Substituted pyridazine compounds as NLRP3 activity inhibitors and therapeutic uses thereof

Abstract

The present application discloses novel substituted pyridazine compounds and analogs, their preparation, pharmaceutical compositions comprising them and their therapeutic use as medicaments for the treatment of diseases or conditions associated with modulation of cytokines such as IL-1 [beta] and IL-18, modulation of NLRP3, or inhibition of activation of NLRP3 or components related to inflammatory processes.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to International Patent Application No. PCT / CN2023 / 102566, filed on June 27, 2023, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This application relates to pyridazine compounds and analogues that act as regulators of cytokines such as IL-1β and IL-18 or NLRP3, as well as methods of their preparation and therapeutic uses. Background Technology

[0004] Nucleotide-binding oligomerization domain-like receptors (or NOD-like receptors, NLRs) are a class of pattern recognition receptors (PPRs) that function as intracellular sensors of pathogen-associated molecular patterns (PAMPs) and damage-or-danger-associated molecular patterns (DAMPs). NLRP3 can be activated by a wide variety of stimuli. Increasing evidence suggests that NLRs play a crucial role in the innate immune response to infection and cellular damage. Among the many NOD-like receptors, protein 3 (NLRP3), which contains a nucleotide-binding oligomerization domain, a leucine-rich repetitive sequence receptor, and a pyrin domain, has been well-characterized as forming inflammasomes containing its oligomers, which recruit the adaptor proteins apoptosis-associated speckle-like protein (ASC) and effector zymogen caspase-1, which contain caspase activation and recruitment domains. The formation of the NLRP3 inflammasome activates caspase-1, which in turn catalyzes proteolytic reactions, releasing pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 [Nat. Rev. Immunol. 2013 Jun;13(6):397-411]. NLRP3 inflammasome activation also leads to the cleavage of cytosin D (GSDMD), which results in pyroptosis, a rapid and pro-inflammatory form of cell death caused by membrane-forming fragments from GSDMD.

[0005] It has been shown that dysregulated NLRP3 inflammasome activation contributes to the pathogenesis of several human diseases. Most notably, gain-of-function mutations in KNORP lead to inherited diseases such as cryopyrin-associated periodic syndrome (CAPS). Furthermore, aberrant activation of the NLRP3 inflammasome exacerbates chronic human diseases such as neurodegenerative diseases (multiple sclerosis, Alzheimer's disease, and Parkinson's disease), metabolic diseases (atherosclerosis and type 2 diabetes), and inflammatory diseases (gout attacks and osteoarthritis). Recently, the role of NLRP3 in the occurrence and progression of cancer has been confirmed [Nat. Immunol. May 2021;22(5):550-559, doi:10.1038 / s41590-021-00886-5].

[0006] A few biologic therapies targeting the NLRP3 / IL-1β innate immune pathway have been approved. These include Anakinra (a recombinant IL-1 receptor antagonist), Canakinumab (a human monoclonal antibody targeting IL-1β), and Rilonacept (a soluble decoy receptor that binds both IL-1β and IL-1α and prevents their interaction with cell surface receptors). Findings from the CANTOS study showed that treatment with canakinumab resulted in a significantly lower recurrence rate of cardiovascular events, demonstrating the clear benefit of targeting inflammation in high-risk patients with cardiovascular disease. Targeting NLRP3 activation via small molecules is also feasible, as exemplified by CRID3 (also known as MCC950). Cryo-electron microscopy has demonstrated the direct binding of CRID3 to the NACHT domain of full-length NLRP3 and one of its analogues [Nature 2022;604:184-189; J Mol Biol. Dec 3, 2021;433(24);167309]. Potential benefits of targeting NLRP3 with a specific small molecule inhibitor rather than with a biologic include protecting other IL-1β-producing inflammasomes from the effects of a specific NLRP3 inhibitor, and the fact that small molecule drugs typically have a much shorter half-life than biologics (e.g., kanamumab has a half-life of 28 days in humans). This latter benefit allows for rapid termination when needed, such as in the case of infection.

[0007] CRID3 (CP-456,773) was discovered by Pfizer researchers in the late 1990s, when its target was not yet clearly defined [US Patent 6,166,064, December 26, 2000; J Pharmacol. Exp Ther 2001;299:187-197]. Its clinical trials were discontinued, presumably due to safety concerns. Since its biological target was identified as NLRP3 in 2015 [Nat. Med. 2015;21:248–255. doi: 10.1038 / nm.3806], several NLRP3 inhibitors with predominantly peripheral distribution have entered clinical trials. However, CRID3 and its derivatives have demonstrated that they fall far short of the brain penetration generally defined in the art. Although a few NLRP3 inhibitors in early clinical trials claimed CNS penetration, the reported CNS penetration of NLRP3 inhibitors has not been independently confirmed. Therefore, there is still a need to develop CNS-penetrating, specific, and safe NLRP3 inhibitors for clinical development.

[0008] Inhibiting the NLRP3 / IL-1β innate immune pathway through small molecule modulators may be a useful and practical approach for the treatment and prevention of many diseases [Na. Rev Drug Disco. 2018;18(5):1141-1160; Pharmacol. Rev2021 July;73:968-1000]. This list includes, but is not limited to, hereditary diseases (cold pyridine-associated periodic syndrome, CAPS), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, traumatic brain injury), metabolic diseases (atherosclerosis and type 2 diabetes), inflammatory diseases (gout attacks and osteoarthritis), cancer, and other related human diseases.

[0009] Various pyridazine derivatives or analogues have been disclosed as NLRP3 inhibitors. See, for example, WO2020 / 234715, WO2021 / 193897, WO2022 / 135567, WO2022 / 166890, WO2022 / 216971, U.S. Patent No. 11,319,319, U.S. Patent No. 11,618,751B1, WO2022 / 230912, WO2022 / 238347, WO2022 / 253326, WO2023 / 275366, WO2023 / 278438, WO2023 / 003002, WO2023 / 028534, WO2023 / 028536, WO2023 / 066377, WO2023 / 066825, WO2023 / 088856, WO2023 / 088987, CN115947691, WO2023 / 129987, WO2023 / 13127 7. WO2023 / 159148, WO2023 / 178099, WO2023 / 183943, WO2023 / 186020, WO2023 / 194964, W O2023 / 220408, WO2023 / 232917, WO2024 / 006559, WO2024 / 013395, WO2024 / 017924, WO20 24 / 023266、WO2024 / 028782、WO2024 / 033845、WO2024 / 041460、WO2024 / 064245、WO2024 / 090469, WO2024 / 094150, WO2024 / 094185, WO2024 / 097598, WO2024 / 097629, WO2024 / 099992, WO2024 / 099993, WO2024 / 099996, WO2024 / 109922, WO2024 / 121086, and WO2024 / 121184. This comprehensive compilation of NLRP3 inhibitors based on pyridazines and related structures shows that, based on the observation that approximately 95% of the examples contain nitrogen-linked groups, nitrogen-linked groups are superior to oxygen or carbon-linked groups in pyridazines and related compounds. Where directly comparable, compounds with oxygen or methylene-linked groups are less potent than similar compounds with NH-linked groups. Many patents outline the aforementioned compounds as having undesirable chemical or physical properties for CNS penetration, possibly due to, for example, excessively high topological polar surface area (tPSA) and / or an excessive number of hydrogen bond donors and acceptors. As a result, these compounds can only be used as peripherally restricted NLRP3 inhibitors. Therefore, there is a high demand for developing CNS-penetrating NLRP3 inhibitors.

[0010] Therefore, there remains a need to develop new compounds with robust CNS penetration and suitable pharmacokinetics, safety and chemical / physical properties as NLRP3 inhibitors that can be used to treat a variety of diseases and conditions. Summary of the Invention

[0011] This disclosure aims to meet the aforementioned needs by providing pyridazine compounds and their derivatives as NLRP3 inhibitors, particularly CNS-permeable NLRP3 inhibitors.

[0012] In one aspect, this disclosure provides compounds having the structure of Formula I or stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts or prodrugs thereof:

[0013] ,

[0014] (I)

[0015] in:

[0016] Indicates a single bond or a double bond;

[0017] X is NR1, CH2, O, S, or a bond;

[0018] R1 is H, alkyl, cycloalkyl, alkyl-CO- or heterocyclic, wherein each of the alkyl, cycloalkyl, alkyl-CO- or heterocyclic group is optionally substituted by 1 to 5 groups independently selected from R7;

[0019] R2 is independently selected from R7 each time it appears, or two R2 groups and the connecting atom between them form a 3- to 6-membered ring optionally containing one or two heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted by one to five groups independently selected from R7; or two non-adjacent R2 groups together form a 1- to 3-membered bridge optionally containing a heteroatom selected from O, N, and S, wherein the bridge is optionally substituted by one to three substituents independently selected from R7;

[0020] Alternatively, R1 and the adjacent R2 and the connecting atom in between form a 5- or 6-membered heterocyclic group that optionally includes an additional heteroatom independently selected from O, N and S, wherein the heterocyclic group is optionally substituted by 1 to 3 groups independently selected from R7.

[0021] W1 and W2 together are selected from: (i) both are empty, (ii) both are O, (iii) empty and O, and (iv) NR3 and O, wherein R3 is H, alkyl, cycloalkyl, alkyl-CO-, CN, NO2, aryl or heteroaryl, wherein each of the alkyl, cycloalkyl, alkyl-CO-, aryl and heteroaryl is optionally substituted by 1 to 5 groups independently selected from R8;

[0022] Alternatively, R3 and R2 together with the connecting atoms between them form a 5- to 8-membered heterocycle, which optionally contains an additional heteroatom independently selected from O, N, and S and optionally is substituted by 1 to 3 groups independently selected from R7.

[0023] Y is CR 4a N or C=O;

[0024] Z is CR 4b The value of Y is N or N-R9, provided that Y and Z are not both N; and if Y is C=O, then Z is N-R9.

