyl-C 3-6 Cycloalkyl, -C 2-6 Alkinyl C 2-6 Heterocyclic alkyl, -C 2-6 Alkinyl-aryl, -C 2-6 Alkynyl heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC 2-6 Alkinyl, -(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 Selected from, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0095] Another embodiment of the present invention, each R a These are independently grouped as: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -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 Alkenil-C 3-6 Cycloalkyl, -C 2-6 Alkenil-C 2-6 Heterocyclic alkyl, -C 2-6 Alkenyl-aryl, -C 2-6 Alkenyl heteroaryl, -C 2-6 Alkinyl-C 3-6 Cycloalkyl, -C 2-6 Alkinyl C 2-6 Heterocyclic alkyl, -C 2-6 Alkinyl-aryl, -C 2-6 Alkynyl heteroaryl, -(CH2) p -OC 1-6 Alkyl, -(CH2) p -OC 2-6 Alkenyl, -(CH2) p -OC2-6 Alkinyl, -(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 Selected from alkyl-heteroaryls, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0096] Another embodiment of the present invention, each R a These are independently grouped as: CN, oxo, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-6 Cycloalkyl, -C 2-6 Heterocyclic alkyl, aryl, heteroaryl, and -C(O)C 1-6 Selected from alkyl groups, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0097] Another embodiment of the present invention, each R a These are independently grouped as: 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 Selected from alkyl groups, each R a It is either not substituted, or contains halogen, CF3, OH, C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0098] Another embodiment of the present invention, each R b These are independently grouped as: 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 Selected from, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0099] Another embodiment of the present invention, each R b These are independently grouped as: 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 Selected from, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each Rb These are independently grouped: 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 Selected from, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0100] Another embodiment of the present invention, each R b These are independently grouped as: 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 Selected from, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each R b These are independently grouped into: 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 Selected from, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0101] Another embodiment of the present invention, each R b These are independently grouped as: 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 Selected from, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each R b These are independently grouped into: 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 Selected from, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0102] Another embodiment of the present invention, each R b These are independently 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 Selected from, each R bThese are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each R b The groups are independently: 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 Selected from, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0103] Another embodiment of the present invention, each R b These are independently grouped into: 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 Selected from, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R bThe groups are independently selected from: OH, Cl, F, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane, and each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each R b These are independently grouped into: 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 Selected from, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R b The following groups are independently selected: Cl, F, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane, and each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0104] Another embodiment of the present invention, each R b These are independently 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 Selected from, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R b The group is independently selected from OH, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane, and each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each R b The groups are independently: 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 Selected from, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R b The groups are independently selected from -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane, and each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0105] Another embodiment of the present invention, each R b The groups are independently selected from CN, -OH, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane, and each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each R b The group is independently selected from CN, -CH3, -CF3, -CF2H, -OCF2H, and cyclopropane, and each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0106] Another embodiment of the present invention, each R b These are independently grouped as: CN, -OH, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Selected from heterocyclic alkyl groups, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each R b These are independently grouped into: CN, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Selected from heterocyclic alkyl groups, each R bThese are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0107] Another embodiment of the present invention, each R b These are independently the groups: CN, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Selected from heterocyclic alkyl groups, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each R b The groups are independently: CN, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Selected from heterocyclic alkyl groups, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0108] Another embodiment of the present invention, each R b The groups are: CN, -OH, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Selected from cycloalkyl, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each R b The groups are: CN, oxo, halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Selected from cycloalkyl, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0109] Another embodiment of the present invention, each R b These are independently grouped as: CN, -OH, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Selected from cycloalkyl, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each R b These are independently grouped: CN, oxo, -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Selected from cycloalkyl, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0110] Another embodiment of the present invention, each R b The group consists of -OH, halogens, and -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Selected from cycloalkyl, each R bThese are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each R b Group: Halogen, -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Selected from cycloalkyl, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0111] Another embodiment of the present invention, each R b These are independently the groups: -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Selected from cycloalkyl, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another embodiment of the present invention, each R b The group is independently grouped: -C 1-6 Alkyl, -OC 1-6 Alkyl and -C 3-6 Selected from cycloalkyl, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups.

[0112] Another embodiment of the present invention, each R b These are independently the groups: -OH, -C 1-6 Alkyl and -OC1-6 Selected from alkyl groups, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R b These are independently the groups: -OH, -C 1-6 Alkyl and -OC 1-6 Selected from alkyl groups, each R b These are either not substituted, or F, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another class of this embodiment, each R b R is independently OH, -CH3, -CF3, -CF2H, or -OCF2H. In another embodiment of the present invention, each R b The group is independently grouped: -C 1-6 Alkyl and -OC 1-6 Selected from alkyl groups, each R b These are either not substituted, halogen, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In one class of this embodiment, each R b The group is independently grouped: -C 1-6 Alkyl and -OC 1-6 Selected from alkyl groups, each R b These are either not substituted, or F, CF3, CF2H, OCF3, CN, CH2CF3, CF2CH3, -C 1-6 Alkyl and -OC 1-6 It is substituted with 1 to 6 substituents selected from alkyl groups. In another class of this embodiment, each R b These are independently -CH3, -CF3, -CF2H, or -OCF2H.

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

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

[0115] Another embodiment of the present invention, each R c These are independently grouped as: hydrogen, halogen, and -C 1-6 Selected from alkyl groups, the alkyl groups are either unsubstituted or contain CF3, halogens, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0116] In another embodiment, each R c These are independently in the groups: hydrogen and -C 1-6 Selected from alkyl groups, the alkyl groups are either unsubstituted or contain CF3, halogens, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, each R c is -CH3. In another embodiment, R c It is hydrogen.

[0117] In another embodiment, R c is -C 1-6 It is an alkyl group, and the alkyl group is either unsubstituted or contains CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, each R c It is -CH3.

[0118] Another embodiment of the present invention, each R d These are independently grouped as: CF3, halogen, and -C 1-6 Selected from alkyl groups, the alkyl groups are either unsubstituted or contain CF3, halogens, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0119] Another embodiment of the present invention, each R d These are independently grouped: halogen and -C 1-6 Selected from alkyl groups, the alkyl groups are either unsubstituted or contain CF3, halogens, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, each R d The group is independently selected from halogens and -CH3. In another embodiment of the present invention, each R d It is a halogen.

[0120] Another embodiment of the present invention, each R d is -C 1-6 It is an alkyl group, and the alkyl group is either unsubstituted or contains CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, each R d It is -CH3.

[0121] Another embodiment of the present invention, each R e These are independently grouped as: CF3, halogen, and -C 1-6 Selected from alkyl groups, the alkyl groups are either unsubstituted or contain CF3, halogens, OH, and -OC. 1-6It is substituted with 1 to 3 substituents selected from alkyl groups.

[0122] Another embodiment of the present invention, each R e These are independently grouped: halogen and -C 1-6 Selected from alkyl groups, the alkyl groups are either unsubstituted or contain CF3, halogens, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, each R e The group is independently selected from halogens and -CH3. In another embodiment of the present invention, each R e It is a halogen.

[0123] Another embodiment of the present invention, each R e is -C 1-6 It is an alkyl group, and the alkyl group is either unsubstituted or contains CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, each R e It is -CH3.

[0124] Another embodiment of the present invention, each R f These are independently grouped as: CF3, halogen, and -C 1-6 Selected from alkyl groups, the alkyl groups are either unsubstituted or contain CF3, halogens, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0125] Another embodiment of the present invention, each R f These are independently grouped: halogen and -C 1-6 Selected from alkyl groups, the alkyl groups are either unsubstituted or contain CF3, halogens, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, each R f The group is independently selected from halogens and -CH3. In another embodiment of the present invention, each R f It is a halogen.

[0126] Another embodiment of the present invention, each R f is -C 1-6 It is an alkyl group, and the alkyl group is either unsubstituted or contains CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, each R f It is -CH3.

[0127] Another embodiment of the present invention, each R g These are independently grouped as: CF3, halogen, and -C 1-6 Selected from alkyl groups, the alkyl groups are either unsubstituted or contain CF3, halogens, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0128] Another embodiment of the present invention, each R g These are independently grouped: halogen and -C 1-6 Selected from alkyl groups, the alkyl groups are either unsubstituted or contain CF3, halogens, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, each R g The group is independently selected from halogens and -CH3. In another embodiment of the present invention, each R g It is a halogen.

[0129] Another embodiment of the present invention, each R g is -C 1-6 It is an alkyl group, and the alkyl group is either unsubstituted or contains CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, each R g It is -CH3.

[0130] Another embodiment of the present invention, each R h These are independently grouped: hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C2-6 Selected from heterocyclic alkyl groups, alkyl, cycloalkyl and heterocyclic alkyl groups are either unsubstituted or -CF3, halogen, OH and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R h is -C 2-6 It is a heterocyclic alkyl group, where the heterocyclic alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0131] Another embodiment of the present invention, each R h These are independently grouped: hydrogen, -C 1-6 Alkyl and -C 3-6 Selected from cycloalkyl groups, the alkyl and cycloalkyl groups are either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R h is -C 3-6 It is a cycloalkyl group, where the cycloalkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0132] Another embodiment of the present invention, each R h These are independently grouped: hydrogen and -C 1-6 Selected from alkyl groups, where the alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In another embodiment of the present invention, R h is hydrogen. In another embodiment of the present invention, R h is -C 1-6 It is an alkyl group, and the alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0133] Another embodiment of the present invention, each R i These are independently grouped: hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Selected from heterocyclic alkyl groups, alkyl, cycloalkyl and heterocyclic alkyl groups are either unsubstituted or contain CF3, halogens, OH and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R i is -C 2-6 It is a heterocyclic alkyl group, where the heterocyclic alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0134] Another embodiment of the present invention, each R i These are independently grouped: hydrogen, -C 1-6 Alkyl and -C 3-6 Selected from cycloalkyl groups, the alkyl and cycloalkyl groups are either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R i is -C 3-6 It is a cycloalkyl group, where the cycloalkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0135] Another embodiment of the present invention, each R i These are independently grouped: hydrogen and -C 1-6 Selected from alkyl groups, where the alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In another embodiment of the present invention, R i is hydrogen. In another embodiment of the present invention, R i is -C 1-6 It is an alkyl group, and the alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC.1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0136] Another embodiment of the present invention, each R j These are independently grouped: hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Selected from heterocyclic alkyl groups, alkyl, cycloalkyl and heterocyclic alkyl groups are either unsubstituted or contain CF3, halogens, OH and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R j is -C 2-6 It is a heterocyclic alkyl group, where the heterocyclic alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0137] Another embodiment of the present invention, each R j These are independently grouped: hydrogen, -C 1-6 Alkyl and -C 3-6 Selected from cycloalkyl groups, the alkyl and cycloalkyl groups are either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R j is -C 3-6 It is a cycloalkyl group, where the cycloalkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0138] Another embodiment of the present invention, each R j These are independently grouped: hydrogen and -C 1-6 Selected from alkyl groups, where the alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In another embodiment of the present invention, R jis hydrogen. In another embodiment of the present invention, R j is -C 1-6 It is an alkyl group, and the alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0139] Another embodiment of the present invention, each R k The group is independently grouped: -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Selected from heterocyclic alkyl groups, the alkyl, cycloalkyl, and heterocyclic alkyl groups are either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R k is -C 2-6 It is a heterocyclic alkyl group, where the heterocyclic alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0140] Another embodiment of the present invention, each R k The group is independently grouped: -C 1-6 Alkyl and -C 3-6 Selected from cycloalkyl groups, the alkyl and cycloalkyl groups are either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R k is -C 3-6 It is a cycloalkyl group, where the cycloalkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

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

[0142] Another embodiment of the present invention, each R L These are independently grouped: hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Selected from heterocyclic alkyl groups, the alkyl, cycloalkyl, and heterocyclic alkyl groups are either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R L is -C 2-6 It is a heterocyclic alkyl group, where the heterocyclic alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0143] Another embodiment of the present invention, each R L These are independently grouped: hydrogen, -C 1-6 Alkyl and -C 3-6 Selected from cycloalkyl groups, the alkyl and cycloalkyl groups are either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R L is -C 3-6 It is a cycloalkyl group, where the cycloalkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0144] Another embodiment of the present invention, each R L These are independently grouped: hydrogen and -C 1-6 Selected from alkyl groups, where the alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In another embodiment of the present invention, R L is hydrogen. In another embodiment of the present invention, RL is -C 1-6 It is an alkyl group, and the alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R L It is -CH3.

[0145] Another embodiment of the present invention, each R m The group is independently grouped: -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Selected from heterocyclic alkyl groups, alkyl, cycloalkyl and heterocyclic alkyl groups are either unsubstituted or -CF3, halogen, OH and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R m is -C 2-6 It is a heterocyclic alkyl group, where the heterocyclic alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0146] Another embodiment of the present invention, each R m The group is independently grouped: -C 1-6 Alkyl and -C 3-6 Selected from cycloalkyl groups, the alkyl and cycloalkyl groups are either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R m is -C 3-6 It is a cycloalkyl group, where the cycloalkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

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

[0148] Another embodiment of the present invention, each R n These are independently grouped: hydrogen, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Selected from heterocyclic alkyl groups, the alkyl, cycloalkyl, and heterocyclic alkyl groups are either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R n is -C 2-6 It is a heterocyclic alkyl group, where the heterocyclic alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0149] Another embodiment of the present invention, each R n These are independently grouped: hydrogen, -C 1-6 Alkyl and -C 3-6 Selected from cycloalkyl groups, the alkyl and cycloalkyl groups are either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In one class of this embodiment, R n is -C 3-6 It is a cycloalkyl group, where the cycloalkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0150] Another embodiment of the present invention, each R n These are independently the groups: hydrogen and C 1-6 Selected from alkyl groups, where the alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In another embodiment of the present invention, each R nis hydrogen. In another embodiment of the present invention, each R n is -C 1-6 It is an alkyl group, and the alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0151] Another embodiment of the present invention, each R o These are independently groups: OH, -C 1-6 Alkyl, -C 3-6 Cycloalkyl, and -C 2-6 Selected from heterocyclic alkyl groups, alkyl, cycloalkyl and heterocyclic alkyl groups are either unsubstituted or -CF3, halogen, OH and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0152] Another embodiment of the present invention, each R o These are independently the groups: OH and -C 1-6 Selected from alkyl groups, where the alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups. In another embodiment of the present invention, each R o is OH. In another embodiment of the present invention, each R o is -C 1-6 It is an alkyl group, and the alkyl group is either unsubstituted, -CF3, halogen, OH, and -OC. 1-6 It is substituted with 1 to 3 substituents selected from alkyl groups.

[0153] In another embodiment of the present 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, 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 present 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 present 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 present invention, u is 0, 1, 2, 3, 4, 5, or 6. In another embodiment, u is 0, 1, 2, 3, 4, or 5. In another embodiment, u is 1, 2, 3, 4, 5, or 6. In another embodiment, u is 1, 2, 3, 4, or 5. In another embodiment, u is 0, 1, 2, 3, or 4. In another embodiment, u is 1, 2, 3, or 4. In another embodiment, u is 0, 1, 2, or 3. In another embodiment, u is 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 present 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, 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 present 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 of the present invention, the present invention relates to a compound of structural formula Ia or a pharmaceutically acceptable salt thereof. [ka]

[0160] In another embodiment of the present invention, the present invention relates to a compound of structural formula Ib or a pharmaceutically acceptable salt thereof. [ka]

[0161] In another embodiment of the present invention, the present invention relates to a compound of structural formula Ic or a pharmaceutically acceptable salt thereof. [ka]

[0162] In another embodiment of the present invention, the present invention relates to a compound of structural formula Id or a pharmaceutically acceptable salt thereof. [ka]

[0163] In another embodiment of the present invention, the present invention relates to a compound of structural formula Ie or a pharmaceutically acceptable salt thereof. [ka]

[0164] In another embodiment of the present invention, the present invention relates to a compound of the structural formula If or a pharmaceutically acceptable salt thereof. [ka]

[0165] In another embodiment of the present invention, the present invention relates to a compound of structural formula Ig or a pharmaceutically acceptable salt thereof. [ka]

[0166] In another embodiment of the present invention, the present invention relates to a compound of structural formula Ih or a pharmaceutically acceptable salt thereof. [ka]

[0167] In another embodiment of the present invention, the present invention relates to a compound of structural formula Ii or a pharmaceutically acceptable salt thereof. [ka]

[0168] In another embodiment of the present invention, the present invention relates to a compound of structural formula Ij or a pharmaceutically acceptable salt thereof. [ka]

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

[0170] The compounds of structural formula I include compounds of structural formulas Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, and Ik, as well as their pharmaceutically acceptable salts, hydrates, and solvates.

[0171] Another embodiment of the present invention is, R 1 C 2-12 It is a heterocyclic alkyl group, R 1 However, it is not substituted, R a Substituted by 1 to 6 substituents selected from; R 2 It is a heteroaryl, and R 2 However, it is not substituted, R b Substituted by 1 to 5 substituents selected from; R3 However, group: 1) Hydrogen, and 2)-C 1-6 Alkyl Selected from; R 3 However, it is not substituted, R d Substituted by 1 to 5 substituents selected from; R 4 However, 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 4 However, it is not substituted, R e Substituted by 1 to 5 substituents selected from; R 5 However, 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 However, it is not substituted, R f Substituted by 1 to 5 substituents selected from; R 6 However, group: 1) Hydrogen, 2)-C 1-6 Alkyl, and 3)-OC 1-6 Alkyl Selected from, R 6 However, it is not substituted, R g Substituted by 1 to 5 substituents selected from; This relates to the compound of structural formula I or a pharmaceutically acceptable salt thereof, wherein the other substituents are as defined above.