[0025] Alternatively, Y and Z together form S;

[0026] Alternatively, Y and Z together form part of an existing 5- to 7-membered carbon ring, 5- to 7-membered heterocycle, 6-membered aromatic ring, or heteroaromatic ring, or 5-membered heteroaromatic ring, fused with an existing ring containing NN, each ring optionally being composed of 1 to 3 independently selected from R. 4a R 4b R9, R 10 and R 11 Substituents of the substituents;

[0027] R 4a and R 4b Independently selected from H, alkyl, cycloalkyl, CN, haloalkyl, phenyl, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-NHR 9 and -C 1-6 Alkyl-N(R) 9 )2;

[0028] R5 represents OH and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0029] R6 is independently selected from hydrogen and C each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5- or 6-membered heterocyclic, 5- or 6-membered heteroaryl, halogen, CN, SF5, NHR9, N(R9)2, OR9, and SR9;

[0030] Alternatively, two adjacent R6 groups together with the connecting atom between them form a 5- or 6-membered carbon ring, heterocycle, aromatic ring, or heteroaromatic ring that is fused with the existing benzene ring;

[0031] R7 is selected independently from H and C each time it appears. 1-6 Alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2 and CO2R9;

[0032] R8 is selected independently from H and C each time it appears. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl halogens, CN, phenyl groups, and halogens;

[0033] R9 is independently H or C each time it appears. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl;

[0034] R 10 Each occurrence is independently H or C. 1-6 Alkyl, C 3-6 cycloalkyl, halogen, or CF3;

[0035] R 11 Each occurrence is independently H or C. 1-6 Alkyl, C 3-6 cycloalkyl or =O;

[0036] m is 0, 1, or 2;

[0037] n can be 0, 1, 2, 3 or 4, provided that m + n ≥ 2;

[0038] i is 0, 1, 2, 3, 4; and

[0039] j is 0, 1, 2, 3, or 4.

[0040] In another aspect, this disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound or stereoisomer, tautomer, isotope derivative, pharmaceutically acceptable salt or prodrug according to any one of the disclosed embodiments, and one or more pharmaceutically acceptable carriers.

[0041] On the other hand, this disclosure provides a method for treating or preventing a disease or condition that responds to inhibition of NLRP3 in a subject in need, the method comprising administering to the subject an effective amount of a compound or stereoisomer, tautomer, isotope derivative, pharmaceutically acceptable salt, or prodrug according to any of the disclosed embodiments.

[0042] In another aspect, this disclosure provides a method for treating or preventing a disease or condition that responds to inhibition of NLRP3 in a subject in need, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound or stereoisomer thereof, tautomer, isotope derivative thereof, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier according to any one of the disclosed embodiments.

[0043] On the other hand, this disclosure provides the use of the compound or its stereoisomers, tautomers, isotopic derivatives, pharmaceutically acceptable salts or prodrugs according to any of the disclosed embodiments for the treatment or prevention of diseases or conditions that respond to inhibition of NLRP3 in subjects of need.

[0044] On the other hand, this disclosure provides the use of the compound or stereoisomers, tautomers, isotopic derivatives, pharmaceutically acceptable salts or prodrugs according to any of the disclosed embodiments for the manufacture of a medicament for the treatment or prevention of a disease or condition that responds to inhibition of NLRP3 in a subject of need.

[0045] In some embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject of need, the method comprising administering an effective amount of a compound or stereoisomer, tautomer, isotope derivative, pharmaceutically acceptable salt or prodrug, or pharmaceutical composition comprising any of the disclosed embodiments, wherein the disease or condition is a neurodegenerative disease, metabolic disease, inflammatory syndrome, autoinflammatory disease, cancer, or genetic disease.

[0046] In any aspect or embodiment disclosed, the compound includes, but is not limited to, any compound of formula (I), (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), (Ie-1), (If), (If-1), (If-2), (If-2-a), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ih), (Ih-1), (Ii), (Ii-1), (Ij), (Ij-1), (Ik), (Ik-1), (Ik-2), (Ik-3), (Il), (Il-1), (Im), (In) or (In-1), or any of the following stereoisomers, tautomers, isotopic derivatives, pharmaceutically acceptable salts or prodrugs thereof.

[0047] Other aspects and advantages of this disclosure will be better understood by those skilled in the art in light of the following detailed description, embodiments, and claims. Detailed Implementation

[0048] This disclosure provides novel thio-linked pyridazines that, compared to known pyridazines with any linking group, exhibit an unexpected and superior combination of potency, selectivity, safety, brain penetration, and pharmacokinetic characteristics—prerequisites for candidate selection in preparation for human trials. As of the date of this application, the inventors are not aware of any thioether-linked pyridazine compounds disclosed below as potent brain-penetrating NLRP3 inhibitors. More importantly, the inventors have discovered that thio-linked pyridazine compounds, compared to known pyridazines with any linking group, exhibit an unexpected and superior combination of potency, selectivity, safety, brain penetration, and pharmacokinetic characteristics—prerequisites for candidate selection in preparation for human trials.

[0049] In one aspect, this disclosure provides compounds having the structure of Formula I or stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts or prodrugs thereof:

[0050] ,

[0051] (I)

[0052] in:

[0053] Indicates a single bond or a double bond;

[0054] X is NR1, CH2, O, S, or a bond;

[0055] R1 is H, alkyl, cycloalkyl, alkyl-CO- or heterocyclic, wherein each of the alkyl, cycloalkyl, alkyl-CO- or heterocyclic group is optionally substituted by 1 to 5 groups independently selected from R7;

[0056] R2 is independently selected from R7 each time it appears, or two R2 groups and the connecting atom between them form a 3- to 6-membered ring optionally containing one or two heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted by one to five groups independently selected from R7; or two non-adjacent R2 groups together form a 1- to 3-membered bridge optionally containing a heteroatom selected from O, N, and S, wherein the bridge is optionally substituted by one to three substituents independently selected from R7;

[0057] Alternatively, R1 and the adjacent R2 and the connecting atom in between form a 5- or 6-membered heterocyclic group that optionally includes an additional heteroatom independently selected from O, N and S, wherein the heterocyclic group is optionally substituted by 1 to 3 groups independently selected from R7.

[0058] W1 and W2 together are selected from: (i) both are empty, (ii) both are O, (iii) empty and O, and (iv) NR3 and O, wherein R3 is H, alkyl, cycloalkyl, alkyl-CO-, CN, NO2, aryl or heteroaryl, wherein each of the alkyl, cycloalkyl, alkyl-CO-, aryl and heteroaryl is optionally substituted by 1 to 5 groups independently selected from R8;

[0059] Alternatively, R3 and R2 together with the connecting atoms between them form a 5- to 8-membered heterocycle, which optionally contains an additional heteroatom independently selected from O, N, and S and optionally is substituted by 1 to 3 groups independently selected from R7.

[0060] Y is CR 4a N or C=O;

[0061] Z is CR 4b The value of Y is N or N-R9, provided that Y and Z are not both N; and if Y is C=O, then Z is N-R9.

[0062] Alternatively, Y and Z together form S;

[0063] Alternatively, Y and Z together form part of an existing 5- to 7-membered carbon ring, 5- to 7-membered heterocycle, 6-membered aromatic ring, or heteroaromatic ring, or 5-membered heteroaromatic ring, fused with an existing ring containing NN, each ring optionally being composed of 1 to 3 independently selected from R. 4a R 4b R9, R 10 and R 11 Substituents of the substituents;

[0064] R 4a and R 4b Independently selected from H, alkyl, cycloalkyl, CN, haloalkyl, phenyl, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-NHR 9 and -C 1-6 Alkyl-N(R) 9 )2;

[0065] R5 represents OH and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0066] R6 is independently selected from hydrogen and C each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6Cycloalkyl, 5- or 6-membered heterocyclic, 5- or 6-membered heteroaryl, halogen, CN, SF5, NHR9, N(R9)2, OR9, and SR9;

[0067] Alternatively, two adjacent R6 groups together with the connecting atom between them form a 5- or 6-membered carbon ring, heterocycle, aromatic ring, or heteroaromatic ring that is fused with the existing benzene ring;

[0068] R7 is selected independently from H and C each time it appears. 1-6 Alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2 and CO2R9;

[0069] R8 is selected independently from H and C each time it appears. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl halogens, CN, phenyl groups, and halogens;

[0070] R9 is independently H or C each time it appears. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl;

[0071] R 10 Each occurrence is independently H or C. 1-6 Alkyl, C 3-6 cycloalkyl, halogen, or CF3;

[0072] R 11 Each occurrence is independently H or C. 1-6 Alkyl, C 3-6 cycloalkyl or =O;

[0073] m is 0, 1, or 2;

[0074] n can be 0, 1, 2, 3 or 4, provided that m + n ≥ 2;

[0075] i is 0, 1, 2, 3, 4; and

[0076] j is 0, 1, 2, 3, or 4.

[0077] In some embodiments, in a compound of formula (I) or a stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt or prodrug:

[0078] X is NR1, CH2, O, S, or a bond;

[0079] R1 represents H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 alkyl-CO-, 4-6 membered heterocyclic group, wherein the C 1-5Alkyl, C 3-6 cycloalkyl, C 1-4 The alkyl-CO- and 4-6-membered heterocyclic groups are each optionally substituted by 1 to 3 independently selected groups from R7;

[0080] R2 is independently selected from R7 each time it appears, or two R2 groups and the connecting atom between them form a 3- to 6-membered ring that optionally contains a heteroatom selected from O, N and S, and the ring is optionally substituted by one or two groups independently selected from R7; or two non-adjacent R2 groups together form a 1- to 3-membered bridge that optionally contains a heteroatom selected from O, N and S, wherein the bridge is optionally substituted by one to three substituents independently selected from R7;

[0081] Alternatively, R1 and the adjacent R2 and the connecting atom in between form a 5- or 6-membered heterocyclic group that optionally includes an additional heteroatom selected from O, N and S, wherein the heterocyclic group is optionally substituted by 1 to 3 groups independently selected from R7.

[0082] W1 and W2 are selected together from: (i) both are empty, (ii) both are 0, (iii) empty and 0, and (iv) NR3 and 0, where R3 is H and C. 1-5 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkyl-CO, CN, NO2, C6 aryl, or optionally substituted with 1 to 3 groups independently selected from R8, 5- or 6-membered heteroaryl;

[0083] Alternatively, R3 and R2 together with the connecting atoms in between form a 5- to 8-membered heterocycle, which optionally includes an additional heteroatom selected from O, N, and S as part of the ring, and optionally is substituted by one or two groups independently selected from R7.

[0084] Y is CR 4a N or C=O;

[0085] Z is CR 4b The value of Y is N or N-R9, provided that Y and Z are not both N; and if Y is C=O, then Z is N-R9.

[0086] Alternatively, Y and Z together form S;

[0087] Alternatively, Y and Z together are a 5- to 7-membered carbon ring, a 5- to 7-membered heterocyclic ring, a 6-membered aromatic ring or a heterocyclic ring, or a 5-membered heterocyclic ring, wherein the ring is optionally selected independently by one or two of R. 4a R 4b R9, R 10 and R 11 Substituents of the substituents;

[0088] R 4a and R 4b Independently selected from H and C 1-4 Alkyl, C 3-6 cycloalkyl, CN, CF3 or phenyl;

[0089] R5 is OH, OCHF2, OCF3, CHF2, CF3, CF3CH2, or OMe;

[0090] R6 is independently selected from H, CF3, CF2CF3, OCF3, and C each time it appears. 3-6 cycloalkyl, C 1-4 Alkyl, CHF2, OCHF2, halogen, CN, SF5, NHR9, N(R9)2, OR9 and SR9;

[0091] Alternatively, the two R6 groups together with the connecting atom between them form a 5- or 6-membered carbon ring, heterocycle, aromatic ring, or heteroaromatic ring that fused with the existing benzene ring;

[0092] R7 is selected independently from H and C each time it appears. 1-4 Alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2 and CO2R9;

[0093] R8 is selected independently from H and C each time it appears. 1-4 Alkyl, cyclopropyl, CF3, CHF2, CN, phenyl, and halogens;

[0094] R9 is independently H or C each time it appears. 1-4 Alkyl or cyclopropyl;

[0095] R 10 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, halogen, or CF3;

[0096] R 11 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, or =O;

[0097] m is 0, 1, or 2;

[0098] n can be 0, 1, 2, 3 or 4, provided that m + n ≥ 2;

[0099] i is 0, 1, 2, or 3; and

[0100] j can be 0, 1, or 2.

[0101] In some embodiments, in a compound of formula (I) or a stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt or prodrug:

[0102] X is NR1 or O;

[0103] R1 is hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-C(O)OR 9 Or 4- to 6-membered heterocyclic groups, each group other than hydrogen is optionally composed of 1 to 3 independently selected C 1-4 Substitution with alkyl, halogen, CN, =O, OR9, SR9, NHR9 and N(R9)2 groups;

[0104] R2 is selected independently from C each time it appears. 1-6 Alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9, or two adjacent R2 groups and a connecting atom between them, form a 5- or 6-membered ring optionally comprising one or two heteroatoms independently selected from O, N, and S, wherein the ring is optionally surrounded by one to three heteroatoms independently selected from C. 1-4 The groups are substituted with alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9 groups; or two non-adjacent R2 groups are optionally formed by one or two independent groups selected from C. 1-4 C-substituents of alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9 1-3 Alkyl bridges;

[0105] W1 and W2 together are selected from: (i) both are empty, (ii) both are 0, and (iii) empty and 0;

[0106] Y is CR 4a Or N;

[0107] Z is CR 4b Or N, provided that Y and Z are not both N at the same time;

[0108] Alternatively, Y and Z together are a 5- or 6-membered carbon ring, a 5- or 6-membered heterocyclic ring, a 6-membered aromatic ring or heteroaromatic ring, or a 5-membered heteroaromatic ring, each of which is fused with an existing ring comprising N and N, and each is optionally composed of 1 to 3 independently selected from halogens, CN, =O (excluding aromatic and heteroaromatic rings), C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl, phenyl, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-NHR9 and -C 1-6 Alkyl-N(R) 9 Substitution of )2 by substituents;

[0109] R 4a and R 4b Independently selected from H and C 1-6 Alkyl, C 3-6 cycloalkyl, CN, C 1-6 Halogenated alkyl, phenyl, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-NHR 9 and -C 1-6 Alkyl-N(R) 9 )2;

[0110] R5 represents OH and C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups;

[0111] R6 is independently selected from hydrogen and C each time it appears. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5- or 6-membered heterocyclic, 5- or 6-membered heteroaryl, halogen, CN, NHR9, N(R9)2, OR9 or SR9;

[0112] R9 is independently H or C each time it appears. 1-4 Alkyl, or C 1-4 Halogenated alkyl, or C 3-6 cycloalkyl;

[0113] m is 1 or 2;

[0114] n is 1, 2, or 3;

[0115] i is 0, 1, 2, 3; and

[0116] j is 1, 2, or 3.

[0117] In some embodiments, this disclosure provides compounds having the structure of formula (Ia) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0118] ,

[0119] (Ia)

[0120] Wherein X, m, n, R2, Y, Z, R5 and R6 are defined as in any of the disclosed embodiments.

[0121] In some embodiments, in a compound of formula (I) or (Ia) or a stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt or prodrug, wherein Selected from:

[0122]

[0123] in:

[0124] Z1, Z2, Z3, and Z4 are independently selected from CR 10 and N, provided that at most one of them is N;

[0125] Z5 is O, NR9, S, SO or SO2;

[0126] Y 1 For key, CHR 11 Or SO2;

[0127] o and p are selected from the following combinations:

[0128]

[0129] q = 0, 1, or 2; and

[0130] All other groups are as defined in any of the disclosed embodiments.

[0131] In some embodiments, this disclosure provides compounds having the structure of formula (Ia-1) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0132] ,

[0133] (Ia-1)

[0134] in:

[0135] X is NR1 or O;

[0136] Y and Z as disclosed As defined in any implementation scheme;

[0137] R5 is independently selected from OH, halogen, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy and C 1-2 Halogenated alkoxy groups;

[0138] R 6aIndependently selected from halogen, CN, OR9, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl;

[0139] R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0140] R9 is either H or C each time it appears. 1-4 alkyl.

[0141] In some embodiments, this disclosure provides compounds having the structure of formula (Ib) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0142] ,

[0143] (Ib)

[0144] Where n1 = 0, 1 or 2; and R1, R2, Y, Z, R5 and R6 are defined as in any of the disclosed embodiments.

[0145] In some embodiments, this disclosure provides compounds having the structure of formula (Ib-1) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0146] ,

[0147] (Ib-1)

[0148] in:

[0149] Y and Z as disclosed As defined in any implementation scheme;

[0150] n1 is either 0 or 1;

[0151] R5 is independently selected from OH, halogen, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy and C 1-2 Halogenated alkoxy groups;

[0152] R 6a Independently selected from halogen, CN, OR9, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl;

[0153] R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0154] R9 is either H or C each time it appears. 1-4 alkyl.

[0155] In some embodiments, this disclosure provides compounds having the structure of formula (Ic) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0156]

[0157] (Ic)

[0158] in:

[0159] r is 0, 1, or 2; and

[0160] Y, Z, R1, R2, j, R6, and R7 are defined as in any of the disclosed embodiments.

[0161] In some embodiments, this disclosure provides compounds having the structure of formula (Ic-1) or stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts or prodrugs thereof;

[0162] ,

[0163] (Ic-1)

[0164] in:

[0165] r is 0 or 1;

[0166] Y and Z as disclosed As defined in any implementation scheme;

[0167] R5 is independently selected from OH, halogen, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy and C 1-2 Halogenated alkoxy groups;

[0168] R 6a Independently selected from halogen, CN, OR9, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl;

[0169] R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and

[0170] R9 is either H or C each time it appears. 1-4 alkyl.

[0171] In some embodiments, this disclosure provides compounds having the structure of formula (Id) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0172] ,

[0173] (Id)

[0174] X, R2, m, n, Y, Z, and R6 are defined as in any of the disclosed embodiments.

[0175] In some embodiments, this disclosure provides compounds having the structure of formula (Id-1) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0176] ,

[0177] (Id-1)

[0178] in:

[0179] X is NR1 or O;

[0180] Y and Z as disclosed As defined in any implementation scheme;

[0181] R 6a Independently selected from halogen, CN, OR9, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl;

[0182] R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and

[0183] R9 is either H or C each time it appears. 1-4 alkyl.

[0184] In some embodiments, this disclosure provides compounds having the structure of formula (Ie) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0185] ,

[0186] (Ie)

[0187] in:

[0188] n1 = 0 or 1; and

[0189] R1, R2, Y, Z and R6 are defined as in any of the disclosed embodiments.

[0190] In some embodiments, this disclosure provides compounds having the structure of formula (Ie-1) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0191] ,

[0192] (Ie-1)

[0193] in:

[0194] n1 = 0 or 1;

[0195] Y and Z as disclosed As defined in any implementation scheme;

[0196] R 6a Independently selected from halogen, CN, OR9, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl;

[0197] R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and

[0198] R9 is either H or C each time it appears. 1-4 alkyl.

[0199] In some embodiments, this disclosure provides compounds having the structure of formula (If) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0200] ,

[0201] (If)

[0202] in:

[0203] n1 = 0 or 1; and

[0204] R1, R2, i, j, R 4a R 4b R6 is as defined in any of the disclosed implementation schemes.

[0205] In some embodiments, in a compound of formula (If), or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug:

[0206] n1 is 1;

[0207] i is 0, 1, or 2;

[0208] j is 1 or 2;

[0209] R1 is hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 or -C 1-6 Alkyl-C(O)OR 9 ;

[0210] R2 is independently hydrogen or C each time it appears. 1-6 Alkyl or halogen; or two non-adjacent R2 groups together forming a C group optionally substituted with one or two independent substituents selected from R7. 1-3 Alkyl bridges;

[0211] R 4a and R 4b Independently selected from H and C 1-6 Alkyl, CN, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-NHR 9 and -C 1-6 Alkyl-N(R) 9 )2;

[0212] R5 represents OH, halogen, or C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups;

[0213] R6 is independently selected from hydrogen, halogen, CN, OR9, and C each time it appears. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl;

[0214] R7 is hydrogen, C 1-4 Alkyl, halogen, or OR9; and

[0215] R9 is either H or C each time it appears. 1-4 alkyl.

[0216] In some embodiments, this disclosure provides compounds having the structure of formula (If-1) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0217] ,

[0218] (If-1)

[0219] in:

[0220] R1 is -CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2OH;

[0221] R2 is either H or F;

[0222] R 4a It can be H, CN, -CH3, -CH2OH or -CH2NHCH3;

[0223] R 4b It is H or -CH3;

[0224] R5 is -OH, -CF3, or -OCHF2;

[0225] R6 can be H, F, Cl, -CF3, or -CH3; and

[0226] R 6a -CF3, -CH3, cyclopropyl, Cl or .