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

[0173] Examples (but not limited to) 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-methylpyrrolidine-3-ol; 2)(S)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]-pyridazin-4-yl)-3-methylpyrrolidine-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-methylpyrrolidine-3-ol; 11)(cis)-4-(1-(benzofuran-5-yl)pyrido[3,4-d]pyridazine-4-yl)-2,6-dimethylmorpholine; 12)(S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidine-3-ol; 13)(3S,4s,5R)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazino[4,5-d]pyridazin-1-yl)-3,4,5-trimethylpiperidine-4-ol; 14) 2-(4-((cis)-2,6-dimethylmorpholino)-5-methylphthalazine-1-yl)-5-(trifluoromethyl)phenol; 15)2-(4-((cis)-2,6-dimethylmorpholino)-8-methylphthalazine-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-trimethylpiperidine-4-ol; 17)(3S,4s,5R)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3,4,5-trimethylpiperidine-4-ol; 18)(3S,4r,5R)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-3,5-dimethylpiperidine-4-ol; 19)(3S,4r,5R)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethylpiperidine-4-ol; 20)2-(4-((cis)-2,6-dimethylmorpholino)-6-methylphthalazine-1-yl)-5-(trifluoromethyl)phenol; 21)2-(4-((cis)-2,6-dimethylmorpholino)-7-methylphthalazine-1-yl)-5-(trifluoromethyl)phenol; 22)(S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]- Pyridazine-8-yl)-3-methylpyrrolidine-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-trimethylpiperidine-4-ol; 25)8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-oxa-1,8-diazaspiro[4.5]decane-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)pyrrolidine-3-ol; 28)(S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-(trifluoromethyl)pyrrolidine-3-ol; 29)(R)-3-(difluoromethyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidine-3-ol; 30)(S)-3-(difluoromethyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidine-3-ol; 31)(R)-2-(8-(1-oxa-7-azaspiro[4,4]nonan-7-yl)pyrido[2,3-d]pyridazine-5-yl)-5-(trifluoromethyl)phenol; 32)(S)-2-(8-(1-oxa-7-azaspiro[4,4]nonan-7-yl)pyrido[2,3-d]pyridazine-5-yl)-5-(trifluoromethyl)phenol; 33)2-(8-(1-oxa-8-azaspiro[4,5]decane-8-yl)pyrido[2,3-d]pyridazine-5-yl)-5-(trifluoromethyl)phenol; 34)2-(8-(2-oxa-8-azaspiro[4,5]decane-8-yl)pyrido[2,3-d]pyridazine-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]undecane-3-one; 36)2-(8-((cis)-4,4-difluoro-3,5-dimethylpiperidine-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]decane-1-yl)ethane-1-one; 38)1-(8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-2,8-diazaspiro[4.5]decane-2-yl)ethane-1-one; 39)8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-3-methyl-1-oxa-3,8-diazaspiro[4.5]decane-2-one; 40)2-(8-(4,4-dimethyl-1-oxa-8-azaspiro[4.5]decane-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-phenylpyrrolidine-3-ol; 42)(S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-phenylpyrrolidine-3-ol; 43)8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-methyl-1,8-diazaspiro[4.5]decane-2-one; 44)8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-oxa-3,8-diazaspiro[4.5]decane-2-one; 45)2-(8-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-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]decane-2-one; 47)(R)-4,4-difluoro-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidine-3-ol; 48)(S)-4,4-difluoro-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidine-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)pyrrolidine-3-ol; 52)(S)-3-cyclopropyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidine-3-ol; 53)(R)-3-((dimethylamino)methyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido-[2,3-d]pyridazin-8-yl)pyrrolidine-3-ol; 54)(S)-3-((dimethylamino)methyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido-[2,3-d]pyridazin-8-yl)pyrrolidine-3-ol; 55)(R)-3-ethyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-pyrrolidine-3-ol; 56)(S)-3-ethyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-pyrrolidine-3-ol; 57)(R)-2-(8-(3-(hydroxymethyl)-3-methylpyrrolidine-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 58)(S)-2-(8-(3-(hydroxymethyl)-3-methylpyrrolidine-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 59)(R)-2-(8-(3-(2-hydroxypropan-2-yl)pyrrolidine-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 60)(S)-2-(8-(3-(2-hydroxypropan-2-yl)pyrrolidine-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-methylpyrrolidine-3-ol; and 69)(S)-1-(3-(difluoromethyl)-5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidine-3-ol; Or a pharmaceutically acceptable salt thereof.

[0174] Other exemplary (but not limiting) examples of the 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-methylpyrrolidine-3-ol; 2)(S)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]-pyridazin-4-yl)-3-methylpyrrolidine-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-methylpyrrolidine-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; Alternatively, a pharmaceutically acceptable salt thereof.

[0175] While the specific stereochemistry described above is preferred, other stereoisomers, such as diastereomers, enantiomers, epimers, and mixtures thereof, may also be useful in the treatment of NLRP3-mediated diseases.

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

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

[0178] Unless otherwise defined, "alkyl" refers to a saturated carbon chain that can be linear, branched, or a combination thereof. Other groups with the prefix "alk," such as alkoxy and alkanoyl, can also be linear, branched, or a combination thereof, unless otherwise defined. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, and nonyl.

[0179] Unless otherwise defined, "alkenyl" refers to a carbon chain that contains at least one carbon-carbon double bond and can be linear, branched, or a combination thereof. Examples of alkenyls include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, and 2-methyl-2-butenyl.

[0180] Unless otherwise defined, "alkenyl" refers to a carbon chain that contains at least one carbon-carbon triple bond and can be linear, branched, or a combination thereof. Examples of alkenyls include ethynyl, propargyl, 3-methyl-1-pentynyl, and 2-heptynyl.

[0181] "Cycloalkyl" refers to a saturated monocyclic, bicyclic, spirocyclic, or bridging carbon ring having a specified number of carbon atoms. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In one embodiment, cycloalkyl is -C 3-12 It is a cycloalkyl. In another embodiment of the present invention, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In another embodiment, the cycloalkyl is cyclopropyl.

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

[0183] "Heterocyclic alkyl" means a saturated monocyclic, bicyclic, spirocyclic, fused, or bridging ring or ring system having a specific number of carbon atoms and containing at least one ring heteroatom selected from N, NH, S (including SO and SO2), and O. The heterocyclic alkyl ring may be substituted on the ring carbon and / or ring nitrogen or sulfur. Examples of heterocyclic alkyls include tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, azetidinyl, piperadinyl, piperidinyl, morpholinyl, oxetanyl, and tetrahydropyranyl. In one embodiment of the present invention, the heterocyclic alkyl is C 2-12 It is a heterocyclic alkyl. In another embodiment, the heterocyclic 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] A "heterocyclic alkenyl" refers to a monocyclic, bicyclic, spirocyclic, fused, or bridged ring or ring system having a specified number of carbon atoms, 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" refers to a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or ring system containing 6 to 14 carbon atoms, in which at least one of the rings is aromatic. Examples of aryls include phenyl and naphthyl. In one embodiment, the aryl is phenyl.

[0186] "Heteroaryl" means 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 (SO and SO2, etc.) and O, where at least one of the heteroatom-containing rings is aromatic. Examples of heteroaryls include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridadinyl, pyrazinyl, benzoisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, and dibenzofuranyl. In one embodiment, the heteroaryl is pyridine or benzofuran. In another embodiment, the heteroaryl is pyridine. In another embodiment, the heteroaryl is benzofuran.

[0187] "Halogens" include 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" represents =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 of the components or in formula I, any of the variable elements (e.g., R 1 , R a When terms such as (etc.) appear multiple times, the definition for each case is independent of all other definitions for each case. Furthermore, combinations of substituents and / or variable elements are only possible if such combinations result in a stable compound. A wavy line crossing a bond in a substituent variable element represents a bond point.

[0193] Under the nomenclature used throughout this disclosure, the binding site is described first, followed by the terminal portion of the specified side chain. For example, C 1-5 Alkylcarbonylamino C 1-6 Alkyl substituents are equivalent to the following: [ka]

[0194] When selecting the compound of the present invention, various substituents, namely, R 1 , R 2 It will be obvious to those skilled in the art that these should be selected in accordance with well-known principles regarding the connectivity and stability of chemical structures.

[0195] The term "substituted" means that a compound is substituted to varying degrees by the named substituents. Where multiple substituent parts are disclosed or claimed, a substituted compound may be independently substituted by one or more disclosed or claimed substituent parts, either individually or in combination. Independently substituted means that the (two or more) substituents may be identical or distinct.

[0196] The term "pharmaceutically acceptable" is used herein to mean a compound, material, composition, salt, and / or dosage form that is safe and appropriate for administration to humans or animals, based on reasonable medical judgment and in accordance with all applicable government regulations.

[0197] Compounds of formula I may contain one or more chiral centers and can therefore exist as racemates and racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers. The present invention encompasses all such isomeric forms of compounds of formula I.

[0198] The independent synthesis of optical isomers and diastereoisomers, or their chromatographic separation, can be achieved according to methods known in the art by appropriately modifying the methods disclosed herein. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or intermediates derivatized with reagents containing, if necessary, chiral centers of known absolute configurations or atoms heavy enough to perform absolute assignment.

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

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

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

[0202] A tautomer is defined as a compound that undergoes rapid proton transfer from one atom to another. Some of the compounds described herein may exist as tautomers with different hydrogen bond sites. Examples of such compounds include ketones and their enol forms, known as keto-enol tautomers. Not only individual tautomers, but also mixtures thereof, are encompassed by the compounds of formula I.

[0203] In compounds of general formula I, atoms may exist in their natural isotopic abundance, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but atomic weights or mass numbers that differ from the atomic weights or mass numbers found in the vast majority of nature. The present invention is intended to encompass all appropriate isotopic variants of compounds of structural formula I. For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H) is one example. Protium is the overwhelming majority of hydrogen isotopes found in nature. Enriching with deuterium may yield certain therapeutic benefits, such as increased in vivo half-life or reduced required dosage, or compounds useful as criteria for characterizing biological samples. Because tritium is radioactive, it can provide radiolabeled compounds useful as tracers in metabolic or kinetic studies. The isotope-enriched compounds contained in structural formula I can be prepared using appropriate isotope-enriched reagents and / or intermediates by conventional methods well known to those skilled in the art, or by methods similar to those described in the schemes and examples herein, without requiring excessive experimentation.

[0204] Furthermore, since some of the crystalline forms of the compounds of the present invention may exist as polymorphs, these are also included in the present invention. Additionally, some of the compounds of the present invention can form solvates with water or common organic solvents. Such solvates are included within the scope of the present invention.

[0205] It is generally preferable to administer the compounds of the present invention as enantiomerically pure formulations. 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 diastereomer salts.

[0206] salt When used herein, the compounds of the present invention will be understood to include pharmaceutically acceptable salts, as well as pharmaceutically unacceptable salts when used as precursors to free compounds or pharmaceutically acceptable salts thereof, or in other synthetic operations.