[0227] In some embodiments, this disclosure provides compounds having the structure of formula (If-2) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0228] ,

[0229] (If-2)

[0230] in:

[0231] r is 0, 1, or 2;

[0232] R1 is hydrogen, C 1-6 Alkyl, C 1-6Alkyl-CO-, -C 1-6 Alkyl-OR 9 or -C 1-6 Alkyl-C(O)OR 9 ;

[0233] R2 is hydrogen, C 1-6 Alkyl or halogen;

[0234] R 4a and R 4b Independently selected from H and C 1-6 Alkyl, CN, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-NHR 9 and -C 1-6 Alkyl-N(R) 9 )2;

[0235] R5 represents OH, halogen, or C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups;

[0236] R6 is independently selected from hydrogen, halogen, CN, OR9, and C each time it appears. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl;

[0237] R7 is C 1-4 Alkyl, halogen, and OR9; and

[0238] R9 is either H or C each time it appears. 1-4 alkyl.

[0239] In some embodiments, this disclosure provides compounds having the structure of formula (If-2-a) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0240] ,

[0241] (If-2-a)

[0242] in:

[0243] R1 is -CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2OH;

[0244] R 4aIt can be H, CN, -CH3, -CH2OH or -CH2NHCH3;

[0245] R 4b It is H or -CH3;

[0246] R5 is -OH, -CF3, or -OCHF2;

[0247] R6 can be H, F, Cl, -CF3, or -CH3; and

[0248] R 6a -CF3, -CH3, cyclopropyl, Cl or .

[0249] In some embodiments, this disclosure provides compounds having the structure of formula (Ig) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0250] ,

[0251] (Ig)

[0252] in:

[0253] n1 = 0 or 1;

[0254] R1, R2, R5, R6 and R 10 As defined in any of the disclosed implementation schemes; and

[0255] Z1, Z2, Z3, and Z4 are each independently CR 10 Or N, provided that no more than one of them is N.

[0256] In some embodiments, this disclosure provides compounds having the structure of formula (Ig-1), (Ig-2), or (Ig-3), or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0257] ,

[0258] in:

[0259] i is 0, 1, or 2;

[0260] R1 is independently hydrogen or C each time it appears. 1-6 Alkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 or -C 1-6 Alkyl-C(O)OR 9 ;

[0261] R2 is independently hydrogen or C each time it appears. 1-6 Alkyl or halogen;

[0262] R5 is independently OH, halogen, or C each time it appears. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups;

[0263] R 6a Each occurrence is independently selected from halogen, CN, OR9, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl;

[0264] R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0265] R9 is either H or C each time it appears. 1-4 Alkyl groups; and

[0266] R 10 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, halogen, or CF3.

[0267] In some embodiments, in a compound of formula (Ig), (Ig-1), (Ig-2), or (Ig-3), or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof:

[0268] i is 0;

[0269] R1 is -CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2OH;

[0270] R5 is -OH, -CF3, or -OCHF2;

[0271] R6 is H, F, or -CH3; and

[0272] R 6a -CF3, -CH3, cyclopropyl, Cl or ;and

[0273] R 10 For H.

[0274] In some embodiments, this disclosure provides compounds having the structure of formula (Ih), (Ii), or (Ij), or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0275] ,

[0276] in:

[0277] n1 = 0 or 1; and

[0278] R1, R2, R5, R6 and R 10 As defined in any of the disclosed implementation schemes.

[0279] In some embodiments, this disclosure provides compounds having the structure of formula (Ih-1), (Ii-1), or (Ij-1), or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0280] ,

[0281] in:

[0282] i is 0, 1, or 2;

[0283] R1 is independently hydrogen or C each time it appears. 1-6 Alkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 or -C 1-6 Alkyl-C(O)OR 9 ;

[0284] R2 is independently hydrogen or C each time it appears. 1-6 Alkyl or halogen;

[0285] R5 is independently OH, halogen, or C each time it appears. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups;

[0286] R 6a Each occurrence is independently selected from halogen, CN, OR9, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl;

[0287] R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C1-4 Halogenated alkyl groups;

[0288] R9 is either H or C each time it appears. 1-4 Alkyl groups; and

[0289] R 10 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, halogen, or CF3.

[0290] In some embodiments, in compounds of formula (Ih), (Ii), (Ij), (Ih-1), (Ii-1), or (Ij-1), or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0291] i is 0;

[0292] R1 is -CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2OH;

[0293] R5 is -OH, -CF3, or -OCHF2;

[0294] R6 can be H, F, Cl, -CF3, or -CH3; and

[0295] R 6a -CF3, -CH3, cyclopropyl, Cl or ;and

[0296] R 10 It can be H or -CH3.

[0297] In some embodiments, this disclosure provides compounds having the structure of formula (Ik) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0298] ,

[0299] (Ik)

[0300] in:

[0301] n1 = 0 or 1;

[0302] i is 0, 1, or 2;

[0303] q is 0 or 1;

[0304] Y 1 For -CH2- or -S(O)2-; and

[0305] R1, R2, R5, R6 and R 11 As defined in any of the disclosed implementation schemes.

[0306] In some embodiments, this disclosure provides compounds having the structure of formula (Ik-1), (Ik-2), or (Ik-3), or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0307] ,

[0308] in:

[0309] i is 0, 1, or 2;

[0310] R1 is independently hydrogen or C each time it appears. 1-6 Alkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 or -C 1-6 Alkyl-C(O)OR 9 ;

[0311] R2 is independently hydrogen or C each time it appears. 1-6 Alkyl or halogen;

[0312] R5 is independently OH, halogen, or C each time it appears. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups;

[0313] R 6a Each occurrence is independently selected from halogen, CN, OR9, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl;

[0314] R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0315] R9 is either H or C each time it appears. 1-4 Alkyl groups; and

[0316] R 11 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, halogen, or CF3.

[0317] In some embodiments, in a compound of formula (Ik), (Ik-1), (Ik-2), or (Ik-3), or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof:

[0318] i is 0;

[0319] R1 is -CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2OH;

[0320] R5 is -OH, -CF3, or -OCHF2;

[0321] R6 can be H, F, Cl, -CF3, or -CH3; and

[0322] R 6a -CF3, -CH3, cyclopropyl, Cl or ;and

[0323] R 11 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, or =O.

[0324] In some embodiments, this disclosure provides compounds having the structure of formula (Il) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0325] ,

[0326] (Il)

[0327] in:

[0328] n1 = 0 or 1; and

[0329] R1, R2, R 4b R5 and R6 are as defined in any of the disclosed implementation schemes.

[0330] In some embodiments, this disclosure provides compounds having the structure of formula (1l-1) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0331] ,

[0332] (Il-1)

[0333] in:

[0334] i is 0, 1, or 2;

[0335] R1 is independently hydrogen or C each time it appears. 1-6 Alkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 or -C 1-6 Alkyl-C(O)OR 9 ;

[0336] R2 is independently hydrogen or C each time it appears. 1-6 Alkyl or halogen;

[0337] R 4b For H, C 1-6 Alkyl, CN or C 1-6 Halogenated alkyl groups,

[0338] R5 is independently OH, halogen, or C each time it appears. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups;

[0339] R 6a Each occurrence is independently selected from halogen, CN, OR9, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl;

[0340] R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and

[0341] R9 is either H or C each time it appears. 1-4 alkyl.

[0342] In some embodiments, in a compound of formula (Il) or (Il-1), or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug:

[0343] i is 0;

[0344] R1 is -CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2OH;

[0345] R 4b It is H or -CH3;

[0346] R5 is -OH, -CF3, or -OCHF2;

[0347] R6 can be H, F, Cl, -CF3, or -CH3; and

[0348] R 6a -CF3, -CH3, cyclopropyl, Cl or .

[0349] In some embodiments, this disclosure provides compounds having the structure of formula (Im) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0350] ,

[0351] (Im)

[0352] in:

[0353] n = 0 or 1; and

[0354] R1, R2, R6 and R9 are defined as in any of the disclosed embodiments.

[0355] In some embodiments, this disclosure provides compounds having the structure of formula (In) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0356] ,

[0357] (In)

[0358] Wherein Y, Z, R2, m, n, i and R6 are defined as in any of the disclosed embodiments.

[0359] In some embodiments, this disclosure provides compounds having the structure of formula (In-1) or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0360] ,

[0361] (In-1)

[0362] in:

[0363] i can be 0, 1, 2, or 3;

[0364] R2 is H, F, or -CH3;

[0365] R 4a It can be H, CN, -CH3, -CH2OH or -CH2NHCH3;

[0366] R 4b It is H or -CH3;

[0367] R5 is -OH, -CF3, or -OCHF2;

[0368] R6 can be H, F, Cl, -CF3, or -CH3; and

[0369] R 6a-CF3, -CH3, cyclopropyl, Cl or .

[0370] In some embodiments, this disclosure provides compounds selected from the following: stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs thereof:

[0371] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

[0372] and .

[0373] In another aspect, this disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound or stereoisomer, tautomer, isotope derivative, pharmaceutically acceptable salt or prodrug according to any one of the disclosed embodiments, and one or more pharmaceutically acceptable carriers.

[0374] On the other hand, this disclosure provides a method for treating or preventing a disease or condition that responds to inhibition of NLRP3 in a subject in need, the method comprising administering to the subject an effective amount of a compound or stereoisomer, tautomer, isotope derivative, pharmaceutically acceptable salt, or prodrug according to any of the disclosed embodiments.

[0375] In another aspect, this disclosure provides a method for treating or preventing a disease or condition that responds to inhibition of NLRP3 in a subject in need, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound or stereoisomer thereof, tautomer, isotope derivative thereof, pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier according to any one of the disclosed embodiments.

[0376] On the other hand, this disclosure provides the use of the compound or its stereoisomers, tautomers, isotopic derivatives, pharmaceutically acceptable salts or prodrugs according to any of the disclosed embodiments for the treatment or prevention of diseases or conditions that respond to inhibition of NLRP3 in subjects of need.

[0377] On the other hand, this disclosure provides the use of the compound or stereoisomers, tautomers, isotopic derivatives, pharmaceutically acceptable salts or prodrugs according to any of the disclosed embodiments for the manufacture of a medicament for the treatment or prevention of a disease or condition that responds to inhibition of NLRP3 in a subject of need.

[0378] In some embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject of need, the method comprising administering an effective amount of a compound according to any of the disclosed embodiments or a stereoisomer, tautomer, isotope derivative, pharmaceutically acceptable salt or prodrug, or a pharmaceutical composition comprising the aforementioned compound, wherein the disease or condition is a neurodegenerative disease, a metabolic disease, an inflammatory syndrome, an autoinflammatory disease, cancer, or a genetic disease.

[0379] In some embodiments of this disclosure, the neurodegenerative condition is Parkinson's disease or Alzheimer's disease.

[0380] In some embodiments of this disclosure, the metabolic disease is type 2 diabetes or atherosclerosis.

[0381] In some embodiments of this disclosure, the inflammatory disease is a gout attack or osteoarthritis.

[0382] In some embodiments of this disclosure, the inflammatory disease is multiple sclerosis or rheumatoid arthritis.

[0383] In some embodiments of this disclosure, the cancer is lung cancer.

[0384] In some embodiments of this disclosure, the hereditary disease is cold pyridine-associated periodic syndrome.

[0385] In any aspect or embodiment disclosed, the compound includes, but is not limited to, any compound of formula (I), (Ia), (Ia-1), (Ib), (Ib-1), (Ic), (Ic-1), (Id), (Id-1), (Ie), (Ie-1), (If), (If-1), (If-2), (If-2-a), (Ig), (Ig-1), (Ig-2), (Ig-3), (Ih), (Ih-1), (Ii), (Ii-1), (Ij), (Ij-1), (Ik), (Ik-1), (Ik-2), (Ik-3), (Il), (Il-1), (Im), (In) or (In-1), or any of the following stereoisomers, tautomers, isotopic derivatives, pharmaceutically acceptable salts or prodrugs thereof.

[0386] Furthermore, any reasonable combination of the disclosed embodiments that is obvious to those skilled in the art is also covered by this disclosure.

[0387] In one aspect, this disclosure provides compounds having the structure of formula (I), as well as their stereoisomers and pharmaceutically acceptable salts or prodrugs:

[0388] ,

[0389] (I)

[0390] in:

[0391] X is NR1, CH2, O, S, or a bond;

[0392] R1 is H, alkyl, cycloalkyl, alkyl-CO-, heterocyclic, wherein each of the alkyl, cycloalkyl, alkyl-CO-, heterocyclic is optionally substituted by 1 to 5 groups independently selected from R7;

[0393] R2 is independently selected from R7 each time it appears, or two R2 groups or one R1 and one R2 and the connecting atom in between can form a 3-6 membered ring containing 0-3 heteroatoms, wherein the ring is optionally replaced by 1-5 R7 groups;

[0394] W1 and W2 are both empty, O and empty, O and O, or NR3 and O, respectively, wherein R3 is H, alkyl, cycloalkyl, alkyl-CO, CN, NO2, aryl or heteroaryl, wherein the alkyl, cycloalkyl, alkyl-CO, aryl and heteroaryl are each optionally substituted by 1 to 5 R8 groups;

[0395] Alternatively, R3 and R2 together with the connecting atoms in between form a 5-8 membered heterocycle, which includes one or two additional heteroatoms independently selected from O, N and S as part of the ring, and is optionally substituted by one to three R7 groups;

[0396] Y is CR 4’ N or C=O;

[0397] Z is CR4, N, or N-R9, provided that if Y is C=O, then Z is N-R9, and Y and Z are not both N; or, Y and Z together are S.

[0398] Alternatively, Y and Z together form part of a 5-7 membered carbon ring, a 5-7 membered heterocycle, a 6-membered aromatic ring, or a heteroaromatic ring and a 5-membered heteroaromatic ring, each ring optionally composed of 1-3 independently selected from R4, R 4’ R9, R 10 and R 11 Substituents of the substituents;

[0399] R4 and R 4’ Independently selected from H, alkyl, cycloalkyl, CN, CF3 or phenyl;

[0400] R5 represents OH and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups;

[0401] R6 is selected independently from C each time it appears. 1-4 Alkyl, C 1-4 Halogenated alkyl, cycloalkyl, halogen, CN, SF5, NHR9, N(R9)2, OR9 or SR9;

[0402] Alternatively, the two R6s together with the connecting atoms in between form a 5-6 membered carbon ring, heterocycle, aromatic ring, or heteroaromatic ring that fused with the existing benzene ring;

[0403] R7 is independently selected from H, alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2 and CO2R9 each time it appears;

[0404] R8 is selected independently from H and C each time it appears. 1-4 Alkyl, cyclopropyl, CF3, CHF2, CN, phenyl, and halogens;

[0405] R9 is independently H or C each time it appears. 1-4 Alkyl, C 1-4 Halogenated alkyl or cyclopropyl;

[0406] R 10Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, halogen, or CF3;

[0407] R 11 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, or =O;

[0408] m is 0, 1, or 2;

[0409] n can be 0, 1, 2, 3 or 4, provided that m + n ≥ 2;

[0410] i is 0, 1, 2, 3, 4; and

[0411] j is 0, 1, 2, 3, or 4.

[0412] Some implementation methods in this regard:

[0413] X is NR1, CH2, O, S, or a bond;

[0414] R1 represents H and C. 1-5 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkyl-CO, 4-6 membered heterocyclic group, wherein the C 1-5 Alkyl, C 3-6 cycloalkyl, C 1-4 The alkyl-CO and 4-6-membered heterocyclic groups are each optionally substituted by 1-3 independent groups selected from R7;

[0415] R2 is independently selected from R7 each time it appears, or two R2 groups or one R1 and one R2 and the connecting atom in between can form a 3-6 membered ring containing 0-1 heteroatoms, and the ring is optionally replaced by 0-2 R7 groups;

[0416] W1 and W2 are both empty, O and empty, O and O, or NR3 and O, where R3 is H or C. 1-5 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkyl-CO, CN, NO2, phenyl, or 5- or 6-membered heteroaryl groups optionally substituted with 1-3 R8 groups;

[0417] Alternatively, R3 and R2 together with the connecting atoms in between form a 5-8 membered heterocycle, which includes, optionally, one additional heteroatom independently selected from O, N, and S as part of the ring, and is optionally substituted by 0-2 R7 groups;

[0418] Y is CR 4’ N or C=O;

[0419] Z is CR4, N, or N-R9, provided that if Y is C=O, then Z is N-R9, and Y and Z are not both N; or, Y and Z together are S.

[0420] Alternatively, Y and Z together form a subset of 1-2 independent selections from R4, R 4’ R9, R 10 and R 11 The optional substitution of 5-7 membered carbon rings, 5-7 membered heterocycles, 6 membered aromatic rings or heteroaromatic rings and a portion thereof;

[0421] R4 and R 4’ Independently selected from H and C 1-4 Alkyl, C 3-5 cycloalkyl, CN, CF3 or phenyl;

[0422] R5 is OH, OCHF2, OCF3, CHF2, CF3, CF3CH2, or OMe;

[0423] R6 is independently selected from CF3, OCF3, and C each time it appears. 3-6 cycloalkyl, C 1-4 Alkyl, CHF2, OCHF2, halogen, CN, SF5, NHR9, N(R9)2, OR9 and SR9;

[0424] Alternatively, the two R6s together with the connecting atoms in between form a 5-6 membered carbon ring, heterocycle, aromatic ring, or heteroaromatic ring that fused with the existing benzene ring;

[0425] R7 is selected independently from H and C each time it appears. 1-4 Alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2 and CO2R9;

[0426] R8 is selected independently from H and C each time it appears. 1-4 Alkyl, cyclopropyl, CF3, CHF2, CN, phenyl, and halogens;

[0427] R9 is independently H or C each time it appears. 1-4 Alkyl or cyclopropyl;

[0428] R 10 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, halogen, or CF3;

[0429] R 11 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, or =O;

[0430] m is 0, 1, or 2;

[0431] n can be 0, 1, 2, 3 or 4, provided that m + n ≥ 2;

[0432] i is 0, 1, 2, or 3; and

[0433] j can be 0, 1, or 2.

[0434] In some embodiments of this aspect, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0435] X, m, n, i, j, R2, Y, Z, R5 and R6 are defined as in equation (I).

[0436] In some embodiments, this disclosure provides a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug, wherein Selected from:

[0437]

[0438] in:

[0439] Z1, Z2, Z3, and Z4 are independently selected from CR 10 Or N, provided that at most one of them is N;

[0440] Z5 consists of O, NR9, S, SO, and SO2.

[0441] o and p are selected from the following combinations:

[0442]

[0443] q = 0, 1, 2; and all other groups have the same definition as in formula (I).

[0444] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0445] ,

[0446] Where n = 0 or 1; and i, j, R1, R2, Y, Z, R5 and R6 are as defined in equation (I).

[0447] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0448] ,

[0449] X, R2, m, n, Y, Z and R6 are defined as in equation (I).

[0450] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0451] ,

[0452] Where n = 0 or 1; Y and Z are as described above. As defined in equation (I); and i, j, R1, R2, R5 and R6 as defined in equation (I).

[0453] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0454] ,

[0455] Where Y and Z are as follows As defined in equation (I); and i, j, X, R2, m, n and R6 as defined in equation (I).

[0456] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0457] ,

[0458] (Ie)

[0459] Where n = 0 or 1; and i, j, R1, R2, Y, Z and R6 are as defined in equation (I).

[0460] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0461] ,

[0462] (Ie)

[0463] Where n = 0 or 1; Y and Z are as follows: As defined in equation (I); and i, j, R1, R2 and R6 as defined in equation (I).

[0464] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0465] ,

[0466] (If)

[0467] Where n = 0 or 1; and i, j, R1, R2, R4, R 4’ R6 is defined as in equation (I).

[0468] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0469] ,

[0470] (Ig)

[0471] Where n = 0 or 1; i, j, R1, R2, R6 and R 10 As defined in equation (I); and Z1, Z2, Z3, and Z4 as... Defined in [the document / reference].

[0472] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0473] ,

[0474] (Ih)

[0475] Where n = 0 or 1; and i, j, R1, R2, R6 and R 10 As defined in equation (I).

[0476] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0477] ,

[0478] (Ii)

[0479] Where n = 0 or 1; and i, j, R1, R2, R6 and R 10 As defined in equation (I).

[0480] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0481] ,

[0482] (Ij)

[0483] Where n = 0 or 1; and i, j, R1, R2, R6 and R 10 As defined in equation (I).

[0484] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0485] ,

[0486] (Ik)

[0487] Where n = 0 or 1; and i, j, R1, R2, R6 and R 11 As defined in equation (I).

[0488] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0489] ,

[0490] (Il)

[0491] Where n = 0 or 1; and i, j, R1, R2, R4 and R6 are as defined in equation (I).

[0492] In some embodiments, this disclosure provides compounds of the following formula or stereoisomers thereof, or pharmaceutically acceptable salts or prodrugs:

[0493] ,

[0494] (Im)

[0495] Where n = 0 or 1; and i, j, R1, R2, R6 and R9 are as defined in equation (I).