[0207] The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid, including an inorganic or organic base and an inorganic or organic acid. Salts of basic compounds encompassed by the term "pharmaceutically acceptable salt" generally refer to non-toxic salts of the compounds of the present invention prepared by reacting a 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, tartrate, borate, bromide, camusylate, carbonate, chloride, clavulanate, citrate, 2-hydrochloride, edetate, edisylate, estrate, esylate, formate, fumarate, gluceptate, gluconate, glutamate, glycolylars-anilate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionic acid, lactate, lactate. Examples of suitable and pharmaceutically acceptable salts of the compound of the present invention include, but are not limited to, tobionates, laurates, malates, maleates, mandelates, mesylates, methyl bromide, methyl nitrate, methyl sulfate, mucoates, napsylates, nitrates, N-methylglucamine ammonium salts, oleates, oxalates, pamoates (embonates), palmitates, pantothenates, phosphates / diphosphates, polygalacturonates, salicylates, stearates, sulfates, basic acetates, succinates, tannates, tartrates, theoclates, tosylates, triethiozides, trifluoroacetates, and valersates. When the compound of the present invention has an acidic portion, suitable and pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases such as aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese triphosphate, potassium, sodium, and zinc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts.Salts derived from pharmaceutically 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, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0208] Furthermore, if a carboxylic acid (-COOH) or alcohol group is present in the compound of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl can also be used. These include ester and acyl groups known in the industry for altering solubility or hydrolysis properties for use as a sustained-release formulation or prodrug formulation.

[0209] The term "prodrug" means a compound that is rapidly converted in vivo to a parent compound by hydrolysis in the blood, for example, the conversion of a prodrug of formula I to a compound of formula I or a salt thereof. Detailed explanations are 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, in particular 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). These compounds and pharmaceutically acceptable salts thereof may be effective in treating diseases, disorders, and symptoms mediated by inhibition of NOD-like receptor protein 3 (NLPR3).

[0211] The present invention relates to the treatment or prevention of NLRP3-mediated diseases, disorders, or symptoms in subjects determined to have non-silent germline or somatic mutations in NLRP3, such as inflammation, autoimmune diseases, cancer, infectious diseases, central nervous system diseases or disorders, metabolic diseases, cardiovascular diseases, fibrous diseases or fibrosis, respiratory diseases, kidney diseases, liver diseases, ophthalmic or eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, graft-versus-host diseases, allodynia, or NLRP3-related diseases.

[0212] Diseases, disorders, or symptoms mediated by NLRP3 include, but are not limited to, gout, pseudogout, osteoarthritis, familial influenza autoinflammatory syndrome, Mackle-Wells syndrome, neonatal multiorgan inflammatory disease, diabetes mellitus, NASH, sepsis, age-related macular degeneration, diabetic retinopathy, hepatic fibrosis, renal fibrosis, atherosclerosis, heart failure, peripheral artery disease, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colon cancer, Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, hidradenitis suppurativa, pericarditis, myocarditis, pre-eclampsia, dermatomyositis, Still's disease, juvenile idiopathic arthritis, age-related macular degeneration, diabetic retinopathy, acute kidney disease, chronic kidney disease, or rare kidney diseases. Furthermore, diseases, disorders, or symptoms 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 present invention, the symptoms, disease, or disorder are inflammatory joint diseases such as gout, pseudogout, or osteoarthritis.

[0214] In another embodiment, cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Mackle-Wells syndrome, or neonatal onset multi-organ 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 disease or eye disease is age-related macular degeneration or diabetic retinopathy.

[0219] In another embodiment, the fibrotic disease is hepatic fibrosis or renal fibrosis.

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

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

[0222] In another embodiment of the present invention, the central nervous system symptoms, diseases, or disorders are Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0223] In another embodiment, the skin condition 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 symptoms or diseases can be treated, managed, prevented, reduced, alleviated, improved, or suppressed by administering a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0230] The compounds of this invention are used to treat gout, pseudogout, osteoarthritis, familial influenza autoinflammatory syndrome, Mackle-Wells syndrome, neonatal multi-organ inflammatory disease, diabetes, NASH, sepsis, age-related macular degeneration, diabetic retinopathy, hepatic fibrosis, renal fibrosis, atherosclerosis, heart failure, peripheral artery disease, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colon cancer, Parkinson's disease, Alzheimer's disease, traumatic brain injury, and spinal cord disease. It may also be used in the manufacture of pharmaceuticals that may be useful in treating, preventing, managing, alleviating, improving or controlling one or more of the following conditions, diseases, or disorders, including but not limited to injuries, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, hidradenitis suppurativa, pericarditis, myocarditis, pre-eclampsia, dermatomyositis, Still's disease, juvenile idiopathic arthritis, age-related macular degeneration, diabetic retinopathy, acute kidney disease, chronic kidney disease, or rare kidney diseases. The compounds of the present invention may also be used in the manufacture of pharmaceuticals that may be useful in treating, preventing, managing, alleviating, improving or controlling one or more of the symptoms, diseases, or disorders of 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, etc.

[0231] A preferred use of the compound may be to treat one or more of the following diseases by administering a therapeutically effective dose to patients in need of treatment. The compound can be used in the manufacture of pharmaceuticals for the treatment of one or more of these diseases; 1) Gout, 2) Pseudogout, 3) Cryopyrin-associated periodic syndromes, 4) Non-alcoholic steatohepatitis, 5) Fibrosis, 6) Osteoarthritis, 7) arteriosclerosis, 8) Atopic dermatitis, 9)Hidradenitis suppurativa, 10) Alzheimer's disease, and 11) Parkinson's disease.

[0232] Treatment of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway refers to administering the compound of the present invention to a subject having such disease, disorder, or symptom.

[0233] One possible outcome of treatment is the reduction of disease, disorder, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway. Another possible outcome of treatment is the alleviation of disease, disorder, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway. Another possible outcome of treatment is the improvement of disease, disorder, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway. Another possible outcome of treatment is the suppression of disease, disorder, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway. Another possible outcome of treatment is the management of disease, disorder, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway. Another possible outcome of treatment is the prevention of disease, disorder, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway.

[0234] Prevention of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway refers to the administration of the compound of the present invention to subjects at risk of such diseases, disorders, or symptoms. One outcome of prevention may be the reduction of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway in subjects at risk of such diseases, disorders, or symptoms. Another outcome of prevention may be the suppression of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway in subjects at risk of such diseases, disorders, or symptoms. Another outcome of prevention may be the improvement of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway in subjects at risk of such diseases, disorders, or symptoms. Another outcome of prevention may be the alleviation of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway in subjects at risk of such diseases, disorders, or symptoms. Another outcome of prevention may be the management of diseases, disorders, or symptoms mediated by NLPR3 or the NLPR3 inflammasome pathway in individuals at risk of disease, disorder, or symptom.

[0235] The terms “administer” and / or “to administer” the compound should be understood to mean providing the compound of the present invention or a prodrug of the compound of the present invention to an individual or mammal in need of treatment.

[0236] The administration of the compound of structural formula I for the treatment method of the present invention is carried out by administering an effective amount of the compound of structural formula I to a mammal in need of treatment or prophylaxis. The need for prophylactic administration by the method of the present invention is determined using known risk factors. The effective amount of each compound is determined in the final analysis by the physician or veterinarian in charge of the patient, and is determined by factors such as the exact disease to be treated, the severity of the disease and other diseases or symptoms the patient has, other drugs the patient may need simultaneously, the chosen route of administration for treatment, and other factors at the physician's discretion.

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

[0238] Dosage and dosage 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, administration can be done orally, intravenously, by infusion, subcutaneously, percutaneously, intramuscularly, intradermally, intramucosally, intramucosally, rectally, topically, parenterally, orally, pulmonaryly, orally, orally, orally. Dosage forms include tablets, lozenges, dispersants, suspensions, liquids, capsules, creams, ointments, and aerosols. Preferably, the compound of the present invention is administered orally.

[0239] In the treatment or prevention of disorders, diseases and / or symptoms requiring inhibition of NLRP3, the preferred dose level is typically about 0.0001 to 500 mg / kg patient body weight / day, which can be administered as a single or multiple dose. In another embodiment, the preferred dose level may be about 0.001 to about 250 mg / kg / day. In another embodiment, the preferred dose level may be about 0.01 to about 250 mg / kg / day. In another embodiment, the preferred dose level may be about 0.1 to about 100 mg / kg / day. In another embodiment, the preferred dose level may be about 0.05 to 100 mg / kg / day. In another embodiment, the preferred dose level may be about 0.1 to 50 mg / kg / day. In another embodiment, the preferred dose level may be about 0.05 to 0.5 mg / kg / day. In another embodiment, the preferred dose level may be about 0.5 to 5 mg / kg / day. In another embodiment, a preferred dose level may be about 5 to 50 mg / kg / day. For oral administration, the composition is preferably provided in the form of tablets containing 0.01 to 1000 mg of the active ingredient, particularly 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 the active ingredient, for symptomatic adjustment of the dose for the patient being treated. The compound can be administered 1 to 8 times a day, preferably 1 to 4 times a day, more preferably 1 or 2 times a day, and even more preferably 1 time a day. This administration method can be adjusted to obtain the optimal therapeutic response.

[0240] However, it should be understood that specific dose levels and administration frequencies for particular patients may vary and depend on a variety of factors, including the activity of the specific compound used, its metabolic stability and duration of action, age, weight, overall health, sex, diet, method and time of administration, excretion rate, concomitant medications, severity of specific symptoms, and the host being treated.

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

[0242] In pharmaceutical compositions, the term "composition" encompasses products containing an active ingredient and an inert component constituting a carrier, as well as any products directly or indirectly arising from the combination, complexation, or aggregation of two or more components, or the dissociation of one or more components, or other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass all compositions produced by mixing the compounds of the present invention with pharmaceutically acceptable carriers.

[0243] The compounds of the present invention may be used in combination with other agents that may also be useful in treating or improving diseases or symptoms for which the compounds of the present invention are useful. Such other agents can be administered simultaneously with or sequentially with the compounds of the present invention, in the usual routes and amounts. Multiple agents may be administered in the treatment of patients suffering from chronic inflammatory symptoms. The compounds of the present invention may generally be administered to patients who are already taking one or more other agents for these symptoms. 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 well to treatment.