[0496] In some embodiments, this disclosure provides a compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug as defined in any of the foregoing embodiments of this aspect, wherein R1 is methyl, ethyl, isopropyl, or 2-hydroxyethyl.

[0497] In some embodiments, this disclosure provides a compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug as defined in any of the foregoing embodiments of this aspect, wherein R2 is absent, OH, or NH2.

[0498] In some embodiments, this disclosure provides a compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug as defined in any of the foregoing embodiments of this aspect, wherein R4 and R 4’ It is independently selected from H, CH3, CF3 and CN.

[0499] In some embodiments, this disclosure provides a compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug as defined in any of the foregoing embodiments of this aspect, wherein R8 is H or methyl.

[0500] In some embodiments, this disclosure provides a compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug as defined in any of the foregoing embodiments of this aspect, wherein R6 is CF3, Cl, CH3, cyclopropyl, or OCF3.

[0501] In some embodiments, this disclosure provides a compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug as defined in any of the foregoing embodiments of this aspect, wherein the compound is selected from Examples 1-19.

[0502] In another aspect, this disclosure provides pharmaceutical compositions comprising a compound or stereoisomer thereof as defined in any of the foregoing embodiments of this aspect, a pharmaceutically acceptable salt or prodrug, and one or more pharmaceutically acceptable carriers.

[0503] In another aspect, this disclosure provides a method for treating or preventing a disease or condition that responds to inhibition of NLRP3 in a subject in need, the method comprising administering to the subject an effective amount of a compound or stereoisomer thereof as defined in any of the foregoing embodiments of this aspect, a pharmaceutically acceptable salt or prodrug, or a pharmaceutical composition thereof.

[0504] In another aspect, this disclosure provides a method for treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject an effective amount of a compound or stereoisomer thereof as defined in any of the foregoing embodiments of this aspect, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof, wherein the disease or condition is a neurodegenerative disease, a metabolic disease, an inflammatory syndrome, an autoinflammatory disease, cancer, or a genetic disease.

[0505] In some implementation schemes, neurodegenerative diseases are Parkinson's disease and Alzheimer's disease; metabolic diseases are type 2 diabetes or atherosclerosis; inflammatory diseases are gout attacks or osteoarthritis; autoinflammatory diseases are multiple sclerosis or rheumatoid arthritis; cancer is lung cancer; and hereditary diseases are cold pyridine-associated periodic syndrome.

[0506] In another aspect, this disclosure provides pharmaceutical compositions comprising a compound or stereoisomer thereof as defined in any of the foregoing embodiments of this aspect, a pharmaceutically acceptable salt or prodrug, and one or more pharmaceutically acceptable carriers.

[0507] In another aspect, this disclosure provides a method for treating or preventing a disease or condition that responds to inhibition of NLRP3 in a subject in need, the method comprising administering to the subject an effective amount of a compound or stereoisomer thereof as defined in any of the foregoing embodiments of this aspect, a pharmaceutically acceptable salt or prodrug.

[0508] In another aspect, this disclosure provides a method for treating or preventing a disease or condition that responds to inhibition of NLRP3 in a subject in need, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound or stereoisomer thereof as defined in any of the foregoing embodiments of this aspect, a pharmaceutically acceptable salt, or a prodrug.

[0509] In another aspect, this disclosure provides the use of a compound or stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug as defined in any of the foregoing embodiments of this aspect, for the treatment of a disease or condition associated with NLRP3 activity in a subject requiring treatment.

[0510] In another aspect, this disclosure provides a pharmaceutical composition comprising a compound or stereoisomer thereof as defined in any of the foregoing embodiments of this aspect, or a pharmaceutically acceptable salt or prodrug, for use in treating a disease or condition associated with NLRP3 activity in a subject requiring treatment.

[0511] In another aspect, this disclosure provides the use of a compound or stereoisomer thereof, or a pharmaceutically acceptable salt or prodrug as defined in any of the foregoing embodiments of this aspect, in the manufacture of a medicament for treating a disease or condition associated with NLRP3 activity in a subject requiring treatment.

[0512] In some implementations, the disease or condition is a neurodegenerative disease, metabolic disease, inflammatory syndrome, autoinflammatory disease, cancer, or genetic disease that can be treated with NLRP3 inhibitors.

[0513] In some implementations, neurodegenerative diseases are Parkinson's disease or Alzheimer's disease; metabolic diseases are type 2 diabetes or atherosclerosis; inflammatory diseases are gout attacks or osteoarthritis; autoinflammatory diseases are multiple sclerosis or rheumatoid arthritis; cancer is lung cancer; and hereditary diseases are cold pyridine-associated periodic syndrome.

[0514] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0515] The term "alkyl" refers to a branched or unbranched monovalent aliphatic hydrocarbon group derived from an alkane containing 1 to 12 carbon atoms by removing a hydrogen atom. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms. In some embodiments, sometimes preferably, the alkyl group contains 1 to 6 carbon atoms, and in some embodiments, sometimes more preferably, the alkyl group contains 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl, as well as their isomer counterparts. Alkyl groups can be substituted or unsubstituted.

[0516] The term "alkenyl" refers to any monovalent aliphatic hydrocarbon group derived from an alkene containing 2 to 12 carbon atoms by removing a hydrogen atom. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 8 carbon atoms. In some embodiments, sometimes preferably, the alkenyl group contains 2 to 6 carbon atoms, and in some embodiments, sometimes more preferably, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, or dodecenyl, and their isomer counterparts. The alkenyl group can be substituted or unsubstituted.

[0517] The term "alkynyl" refers to a monovalent aliphatic hydrocarbon group derived from an alkyne containing 2 to 12 carbon atoms by removing a hydrogen atom. In some embodiments, the alkynyl group contains 2 to 10 carbon atoms. In some embodiments, the alkynyl group contains 2 to 8 carbon atoms. In some embodiments, sometimes preferably, the alkynyl group contains 2 to 6 carbon atoms, and in some embodiments, sometimes more preferably, the alkynyl group contains 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentyynyl, hexynyl, heptyynyl, octyynyl, nonynyl, decanynyl, undecynyl, or dodecaynyl, and their isomer counterparts. The alkynyl group can be substituted or unsubstituted.

[0518] The term "cycloalkyl" refers to any monovalent group formed by removing a hydrogen atom from a cycloalkane. In some embodiments, the cycloalkyl group contains 3 to 10 carbon atoms. In some embodiments, the cycloalkyl group contains 3 to 8 carbon atoms. In some embodiments, and sometimes preferably, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. The cycloalkyl group may be substituted or unsubstituted.

[0519] The term "heterocyclic group" refers to a monocyclic or polycyclic non-aromatic carbocyclic group containing at least one heteroatom (N, O, and / or S) in a ring. At least one ring in the heterocyclic group's ring system is non-aromatic, and it can have any degree of saturation. The heteroatom can be located on a non-aromatic or aromatic ring of the heterocyclic group. The heterocyclic group can have 3 to 14 ring atoms, sometimes preferably 3 to 10 ring atoms (i.e., the number of atoms constituting the ring skeleton, including the number of carbon atoms and heteroatoms). Sometimes the heterocyclic group can be preferably a 3-, 4-, 5-, 6-, or 7-membered monocyclic group, and sometimes it can be preferably an 8-, 9-, or 10-membered bicyclic group. Examples of heterocyclic groups include, but are not limited to, azepinyl, acridine, carbazole, cyclolinyl, dioxacyclopentyl, imidazolinyl, imidazoalkyl, morpholinyl, ethylene oxide, oxepanyl, thietanyl, piperidinyl, piperazinyl, pyrazolinyl, pyrazolyl, 1,3-dioxaneyl, 1,3-dioxanyl, 1,4-dioxaneyl, 1,4-dioxaneyl, and 1,3-oxothiocyclohexaneyl. xathianyl), 1,4-oxathiocyclohexyl, 2H-1,3-dioxacyclopentyl, 1,3-dithiocyclopentyl, 1,3-dithiocyclopentyl, isoxazolinyl, isoxazolinyl, oxazolinyl, oxazolinyl, oxazolidinone, oxazolidinone, thiazolinyl, 1,3-oxathiolyl, indololinyl, isoindololinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolyl and tetrahydroquinolinyl.

[0520] The term "alkylene" refers to a saturated straight-chain or branched divalent aliphatic hydrocarbon group derived by removing two hydrogen atoms from a parent alkane containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbon atoms), sometimes preferably 1 to 8 carbon atoms, sometimes more preferably 1 to 6 carbon atoms, and sometimes more preferably 1 to 4 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. Alkylenes can be substituted or unsubstituted.

[0521] The term "alkenylene" refers to an alkylene group comprising 2 to 12 carbon atoms as defined above, having at least two carbon atoms and at least one carbon-carbon double bond, preferably C. 2-10 alkenyl, more preferably C 2-8 alkenyl, sometimes more preferably C 2-6 alkenyl groups, and sometimes even more preferably C. 2-4 Idealkyl groups. Non-limiting examples of idealkyl groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, etc. Idealkyl groups can be substituted or unsubstituted.

[0522] In this disclosure, the terms "alkyl" and "alkylene", "alkenyl" and "alkenylene", "aryl" and "arylene", "cycloalkyl" and "cycloalkylene", etc., are sometimes used interchangeably. Therefore, the interpretation of these terms should be based on the context that would be understood by one of ordinary skill in the art.

[0523] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or polycyclic fused ring ("fused" ring system means that each ring in the system shares a pair of adjacent carbon atoms with another ring in the system) group, and has a fully conjugated π-electron system. Preferably, the aryl group is 6- to 10-membered, such as phenyl and naphthyl, with phenyl being the most preferred. The aryl group can be substituted or unsubstituted.

[0524] The term "heteroaryl" refers to a 5- to 14-membered aryl system having 1 to 4 heteroatoms selected from O, S, and N as ring atoms. Preferably, the heteroaryl group is 5- to 10-membered (e.g., 5, 6, 7, 8, 9, and 10-membered), more preferably 5- or 6-membered, such as furanyl, thiopheneyl, phthalazinyl, pyrroleyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, thiazolyl, pyridinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoyindolyl, and benzothiopheneyl, etc. The heteroaryl group can be fused with a ring of aryl, heterocyclic, or cycloalkyl groups, wherein the ring bonded to the parent structure is a heteroaryl group. The heteroaryl group can be substituted or unsubstituted.