[0244] Combination therapy includes therapies in which the compound of the present invention and one or more other drugs are administered in different overlapping schedules. When used in combination with one or more other active ingredients, it is conceivable that the compound of the present invention and the other active ingredients can be used at lower doses than when each is used alone. Therefore, pharmaceutical compositions of the present invention may also include those containing 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) Antilipid denaturing agents; (ii) Anti-inflammatory agents; (iii) Immuno-oncological drugs; (iv) Lipid-lowering agents; (v) Cholesterol-lowering agents; (vi) Hypoglycemic agents including SGLT2 inhibitors; (vii) Anti-angiogenic agents; (viii) Nonsteroidal anti-inflammatory drugs ("NSAIDs"); (ix) Acetylsalicylic acids (ASAs), e.g., aspirin, paracetamol; (x) regenerative therapy treatment; (xi) Checkpoint inhibitors, including anti-PD1 inhibitors and anti-PDL1 inhibitors; (xii) Chemotherapy procedure; (xiii) Radiotherapy; (xiv) surgery; (xv) Uric acid-lowering therapy; (xvi) Anabolic drugs and cartilage regeneration therapies; (xvii) Antifibrotic agent; (xviii) JAK inhibitors; (xix) TNF-A inhibitor; (xx) Antihypertensive drugs; and (xxi) STING / cGAS antagonist The pharmaceutically acceptable salt.

[0246] In another embodiment of the present invention, the pharmaceutical composition is 1) The compound of claim 1 or a pharmaceutically acceptable salt thereof; 2) The following groups: (i) Antilipid denaturing agents; (ii) Anti-inflammatory agents; (iii) Immuno-oncological drugs; (iv) Lipid-lowering agents; (v) Cholesterol-lowering agents; (vi) Hypoglycemic agents including SGLT2 inhibitors; (vii) Anti-angiogenic agents; (viii) Nonsteroidal anti-inflammatory drugs ("NSAIDs"); (ix) Acetylsalicylic acids (ASAs), e.g., aspirin, paracetamol; (x) regenerative therapy treatment; (xi) Checkpoint inhibitors, including anti-PD1 inhibitors and anti-PDL1 inhibitors; (xii) Chemotherapy procedure; (xiii) Radiotherapy; (xiv) surgery; (xv) Uric acid-lowering therapy; (xvi) Anabolic drugs and cartilage regeneration therapies; (xvii) Antifibrotic agent; (xviii) JAK inhibitors; (xix) TNF-A inhibitor; (xx) Antihypertensive drugs; (xxi) STING / cGAS antagonists; and The pharmaceutically acceptable salt One or more compounds selected from or pharmaceutically acceptable salts thereof; and 3) Pharmaceutically acceptable carriers Includes.

[0247] Specific compounds used in combination with the compounds of the present invention include, but are not limited to, anti-lipid denaturing agents (such as DGAT2 inhibitors).

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

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

[0250] Appropriate immunotumor drugs include, but are not limited to, PD-L1 inhibitors, PD-1 inhibitors, and STING antagonists.

[0251] Appropriate blood glucose-lowering agents include, but are not limited to, insulin, SGLT2 inhibitors, metformin, and GLP-1 agonists.

[0252] Appropriate anti-neovascular drugs include, but are not limited to, anti-VEG-F drugs.

[0253] Appropriate 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 tolmetine.

[0254] Appropriate pain relievers include, but are not limited to, acetaminophen and duloxetine.

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

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

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

[0258] Accordingly, a further aspect of the present invention provides the use of an NLRP3 inhibitor and one or more active ingredients for the manufacture of a pharmaceutical product for the treatment or prevention of an NLRP3-mediated disease, disorder, or symptom. Accordingly, a further or alternative aspect of the present invention provides a product comprising an NLRP3 inhibitor and one or more active ingredients as a combination formulation for simultaneous, separate, or sequential use in the treatment or prevention of an NLRP3-mediated disease, disorder, or symptom. Such a combination formulation may be in the form of, for example, a twin pack.

[0259] It will be understood that compound q of the present invention can be used in combination with another pharmaceutical product effective in treating a disease, disorder, or symptom of a cardio-metabolic disease, neurodegenerative disease, inflammatory joint disease, fibrosis, or cancer, for the treatment or prevention of such disease, disorder, or symptom.

[0260] The present invention also provides a method for treating or preventing chronic inflammatory symptoms, comprising administering to a patient in need of such treatment a certain amount of the compound of the present invention and a certain amount of another pharmaceutical product effective in addressing the disorder, disease, or symptoms thereof, wherein together they produce effective relief.

[0261] The present invention also provides a method for treating or preventing chronic inflammatory symptoms, comprising administering to a patient in need of such treatment a certain amount of the compound of the present invention and a certain amount of other pharmaceuticals useful for treating the specific symptoms, disorders, or diseases thereof, thereby providing effective relief together.

[0262] The term "therapeutically effective dose" means the amount of a compound of structural formula I that elicits a physiological or medical response in a cell, tissue, system, animal, or human, including relief of symptoms of the disease being treated, as sought by researchers, veterinarians, physicians, or other clinical professionals. The novel therapeutic methods of the present invention target disorders known to those skilled in the art. The term "mammal" includes humans and pet animals such as dogs and cats.

[0263] The weight ratio of compound I to the second active ingredient can vary and is determined by the effective dose of each ingredient. Generally, the effective dose of each ingredient is used. For example, when compound I is combined with an antilipid denaturing agent, the weight ratio of compound 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 compound I with 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 reaction diagrams and examples illustrate methods that can be used to synthesize the compounds of structural formula I described in the present invention. These reaction diagrams and examples are provided for illustrative purposes of the present invention and should not be construed as limiting the present invention in any way. Unless otherwise stated, all substituents are as defined above. Several strategies based on synthetic transformations known in the organic synthesis literature can be used to produce the compounds of structural 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 (250mm × 30mm × 4 microns), Phenomenex Luna C18 (250mm × 21mm × 5 microns), Agilent Zorbax Bonus-RP (150mm × 21mm × 5 microns), and Waters X-Select CSH C18 (150mm × 19mm × 5 microns). Conditions included high pH (0% to 100% acetonitrile / water eluent containing 0.1 vol% NH4OH) or low pH (0% to 100% acetonitrile / water eluent containing 0.1 vol% TFA or formic acid), as shown in several examples. SFC chiral separation 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 DAD and QDa MS detectors under the following conditions: Waters ACQUITY UPLC BEH C18 1.7 mm 2.1 × 50 mm column, using a mobile phase containing A: 0.1% TFA aqueous solution and B: 0.1% TFA / acetonitrile, with a flow rate of 0.5 mL / min over 2.0 minutes, gradient from 10% B to 90% B, and retention at 90% B for 0.4 minutes. Proton or 1Unless otherwise specified, 1H NMR spectra are obtained using a Bruker 500MHz NEO NMR spectrometer with 5 miProbes, following standard analytical techniques, and the results of the spectral analysis are reported. Chemical shift (δ) values ​​are reported in delta (δ) units, parts per million (ppm). 1 The chemical shifts of the 1H NMR spectrum are provided relative to the signals of the residual non-deuterated solvents (CDCl3 relative to δ7.26 ppm; DMSO d-6 relative to δ2.50 ppm; CD3OD relative to δ3.31 ppm). Multiplicity is reported using the following abbreviations: s = singleline, d = doubleline, t = tripleline, q = quadrupleline, dd = doubleline of doublelines, m = multiline or non-equivalent resonance overlap. Coupling constants (J) are reported in Hertz (Hz).

[0267] The following are typical preparative conditions for separating diastereomer or enantiomer mixtures of compounds using chiral SFCs. [Table 1]

[0268] Abbreviation: The asterisk (*) within a molecule indicates a stereocenter. Ac is acetyl. OAc is acetate. AcOH is acetic acid. aq. is aqueous solution. B2pin2 is bis(pinacolato)diborone. BPin ester is pinacol boronic acid 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 a double line. 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 a double line for double line. dqd is a double line quadruple line double line. DEA is diethanolamine. DIEA is N,N-diisopropylethylamine. DMA is dimethylacetamide. DME is dimethoxyethane. DMF is dimethylformamide. DMSO is dimethyl sulfoxide. dtbbpy is 4,4′-di-tert-butyl-2,2′-dipyridyl. dppf is 1,1′-bis(diphenylphosphin)ferrocene. EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. ESI is electrospray ionization. Et is ethyl. Et2O is diethyl ether. siRNA is ethyl acetate. EtOH is ethanol. equiv is equivalent weight. g is grams. h or hr(s) is time. 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 liter. LAH is lithium aluminum hydride. LC is liquid chromatography. LCMS is liquid chromatography / mass spectrometry. LRMS is low-resolution mass spectrometry. m is multiline. M is molar concentration.Me is methyl. MeOH is methanol. MeCN is acetonitrile. mg is milligrams. min is minutes. mL is milliliters. mM is millimoles. mmol is millimoles. MHz is megahertz. □L is microliters. MS is mass spectrometry. nM is nanomoles. NHPI is N-hydroxyphthalimide. NaHMDS is sodium bis(trimethylsilyl)amide. NH4OAC is ammonium acetate. NMO is 4-methylmorpholine N-oxide. NMP is N-methylpyrrolidone. PCC is pyridinium chlorochromate. Pd / C is carbon-supported palladium. Pd(DPPF)Cl2 is [1,1′-bis-(diphenylphosphino)-ferrocene]dichloropalladium(II). Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium(O). Pd(tBu3P)2 is bis(tri-tert-butylphosphine)-palladium(O). PE is petroleum ether. PG is a protecting group. ph is phenyl. Pr is propyl. prep is preparative. q is quadruplet. rac is racemic. rt or RT is room temperature. s is monotlet. 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.XPhos Pd G3 is (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate. UV stands for ultraviolet light.

[0269] Diagram A [ka]

[0270] Figure A shows the synthesis of aryl and heteroaryl boronates such as A-2 from aryl halides (Cl, Br, or I) such as A-1. Aryl boronate A-2 is produced by palladium-catalyzed Suzuki-Miyaura borylation of aryl halides such as A-1 in the presence of a suitable base.

[0271] Diagram B [ka]

[0272] Figure B shows the synthesis procedure for the phthalazine derivative of formula B-4. The heteroaryl dioic acid of formula B-1 is treated with an acid, such as H2SO4, in a suitable alcohol solvent (ROH), such as MeOH, to obtain the diester of formula B-2. The diester of formula B-2 is condensed with hydrazine and subsequently treated with an aqueous HCl solution to obtain the pyridazine-1,4-dione of formula B-3. The pyridazine-1,4-dione B-3 is reacted with a suitable deoxychlorinating agent (such as POCl3) to obtain the dichlorophthalazine derivative of formula B-4.

[0273] Diagram C [ka]

[0274] Figure C shows the synthetic procedure for producing phthalazine derivatives such as C-2a and C-2b from the precursor of formula B-4. Nucleophilic aromatic substitution (SnAr) proceeds using various secondary amines in the presence of a base such as K2CO3 to obtain the tertiary amines of formulas C-1a and C-1b. Biaryl products are obtained by cross-coupling with a suitable aryl nucleophile such as an arylboronic acid and a palladium catalyst, and if applicable, deprotection with In-Sites to obtain the compounds of formulas C-2a and C-2b. If positional isomers are present, they are separated, preferably by chromatography using reversed-phase HPLC or SFC.

[0275] Diagram D [ka]

[0276] Figure D shows the synthetic procedure for producing phthalazine derivatives such as C-2a from the precursor of formula B-4. The biaryl product of formula D-1 is obtained by Suzuki cross-coupling using a suitable aryl nucleophile such as an arylboronic acid and a palladium catalyst. If positional isomers are present, they are preferably separated chromatographically using silica gel chromatography. Subsequently, nucleophilic aromatic substitution (SnAr) is performed with various secondary amines in the presence of a base such as K2CO3 to produce the tertiary amine of formula C-2a.

[0277] Diagram E [ka]

[0278] Figure E shows a method for producing the alkylated compound 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. The alkylated compound of formula E-1 is obtained by proceeding with cross-electrophilic coupling under nickel catalysis.

[0279] Diagram F [ka]

[0280] Figure F shows a method for producing the tertiary alcohol compound of formula F-2 from the corresponding biaryl chloride D-1 and a suitable alkenyl nucleophile such as pinacol boronate ester. Cross-coupling is carried out under palladium catalysis to obtain the biaryl alkene of formula F-1. Subsequent alkene hydration using Mukaiyama-Magnus conditions is carried out to obtain the tertiary alcohol of formula F-2.

[0281] Diagram G [ka]

[0282] Figure G shows a method for producing alkylated pyridopyridazines of formulas G-2a and G-2b by Minisci-type radical addition to G-1 using a suitable radical precursor, such as zinc sulfinate reagent. The reaction is carried out in the presence of an oxidizing agent such as TBHP to obtain a mixture of positional isomers of the substituted pyridopyridazines of formulas G-2a and G-2b, which is 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), B2pin2 (56 mg, 0.22 mmol), KOAc (60 mg, 0.6 mmol), and PdCl2 (dppf) (15 mg, 0.2 mmol) were added. The mixture was degassed with N2 and stirred at 105°C for 12 hours. The reaction mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The resulting crude mixture was used 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-Dichloropyridadino[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 under reflux for 48 hours, then cooled to room temperature and partitioned between H2O and SiO4. The aqueous layer was extracted with SiO4, the combined organic layers were washed with brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (SiO4:hexane) to obtain the title compound. LCMS[M+H] + = 197.1 (Calculated value: 197.1).

[0285] Stage 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 under reflux for 1 hour with high stirring. The mixture was cooled to room temperature and filtered. The filtered solid was transferred to a vial containing H2O (9 mL), heated to 85°C, and then acidified with concentrated aqueous HCl to pH 3. The mixture was stirred for 20 minutes. The mixture was cooled to room temperature, filtered, and the resulting solid was vacuum-dried to obtain the title compound. LCMS[M+H] + = 165.0 (Calculated value: 165.0).

[0286] Stage 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 and left overnight. The mixture was cooled to room temperature and placed on ice. The suspension was adjusted to pH 7 with saturated NaHCO3 aqueous solution and then diluted with SiO2. The layers were separated, and the aqueous layer was extracted with SiO2 (twice). The combined organic layers were dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (SiO2:hexane) to obtain the title compound. LCMS[M+H] + =201.0 (Calculated value: 201.0).

[0287] Table 1. Using appropriate starting materials, the following compounds were prepared using the same procedure as 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 The racemic tert-butyl(cis)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (Synthonix, 15g, 66.3 mmol) was separated by chiral SFC (Method A) to obtain the corresponding enantiomers. Peak 1: tert-butyl(3aR,7aS)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (6.8g, 30.0 mmol), and Peak 2: tert-butyl(3aS,7aR)-octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (5.7g, 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), 37% formaldehyde aqueous solution (1.65 mL, 22.1 mmol) and NaBH3CN (0.56 g, 8.84 mmol) were added at 0°C. The mixture was heated 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] Stage 3: (3aR,7aR)-6-methyloctahydro-1H-pyrrolo[2,3-c]pyridine: HCl (5.5 mL, 22.0 mmol) in 4M 1,4-dioxane solution was added to 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 overnight at room temperature. 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 DCM solution, 0.7 mL, 0.7 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, the solvent was removed under reduced pressure, and the crude residue was purified by silica gel chromatography (Â:hexane) to obtain the title compound.

[0292] Examples 1 and 2 (S)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrolidine-3-ol (Example 1); and (S)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]-pyridazin-4-yl)-3-methylpyrrolidine-3-ol (Example 2) [ka] Stage 1: (S)-1-(4-chloropyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrolidine-3-ol and (S)-1-(1-chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpyrrolidine-3-ol: 1,4-Dichloropyrido[3,4-d]pyridazine (Ambeed, 300 mg, 1.5 mmol), K2CO3 (415 mg, 3.0 mmol), and (S)-3-methylpyrrolidine-3-ol hydrochloride (PharmaBlock, 206 mg, 1.5 mmol) were suspended in NMP (6 mL). The mixture was heated to 80°C and left overnight. Next, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue containing the title compound was used directly in the next step as a mixture of positional isomers: 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-methylpyrrolidine-3-ol and (S)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-3-methylpyrrolidine-3-ol: A mixture of positional isomers, (S)-1-(4-chloropyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrolidine-3-ol and (S)-1-(1-chloropyrido[3,4-d]pyridazin-4-yl)-3-methylpyrrolidine-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 aqueous solution, 1.54 mL, 4.61 mmol). The mixture was degassed by blowing in Ar for 10 minutes, then sealed and heated under stirring at 100°C for 3 hours. After cooling to room temperature, the crude mixture was placed dry on silica gel and purified by silica gel chromatography (MeOH:DCM) to obtain the title compound as a mixture of positional isomers. The positional isomers were separated by chiral SFC (Method B). The positional isomer that eluted first 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 value: 391.1). A positional isomer that would later elute 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. The following compounds were prepared using appropriate starting materials and the same procedure as described for Examples 1 and 2. Positional isomers (if present) were separated by silica gel chromatography after step 1 or by reversed-phase HPLC after step 2. [Table 3] TIFF0007863148000030.tif249168TIFF0007863148000031.tif95167

[0295] Table 3. The following compounds were prepared using appropriate starting materials and the same procedure as described for Examples 1 and 2. The positional isomer products were separated after step 2 using the chiral SFC method identified in the table. For positional isomer pairs, the isomer that elutes first is listed first. [Table 4]

[0296] Example 22 (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-3-methylpyrrolidine-3-ol [ka] Stage 1: 2-(8-chloropyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol: (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) were dissolved in 1,4-dioxane (30 mL) and H2O (10 mL) and degassed by blowing Ar over them for 10 minutes. The vial was heated to 85°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, diluted with SiO2, and placed dry on silica gel. The title compound was obtained by purification by silica gel chromatography (SiO2:hexane). LCMS[M+H] + =326.0 (Calculated value: 326.0).

[0297] Stage 2: (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidine-3-ol: K2CO3 (151 mg, 1.09 mmol) and (S)-3-methylpyrrolidine-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 hours. The reaction solution was cooled to room temperature and directly purified by preparative reverse-phase HPLC (C18 stationary phase, MeCN / H2O + 0.05% FA) to obtain 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 appropriate starting materials, the following compounds were prepared using the same procedure as described for Example 22.

[0299] [Table 5] TIFF0007863148000035.tif254168TIFF0007863148000036.tif244170TIFF0007863148000037.tif242169TIFF0007863148000038.tif40169

[0300] Table 5. The following compounds were prepared using appropriate starting materials and the same procedure as described for Example 22. The enantiomer products were separated using the chiral SFC method identified in the table. For enantiomer pairs, the isomer that elutes first 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] Stage 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), 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) were added. The mixture was degassed with N2 and then stirred at 100°C for 2 hours. After cooling to room temperature, the mixture was stopped with saturated NaHCO3 aqueous solution and partitioned between H2O and RINKAN. The layers were separated, and the aqueous layer was extracted with RINKAN. The combined organic layers were dehydrated with MgSO4, filtered, and concentrated under reduced pressure. The crude residue obtained was purified by silica gel chromatography (RINKAN:hexane) followed by reverse-phase HPLC (C18 stationary phase, MeCN / H2O + 0.1% TFA). The combined product fraction was stopped with saturated NaHCO3 aqueous solution and diluted with RINKAN. The layers were separated, and the aqueous layer was extracted with RINKAN (three times). The combined organic layer was dehydrated with MgSO4, filtered, and concentrated under reduced pressure. The title compound was obtained by further purification with silica gel chromatography (RINKAN:hexane). LCMS[M+H] + =323.1 (Calculated value: 323.1).