[0525] The term "alkoxy" refers to -O- (alkyl), such as methoxy, ethoxy, propoxy, and butoxy.

[0526] The term "cycloalkoxy" refers to -O- (cycloalkyl), such as cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0527] The term "bond" refers to a covalent bond that uses the symbol "-".

[0528] The term "hydroxyl group" refers to the -OH group.

[0529] The term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, or iodine atoms.

[0530] The term "amino" refers to the -NH2 group.

[0531] The term "alkylthio" refers to alkyl-S-.

[0532] The term "alkylamino" refers to "alkyl-NH-", or sometimes dialkylamino (-NR). a R b ), of which two alkyl groups (R a and R b The alkyl group may be the same or different. Sometimes preferably, the alkyl group is a C1-C6 alkyl group, and sometimes more preferably, the alkyl group is a C1-C4 alkyl group. Examples of alkylamino groups include, but are not limited to, CH3-NH-, -N(CH3)2, -N(CH2CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -NH-Bu t or-N(CH3)(Bu t )wait.

[0533] The term "cyano" refers to the -CN group.

[0534] The term "halogenated alkyl" refers to an alkyl group that is substituted with one or more halogen atoms, wherein the halogen atoms may be the same or different.

[0535] The term "nitro" refers to the -NO2 group.

[0536] The term "oxo group" refers to the =O group.

[0537] The term "carboxyl group" refers to the -C(O)OH group.

[0538] The term "alkoxycarbonyl" refers to the -C(O)O(alkyl) group.

[0539] The term "alkyl carbonyl" refers to -C(O)-alkyl.

[0540] The terms “optional” or “optionally” mean that the event or situation described below may but does not have to occur, and the description includes cases where the event or situation may or may not occur. For example, “optionally alkyl-substituted heterocyclic group” means that an alkyl group may be present but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0541] The term "substituted" means that one or more hydrogen atoms (preferably up to five, more preferably one to three hydrogen atoms) in a group are independently replaced by the corresponding number of substituents. Those skilled in the art can determine, experimentally or theoretically, whether substitution is possible or not without considerable effort. For example, a combination of an amino or hydroxyl group with free hydrogen and a carbon atom with an unsaturated bond (e.g., an alkene) may be unstable.

[0542] As used herein, the term "covalent bonding principle" refers to the fundamental rules and principles governing the formation of covalent bonds in organic compounds as commonly understood by those skilled in the art. For example, carbon atoms are tetravalent and can only form four covalent bonds (e.g., four single bonds, or a double bond plus two single bonds, etc.), and oxygen atoms are divalent and can only form two covalent bonds (two single bonds in -O-, or a double bond in =O).

[0543] In some embodiments, when alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups or portions thereof are substituted, the substituents can be substituted at any available connection point, and the substituents can be one or more, sometimes preferably one to five, and sometimes more preferably one to three groups independently selected from the following: C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkylthio, C1-C6 alkylamino, di(C1-C6 alkyl)amino, mercapto, hydroxyl, nitro, cyano, amino, C3-C6 cycloalkyl, 5 to 10 membered heterocyclic groups, C6-C 10 Aryl, 5- to 10-membered heteroaryl, C3-C6 cycloalkoxy, C1-C6 cycloalkylthio, 5- to 10-membered heterocyclic thio, and oxo. In some embodiments, it is sometimes preferred that the substituents are independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, di(C1-C6 alkyl)amino, mercapto, hydroxy, nitro, cyano, amino, and oxo. In some embodiments, it is sometimes more preferred that the substituents are independently selected from C1-C4 alkyl, halogen, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylamino, di(C1-C4 alkyl)amino, mercapto, hydroxy, nitro, cyano, and amino. As will be understood by those skilled in the art, the oxo (=O) group cannot be a substituent of an aryl or heteroaryl group, or a substituent on an unsaturated carbon in any other group.

[0544] The representation of carbon atoms or ring atoms in substituents (e.g., alkyl, cycloalkyl, carbocyclic, aryl, heteroaryl, or heterocyclic groups) may take different forms, but they should be understood to refer to the same thing as would be understood by a person skilled in the art. For example, alkyl groups containing 1 to 6 carbon atoms can be represented as "C1-C6 alkyl", "C6 ... 1-6 Alkyl or C1-6 Alkyl groups, etc., can also be used for other substituents.

[0545] As used herein, the term "isomer" refers to all possible types of isomerism that a compound may exhibit, as appropriate in the context. These can include stereoisomers, configurational isomers, geometric isomers, or conformational isomers, etc.

[0546] The term "stereoisomer" refers to structurally identical isomers that differ in the spatial arrangement of their atoms, which may or may not be caused by an asymmetric (chiral) center in the structure. It includes enantiomers, diastereomers, or transisomers, as well as mixtures thereof. The term "transisomer" refers to a special type of stereoisomer, namely a conformational stereoisomer, caused by steric hindrance in the molecule, which impedes or significantly slows rotation around a single bond. Some transisomers can be separated and isolated in stable forms. For example, certain compounds of this disclosure can exist under different conditions as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures rich in one transisomer) or as purified transisomers. All such stereoisomers and mixtures thereof are covered within the scope of this disclosure, regardless of whether the compound exists in a chiral form or whether only a single isomer or multiple isomers are present.

[0547] This disclosure also covers cis- / trans- (or Z- / E-) isomers resulting from different configurations of substituents on the double bond (especially C=C), which are sometimes referred to as geometric isomers.

[0548] The compounds disclosed herein may also exist in different tautomeric forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomeric form" refer to structural isomers that exist in equilibrium and readily convert from one isomeric form to another. Non-limiting examples include keto-enol tautomers or imine-enamine tautomers, etc.

[0549] As used in this specification and claims, the terms “comprising” (and any form of inclusion, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of inclusion, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional unlisted elements or method steps.

[0550] Unless otherwise stated herein or clearly contradicted by the context, the terms “a”, “an”, and “the”, as well as similar references, used in this disclosure (especially in the context of the appended claims) should be interpreted as encompassing both the singular and the plural.

[0551] When the plural form is used for compounds and salts, it also refers to a single compound or salt.

[0552] As used herein, the term "and / or" refers to and covers any and all possible combinations of one or more of the related listed items. When used in a list of more than two items, the term "and / or" means that any one of the listed items may be used alone, or any combination of more than two of the listed items may be used.

[0553] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this disclosure or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism, which aids in the absorption of the active ingredient and thus enables it to exhibit biological activity.

[0554] As used herein, the term “pharmaceutically acceptable” means compounds, materials, compositions, and / or dosage forms that, to a reasonable extent of medical judgment, are suitable for contact with a patient’s tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0555] "Pharmaceutically acceptable salt" means a salt of the compounds disclosed herein that is safe and effective for use in mammals and possesses the corresponding biological activity. Salts can be prepared during the final isolation and purification of the compound or prepared alone by reacting a suitable nitrogen atom with a suitable acid. Pharmaceutically acceptable salts are well known in the art. See, for example, SM Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids.

[0556] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and hydrogen bisulfide, as well as organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and related inorganic and organic acids. Preferred pharmaceutically acceptable salts include hydrochloride or hydrobromide.

[0557] Basic addition salts can be prepared during the final separation and purification of compounds by reacting the carboxyl group with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable cations include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, and N-methylmorpholine.

[0558] As used herein, the term "prodrug" refers to a derivative of a compound that can be converted in vivo, for example by hydrolysis under physiological conditions, to produce a parent compound. Common examples of prodrugs in this disclosure include, but are not limited to, esters or amides, such as compounds of formula (IIa), (IIb), or (IIc):

[0559]

[0560] Where R 11 and / or R 12 It is an acyl group (e.g., acetyl, propionyl, formyl, or benzoyl).

[0561] When a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof may be administered as a raw material chemical for therapeutic purposes, the active ingredient may be presented as a pharmaceutical composition. Therefore, this disclosure further provides pharmaceutical compositions comprising any compound of this disclosure or a pharmaceutically acceptable salt thereof, and one or more (preferably one to three) pharmaceutically acceptable carriers, diluents, or other excipients. The carriers, diluents, or other excipients must be acceptable in the sense of compatibility with the other components of the formulation and harmlessness to the treated subject.

[0562] In the compounds disclosed herein, atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched to specific isotopes having the same atomic number but a different atomic mass or mass number than those predominantly found in nature. For example, substitution with a heavier isotope, such as deuterium (i.e., 2 Replacing hydrogen (H) with H or D can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in some cases. Furthermore, certain isotopically labeled compounds (e.g., those with H or D) can also be preferred. 3 H and 14 C) It can be used for the determination of the tissue distribution of compounds and / or substrates. Isotope-labeled compounds can generally be prepared by following procedures similar to those disclosed in the following schemes and / or examples, by replacing non-isotope-labeled reagents with suitable isotope-labeled reagents.

[0563] This disclosure also covers all suitable isotopic derivatives of the disclosed compounds. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, boron, nitrogen, oxygen, or phosphorus, for example... 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O, etc. All isotopic variants of the compounds disclosed herein, whether or not radioactive, are intended to be covered within the scope of this disclosure.

[0564] Pharmaceutical formulations can be present in unit dosage forms containing a predetermined amount of active ingredient per unit dose. Typically, the pharmaceutical compositions of this disclosure are administered once every 1 to 5 days to about 1 to 5 times daily, or as a continuous infusion. Such administration can be used for chronic or acute therapy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound used, the duration of treatment, and the patient's age, sex, weight, and condition. Preferred unit-dose formulations are those containing a daily dose or sub-dose or a suitable portion of the active ingredient as described above. Treatment typically begins with a small dose significantly less than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimal effect for the current condition is achieved. Generally, it is most desirable to administer the compound at concentration levels that typically provide effective results without causing substantially harmful or toxic side effects.

[0565] When the compositions of this disclosure comprise a combination of the compounds of this disclosure and one or more, preferably one or two, additional therapeutic or preventative agents, both the compounds and the additional agents are typically present at a dose level between about 10% and 150%, more preferably between about 10% and 80%, of the dose usually administered in a monotherapy regimen.

[0566] Pharmaceutical formulations are suitable for administration via any suitable route, such as oral (including buccal or sublingual), rectal, nasal, local (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intradermal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrasheath, intralesional, intravenous, or intradermal injection or infusion). Such formulations can be prepared by any method known in the pharmaceutical field, such as by mixing the active ingredient with a carrier or excipient. Oral or injectable administration is preferred.

[0567] Pharmaceutical formulations suitable for oral administration can exist as discrete units, such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water emulsions or water-in-oil emulsions.