[0303] Stage 2: 1-((2R,4r,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-4-(2-methyl-4-(trifluoromethyl)phenyl)phthalazine:A catalyst solution consisting 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 minutes. In another vial, cis-1,3-dioxoisoindolin-2-yl2,6-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 added under Ar, and the catalyst solution (0.7 mL) was added. The vial was sealed and heated under high stirring (>1000 rpm) to 50°C and left 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 obtain 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] Stage 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 for 10 minutes by blowing in Ar, and then 1 M K3PO4 aqueous solution (2.0 mL, 2.03 mmol) was added. The reaction mixture was heated to 100°C and stirred for 2 hours. Next, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and placed dry on silica gel. The compound was then purified by silica gel chromatography (ethyl acetate:hexane) to obtain the title compound. LCMS[M+H] + =402.1 (Calculated value: 401.1).

[0305] Stage 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)3 (98 mg, 0.16 mmol) i The mixture was suspended in PrOH (1.4 mL). O2 was blown into the mixture for 5 minutes, 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 hours. Next, the reaction mixture was cooled to room temperature, the reaction was stopped with excess P(OMe)3, and stirred for 5 minutes. The mixture was diluted with H2O, then with 1 M aqueous HCl, and then with HCl. The layers were separated, the aqueous layer was neutralized to pH 7, and back-extracted with HCl. The combined organic layers were dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (HCl:hexane) to obtain the title compound as two separated diastereomers. The diastereomer that elutes first 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). The title compound was subsequently dissolved and 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-methylpyrrolidine-3-ol (Example 56); and (S)-1-(3-(difluoromethyl)-5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidine-3-ol (Example 57)

change

[0307] Examples of pharmaceutical compositions As a specific embodiment of the oral pharmaceutical composition, a 100 mg tablet is made from 100 mg of one 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. Next, the mixture is lubricated with magnesium stearate and compressed to form a tablet.

[0308] Biological assays Standard NLRP3 inflammasome activation 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 nuclear factor-κB (NF-KB) mediated signaling. This then increases the transcription of inactive NLRP3 and inflammasome-related 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-related speck-like proteins including CARD(ASC), and procaspase 1 into an inflammasome complex. This induces conversion of procaspase 1 to caspase 1, and the production and secretion of mature IL-1β and IL-18 (Kim et al., J. Inflamm. 2015, 12, 41; Ozaki et al., J. Inflamm. Res. 2015, 8, 15 - 27; Rabeony et al., Eur. J. Immunol. 2015, 45, 2847). During the assembly of the inflammasome complex, oligomerization of NLRP3 induces nucleation of ASCs, and after staining and visualizing ASCs using common immunocytochemical methods, they are identified in cells as individual spots, resulting in an event commonly referred to as "ASC SPECK" formation.

[0309] The ability of a compound to inhibit NLRP3 inflammasome activation was measured in vitro by monitoring ASC-SPECK formation in stimulated human monocyte THP-1 cells. 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, 1× penicillin / streptomycin, and 0.05 mM 2-mercaptoethanol. At the start of the assay, undifferentiated THP-1 cells were seeded 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) in 384-well plates (poly-D-lysine coated Cell Carrier Ultra microplates, Perkin Elmer catalog no. 6057500) and incubated overnight. The following day, the culture medium was replaced with assay medium [RPMI (Gibco catalog no. 11875-093), 0.01% bovine serum albumin (BSA)]. The compounds were sequentially diluted with DMSO and added to the wells, and 12.5 μg / mL gramicidin (Enzo Lifescience, catalog no. ALX-350-233-M005) was added after 1 hour. All incubations were performed at 37°C (5% CO2 / 95% air). After 3 hours of treatment with gramicidin, the cells were fixed with 4% paraformaldehyde and stored at 4°C until immunofluorescence staining.

[0310] Immunofluorescence staining: The anti-ASC antibody (MBL catalog number D086-3) was desalted, labeled with the ALEXA488 antibody labeling kit (THERMO catalog number A20181), and then 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 minutes, and then incubated for 1 hour in blocking buffer containing 5% goat serum, 0.3% tween-20, and 0.03% sodium azide in PBS. Cells were stained for 1 hour with a mixture of ASC-Alexa 488 antibody (diluted 1:200 in blocking buffer) and nuclear stain DRAQ5 (diluted 1:5000 in blocking buffer, Thermo catalog number 62251) in blocking buffer. After washing with 0.3% Tween-20 in PBS, the plates were imaged using the Opera Phenix High Content Screening System. The number of DRAQ5-positive cells, including ASC SPECKS cells, was quantified in each well.

[0311] Data Analysis: Using a program developed in-house with TIBCO Spotfire software, standard curve fitting analysis was performed on EC. 50 The value was calculated.

[0312] The compound of the present invention inhibits the activation of the NLRP3 inflammasome in the above biological assay, and EC 50 The value is less than 5 μM. Specific EC values ​​for compounds in Examples 1-57 of the above biological assays. 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] TIFF0007863148000044.tif45170

[0314] The claims should not be limited by the preferred embodiments described in the examples, but should be given the broadest interpretation consistent with the overall description.

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

Claims

1. The present invention relates to a compound of the following structural formula I or a pharmaceutically acceptable salt thereof. [During the ceremony T is an independent group: CR ３ , and selected from N; However, one or two of T, U, V, and W are N; U is an independent group: 1) CR ４ , and 2) N Selected from; V is an independent group: 1) CR ５ , and 2) N Selected from; W is an independent group: 1) CR ６ , and 2) N Selected from; R １ The 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]nonan, 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 Selected from, Here, R １ It is either not substituted or R ａ It is substituted with 1 to 6 substituents selected from; R ２ The group: 1) Aryl, and 2) Heteroaryl Selected from, Here, aryl is substituted by 2 to 5 substituents selected from R ｂ and here, heteroaryl is unsubstituted or substituted by 1 to 5 substituents selected from Rb; R ３ The group: 1) Hydrogen, 2) OH, 3) CN, 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 Selected from, Here, R ３ It is either not substituted or R ｄ It is substituted with 1 to 5 substituents selected from; R ４ The group: 1) Hydrogen, 2) OH, 3) CN, 4)CF ３ 、 5)CF ２ H、 6) -C １－６ Alkyl, 7) -O-C １－６ Alkyl, 8) Halogen, 9) - C ３－６ Cycloalkyl, 10) - C ２－６ Heterocyclic alkyl, and 11) - C １－６ Alkyl-O-C １－６ Alkyl Selected from, Here, R ４ It is either not substituted or R ｅ It is substituted with 1 to 5 substituents selected from; R ５ The group: 1) Hydrogen, 2) OH, 3) CN, 4)CF ３ 、 5)CF ２ H、 6) -C １－６ Alkyl, 7) -O-C １－６ Alkyl, 8) Halogen, 9) - C ３－６ Cycloalkyl, 10) - C ２－６ Heterocyclic alkyl, and, 11) - C １－６ Alkyl-O-C １－６ Alkyl Selected from, Here, R ５ It is either not substituted or R ｆ It is substituted with 1 to 5 substituents selected from; R ６ The group: 1) Hydrogen, 2) OH, 3) CN, 4)CF ３ 、 5)CF ２ H、 6) -C １－６ Alkyl, 7) -O-C １－６ Alkyl, 8) Halogen, 9) - C ３－６ Cycloalkyl, 10) - C ２－６ Heterocyclic alkyl, and 11) - C １－６ Alkyl-O-C １－６ Alkyl Selected from, Here, R ６ It is either not substituted or R ｇ It is substituted with 1 to 5 substituents selected from; Each R ａ These are groups independently: 1) CN, 2) Oxo, 3) -OH, 4) Halogen, 5) -C １－６ Alkyl, 6) -O-C １－６ Alkyl, 7) - C ２－６ Alkenil, 8) -C ２－６ Alkinil, 9) - C ３－６ Cycloalkyl, 10) - C ２－６ Heterocyclic alkyl, 11) Ariel, 12) Heteroaryls, and 13) -C(O)C １－６ Alkyl Selected from, Here, each R ａ is either not substituted, halogen, CF ３ OH, C １－６ Alkyl and -OC １－６ It is substituted with 1 to 6 substituents selected from alkyl groups; Each R ｂ These are groups independently: 1) CN, 2) -OH, 3)-CH ３ 、 4)-CF ３ 、 5)-CF ２ H、 6) -OCF ２ H, and 7) Cyclopropane Selected from, Here, each R ｂ is either not substituted, halogen, CF ３ CF ２ H, OCF ３ , CN, CH ２ CF ３ CF ２ CH ３ , -C １－６ Alkyl and -OC １－６ It is substituted with 1 to 6 substituents selected from alkyl groups; Each R ｄ These are groups independently: 1)CF ３ 、 2) Halogens, and 3) -C １－６ Alkyl Selected from, Here, alkyl is either unsubstituted or CF ３ , halogens, OH and -OC １－６ It is substituted with one to three substituents selected from alkyl groups; Each R ｅ These are groups independently: 1)CF ３ 、 2) Halogens, and 3) -C １－６ Alkyl Selected from, Here, alkyl is either unsubstituted or CF ３ , halogens, OH and -OC １－６ It is substituted with one to three substituents selected from alkyl groups; Each R ｆ These are groups independently: 1)CF ３ 、 2) Halogens, and 3) -C １－６ Alkyl, Selected from, Here, alkyl is either unsubstituted or CF ３ , halogens, OH and -OC １－６ It is substituted with one to three substituents selected from alkyl groups; Each R ｇ These are groups independently: 1)CF ３ 、 2) Halogens, and 3) -C １－６ Alkyl, Selected from, Here, the alkyl is unsubstituted or substituted by 1 to 3 substituents selected from CF ３ , halogen, OH and -OC １－６ alkyl.], However, this excludes the following compounds or pharmaceutically acceptable salts thereof: 1) (S)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3-methylpyrrolidine-3-ol; 2) (S)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]-pyridazin-4-yl)-3-methylpyrrolidine-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-methylpyrrolidine-3-ol; 11) (cis)-4-(1-(benzofuran-5-yl)pyrido[3,4-d]pyridazine-4-yl)-2,6-dimethylmorpholine; 12) (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-(trifluoromethyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidine-3-ol; 13) (3S,4s,5R)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazino[4,5-d]pyridazin-1-yl)-3,4,5-trimethylpiperidine-4-ol; 16) (3S,4s,5R)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-3,4,5-trimethylpiperidine-4-ol; 17) (3S,4s,5R)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3,4,5-trimethylpiperidine-4-ol; 18) (3S,4r,5R)-1-(1-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)-3,5-dimethylpiperidine-4-ol; 19) (3S,4r,5R)-1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)-3,5-dimethylpiperidine-4-ol; 20) 2-(4-((cis)-2,6-dimethylmorpholino)-6-methylphthalazine-1-yl)-5-(trifluoromethyl)phenol; 21) 2-(4-((cis)-2,6-dimethylmorpholino)-7-methylphthalazine-1-yl)-5-(trifluoromethyl)phenol; 22) (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]- Pyridazine-8-yl)-3-methylpyrrolidine-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-trimethylpiperidine-4-ol; 25) 8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-oxo-1,8-diazaspiro[4.5]decane-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)pyrrolidine-3-ol; 28) (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-(trifluoromethyl)pyrrolidine-3-ol; 29) (R)-3-(difluoromethyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidine-3-ol; 30) (S)-3-(difluoromethyl)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidine-3-ol; 31) (R)-2-(8-(1-oxo-7-azaspiro[4.4]nonan-7-yl)pyrido[2,3-d]pyridazine-5-yl)-5-(trifluoromethyl)phenol; 32) (S)-2-(8-(1-oxo-7-azaspiro[4.4]nonan-7-yl)pyrido[2,3-d]pyridazine-5-yl)-5-(trifluoromethyl)phenol; 33) 2-(8-(1-oxo-8-azaspiro[4.5]decane-8-yl)pyrido[2,3-d]pyridazine-5-yl)-5-(trifluoromethyl)phenol; 34) 2-(8-(2-oxo-8-azaspiro[4.5]decane-8-yl)pyrido[2,3-d]pyridazine-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]undecane-3-one; 36) 2-(8-((cis)-4,4-difluoro-3,5-dimethylpiperidine-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]decane-1-yl)ethane-1-one; 38) 1-(8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-2,8-diazaspiro[4.5]decane-2-yl)ethane-1-one; 39) 8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]-pyridazin-8-yl)-3-methyl-1-oxo-3,8-diazaspiro[4.5]decane-2-one; 40) 2-(8-(4,4-dimethyl-1-oxo-8-azaspiro[4.5]decane-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-phenylpyrrolidine-3-ol; 42) (S)-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-phenylpyrrolidine-3-ol; 43) 8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-methyl-1,8-diazaspiro[4.5]decane-2-one; 44) 8-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-1-oxo-3,8-diazaspiro[4.5]decane-2-one; 45) 2-(8-(6,6-difluoro-3-azabicyclo[3.1.0]hexane-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]decane-2-one; 47) (R)-4,4-difluoro-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidine-3-ol; 48) (S)-4,4-difluoro-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidine-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)pyrrolidine-3-ol; 52) (S)-3-cyclopropyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)pyrrolidine-3-ol; 55) (R)-3-ethyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-pyrrolidine-3-ol; 56) (S)-3-ethyl-1-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-pyrrolidine-3-ol; 57) (R)-2-(8-(3-(hydroxymethyl)-3-methylpyrrolidine-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 58) (S)-2-(8-(3-(hydroxymethyl)-3-methylpyrrolidine-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 59) (R)-2-(8-(3-(2-hydroxypropan-2-yl)pyrrolidine-1-yl)pyrido[2,3-d]pyridazin-5-yl)-5-(trifluoromethyl)phenol; 60) (S)-2-(8-(3-(2-hydroxypropan-2-yl)pyrrolidine-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; 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-methylpyrrolidine-3-ol; and 69) (S)-1-(3-(difluoromethyl)-5-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpyrrolidine-3-ol.

2. W is CR ６ The compound or pharmaceutically acceptable salt thereof as described in claim 1.

3. R １ However, group: 1) Morpholine, 2) Piperidine, 3) Pyrrolidine, 4) Tetrahydropyran, and 5) Octahydro-1H-pyrrolo[2,3-c]pyridine Selected from, here, R １ It is either not substituted or R ａ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one to six substituents selected from the above.

4. R １ However, group: 1) Morpholine, 2) Piperidine, 3) Tetrahydropyran, and 4) Octahydro-1H-pyrrolo[2,3-c]pyridine, Selected from, Here, R １ It is either not substituted or R ａ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one to six substituents selected from the above.

5. R ３ However, group: 1) Hydrogen, and 2) -C １－６ Alkyl Selected from, Here, R ３ It is either not substituted or R ｄ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one to five substituents selected from the above.

6. R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

7. R ４ However, group: 1) Hydrogen, 2) OH, 3) CN, 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 Selected from, Here, R ４ It is either not substituted or R ｅ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one to five substituents selected from the above.

8. R ４ However, group: 1) Hydrogen, and 2) -C １－６ Alkyl Selected from, Here, R ４ It is either not substituted or R ｅ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one to five substituents selected from the above.

9. R ５ However, group: 1) Hydrogen, 2) OH, 3) CN, 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 Selected from, Here, R ５ It is either not substituted or R ｆ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one to five substituents selected from the above.

10. R ５ However, group: 1) Hydrogen, 2) -C １－６ Alkyl, and 3) Halogen Selected from, Here, R ５ It is either not substituted or R ｆ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one to five substituents selected from the above.

11. R ６ However, group: 1) Hydrogen, 2) -C １－６ Alkyl, and 3) -O-C １－６ Alkyl Selected from, Here, R ６ It is either not substituted or R ｇ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one to five substituents selected from the above.

12. R ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

13. R ２ is a heteroaryl, where R ２ It is either not substituted or R ｂ It is substituted with 1 to 5 substituents selected from; R ３ However, group: 1) Hydrogen, and 2) -C １－６ Alkyl Selected from, Here, R ３ It is either not substituted or R ｄ It is substituted with 1 to 5 substituents selected from; R ４ However, group: 1) Hydrogen, 2) OH, 3) CN, 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 Selected from, Here, R ４ It is either not substituted or R ｅ It is substituted with 1 to 5 substituents selected from; R ５ However, group: 1) Hydrogen, 2) OH, 3) CN, 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 Selected from, Here, R ５ It is either not substituted or R ｆ It is substituted with 1 to 5 substituents selected from; and, R ６ However, group: 1) Hydrogen, 2) -C １－６ Alkyl, and 3) -O-C １－６ Alkyl Selected from, Here, R ６ It is either not substituted or R ｇ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with one to five substituents selected from the above.

14. W is CR ６ And; R ２ is an aryl, where the aryl is R ｂ It is substituted with 2 to 5 substituents selected from; R ３ is hydrogen; R ４ However, group: 1) Hydrogen, and 2) -C １－６ Alkyl Selected from, Here, R ４ It is either not substituted or R ｅ It is substituted with 1 to 5 substituents selected from; R ５ However, group: 1) Hydrogen, 2) -C １－６ Alkyl, and 3) Halogen Selected from, Here, R ５ It is either not substituted or R ｆ It is substituted with 1 to 5 substituents selected from; and, R ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

15. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. Use of the compound according to claim 1 for the manufacture of a pharmaceutical product useful for treating disorders, symptoms, or diseases in mammals requiring treatment that respond to inhibition of NLRP3.

17. Use of the compound or a pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of a pharmaceutical product for the treatment, prevention, or control of inflammatory disorders, fibrotic disorders, cardiovascular disorders, metabolic disorders, and neurodegenerative disorders.

18. The use according to claim 17, wherein the disorder is an inflammatory disorder.

19. The use according to claim 18, wherein the inflammatory disorder is selected from autoimmune disorders, autoinflammatory disorders, inflammatory joint disorders, inflammatory skin disorders, and neuroinflammatory disorders.

20. The use according to claim 17, wherein the disorder is selected from atherosclerosis, non-alcoholic steatohepatitis, Alzheimer's disease, and Parkinson's disease.

21. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in therapeutic applications.

22. The pharmaceutical composition according to claim 15, for the treatment or prevention of disorders, symptoms, or diseases in patients that respond to inhibition of NLRP3.

23. The pharmaceutical composition according to claim 22, wherein the disorder is selected from inflammatory disorders, fibrotic disorders, cardiovascular disorders, metabolic disorders, and neurodegenerative disorders.

24. The pharmaceutical composition according to claim 23, wherein the disorder is an inflammatory disorder.

25. The pharmaceutical composition according to claim 23, wherein the inflammatory disorder is selected from autoimmune disorders, autoinflammatory disorders, inflammatory joint disorders, inflammatory skin disorders, and neuroinflammatory disorders.

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

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