[0568] For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient can be combined with an orally administered, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, and water. Powders are prepared by pulverizing the compound into a suitable fine particle size and mixing it with a similarly pulverized pharmaceutical carrier such as edible carbohydrates (e.g., starch or mannitol). Flavoring agents, preservatives, dispersants, and coloring agents may also be present.

[0569] Capsules are prepared by preparing a powder mixture as described above and filling it into a shaped gelatin shell. Prior to the filling operation, gliding agents and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol may be added to the powder mixture. Disintegrants or solubilizers, such as agar, calcium carbonate, or sodium carbonate, may also be added to improve the availability of the drug when ingested.

[0570] In addition, suitable binders, lubricants, disintegrants, and colorants may be introduced into the mixture when needed or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethyl cellulose, and polyethylene glycol. Lubricants used in these dosage forms include sodium oleate and sodium chloride. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, and xanthan gum. For example, tablets are formulated by preparing a powder mixture, granulating or slugging, adding lubricants and disintegrants, and compressing into tablets. Powder mixtures are prepared by mixing a suitably pulverized compound with a diluent or matrix as described above and optionally with a binder such as carboxymethyl cellulose, alginate, a gelling agent or polyvinylpyrrolidone, a solution retardant such as paraffin, a reabsorption promoter such as quaternary salts, and / or an absorbent such as bentonite, kaolin, or dicalcium phosphate. Powder mixtures can be granulated by wetting them with a solution of binder such as syrup, starch paste, acadia mucilage, or cellulose or polymer materials and forcing them through a sieve. Alternatively, the powder mixture can be compressed using a tableting machine, resulting in incompletely shaped slugs broken into granules. The granules can be lubricated by adding stearic acid, stearates, talc, or mineral oil to prevent adhesion to tablet forming dies. The lubricated mixture is then compressed into tablets. The compounds disclosed herein can also be combined with free-flowing inert carriers and directly compressed into tablets without granulation or calcination steps. Transparent or opaque protective coatings consisting of shellac sealing coatings, sugar or polymer material coatings, and wax polishing coatings are available. Dyes can be added to these coatings to differentiate different unit doses.

[0571] Oral fluids, such as solutions, syrups, and elixirs, can be prepared in dosage units such that a given amount contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared using a non-toxic solvent. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavoring additives such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, may also be added.

[0572] Where appropriate, dosage units for oral administration can be microencapsulated. Formulations can also be prepared, for example, by coating or embedding particulate materials in polymers or waxes to prolong or maintain release.

[0573] It should be understood that, in addition to the ingredients specifically mentioned above, the formulation may also include other reagents conventional in the art, taking into account the type of formulation discussed, such as flavoring agents, which may be suitable for oral administration.

[0574] The terms “subject” or “patient” include humans and other mammals, including but not limited to cats, dogs, pigs, horses, sheep, goats, monkeys, chimpanzees, etc., with humans being preferred.

[0575] The term "therapeutic effective amount" refers to the amount of a compound or composition sufficient to achieve such treatment of a disease when administered to a subject for the treatment of that disease. "Therapeutic effective amount" can vary, in particular, depending on the compound, the disease and its severity, and the age, weight, or other factors of the subject being treated. When applied to a single active ingredient administered alone, the term refers to the amount of that ingredient alone. When applied to a combination, the term refers to the combined amount of active ingredients that produce a therapeutic effect, whether administered in combination, consecutively, or simultaneously.

[0576] The terms “treat,” “treating,” or “treatment” refer to: (i) the suppression of a disease, symptom, or condition, i.e., preventing its development; and (ii) the relief of a disease, symptom, or condition, i.e., causing the remission of the disease, symptom, and / or condition. Furthermore, the compounds disclosed herein can be used for their preventive effects against disease, symptom, or condition in subjects who may be susceptible to the disease, symptom, and / or condition but have not yet been diagnosed with the disease, symptom, and / or condition.

[0577] When the term "about" is applied to parameters such as pH, concentration, or temperature, it indicates that the parameter may vary by ±10%, and sometimes more preferably within ±5%, and sometimes more preferably within ±2%. As those skilled in the art will understand, when a parameter is not critical, figures are generally given for illustrative purposes only and not for limiting purposes.

[0578] The following non-limiting synthetic schemes, preparation methods and processes, as well as examples, further illustrate certain aspects of this disclosure.

[0579] Compound preparation and bioassay

[0580] As will be appreciated by those skilled in the art, the methods for synthesizing the compounds of various forms described herein will be readily apparent to those of ordinary skill in the art. Synthetic chemical transformations and protecting group methods (protection and deprotection) that can be used to synthesize the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions.

[0581] abbreviation

[0582] The following abbreviations have the following meanings:

[0583] AcOH = Acetic acid

[0584] Boc = tert-butoxycarbonyl

[0585] BOP = benzotriazol-1-yloxytris(dimethylamino) hexafluorophosphate

[0586] CyJohn Phos = (2-Biphenyl)dicyclohexylphosphine

[0587] DBU = 1,8-diazabicyclo[5,4,0]undec-7-ene

[0588] DCM = dichloromethane

[0589] DIAD = diisopropyl azodicarboxylate

[0590] DMF = N,N-dimethylformamide

[0591] DMSO = dimethyl sulfoxide

[0592] EtOH = ethanol

[0593] EtOAc = Ethyl acetate

[0594] FA = Formic acid

[0595] HCHO = Formaldehyde

[0596] HPLC = High Performance Liquid Chromatography

[0597] Hr or h = hours

[0598] LC-MS = Liquid Chromatography-Mass Spectrometry

[0599] LiBHEt3 = Lithium triethylborohydride

[0600] M = mol / L

[0601] m-CPBA = m-chloroperoxybenzoic acid

[0602] Me = methyl

[0603] MeCN = Acetonitrile

[0604] MeOH = Methanol

[0605] MOMCl = Chloromethyl methyl ether

[0606] MsCl = Methanesulfonyl chloride

[0607] NaBH3CN = Sodium cyanoborohydride

[0608] NaH = Sodium hydride

[0609] NMP = 1-Methyl-2-pyrrolidone

[0610] NMR = Nuclear Magnetic Resonance

[0611] NOE = Nuclear Overhauser effect

[0612] Pd(dppf)Cl2 = dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium

[0613] Pd(dtbpf)Cl2 = [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride

[0614] PE = Petroleum Ether

[0615] Pd(OAc)₂ = Palladium(II) acetate

[0616] POCl3 = Phosphorus oxychloride

[0617] Py = pyridine

[0618] RT = room temperature

[0619] Rt = Retention time

[0620] Sat. = saturated

[0621] SFC = Supercritical Fluid Chromatography

[0622] SPhos Pd G2 = Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0623] TBSCl = tert-butyldimethylchlorosilane

[0624] t-Bu-TMG = 2-tert-butyl-1,1,3,3-tetramethylguanidine

[0625] TEA = Triethylamine

[0626] TFA = Trifluoroacetic acid

[0627] TFAA = trifluoroacetic anhydride

[0628] Tf₂O = Trifluoromethanesulfonic anhydride

[0629] THF = Tetrahydrofuran

[0630] TLC = Thin-layer chromatography.

[0631] General conditions and procedures

[0632] In the following examples, the chemical reagents were purchased from commercial sources (e.g., Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Co., Ltd.) and were ready for use without further purification. THF was continuously refluxed from sodium and benzophenone under nitrogen and then freshly distilled, and dichloromethane was continuously refluxed from CaH2 under nitrogen and then freshly distilled.

[0633] Rapid chromatography was performed on a Biotage Isolera One column with 200-300 mesh silica gel particles. Analytical and preparative TLC plates were HSGF 254 (0.15-0.2 mm thick, Shanghai Anbang Co., Ltd., China). NMR spectra were recorded at approximately 20-30 °C using a Brucker AVANCE NEO 400 (Brucker, Switzerland) unless otherwise specified. The following abbreviations were used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet; bs, broad peak. Chemical shifts were reported in parts per million (ppm, δ) relative to the low field of tetramethylsilane. Mass spectrometry was performed using electrospray ionization (ESI) on a Shimadzu LCMS2020 mass spectrometer (Shimadzu, Japan). Compounds may be purified using a variety of methods as needed, including but not limited to preparative chromatography using normal-phase or reversed-phase HPLC, fast column chromatography, or preparative TLC plates under acidic, neutral, or alkaline conditions.

[0634] Preparative HPLC: Unless otherwise specified, use a SHIMADZU LH-40 or FRC-40 equipped with a YMC-Triart C18 column (5 μm, 120A, 250 × 20 mm) and the following solvent systems to purify the compound: H2O, MeCN, and 0.1% FA in H2O; or H2O, MeOH, and 0.1% FA in H2O; or H2O, MeCN, and 0.1% NH4OH / NH4HCO3 in H2O; or H2O, MeCN, and 0.1% NH4OH / NH4HCO3 in H2O. Specific elution gradients are based on retention times obtained using analytical LC-MS; however, generally all elution gradients for H2O and MeCN or MeOH are run at a flow rate of 20 mL / min for 20 minutes. Use automated mixing to ensure the concentration of 0.1% FA in each run. For purification using an eluent containing FA, the final product after lyophilization or drying is a full or partial salt of FA, as clearly visible from NMR. The qualitative properties of these salts are listed in the description of the examples.

[0635] Analytical LC-MS: equipped with Shim-pack Scepter C 18 Analytical LC-MS was performed on a SHIMADZU LCMS2020 instrument with a column (3.0 × 33 mm, 3 μm) (column temperature 40 °C) and using the following solvent systems: Solvent A: 0.05% HCOOH in H2O; and Solvent B: MeCN. All compounds were run at a flow rate of 1.2 mL / min for 3 minutes using the same elution gradient, i.e., 20% to 95% of Solvent B.

[0636] Preparative chiral SFC separation: Stereoisomer mixtures were separated on one of the following columns using a Waters SFC 80 (Waters, USA) or Nexera UC Prep (Shimadzu, Japan) system: ChiralPak AS-H (21.2 × 250 mm, 5 μm), ChiralPak IA (21.2 × 250 mm, 5 μm), ChiralPak AD-H (21.2 × 250 mm, 5 μm), or ChiralPak IC (21.2 × 250 mm, 5 μm); eluted with 0.05% diethylamine / CO2 in MeOH, or 0.05% diethylamine / CO2 in EtOH, or 0.05% diethylamine / CO2 in isopropanol at a flow rate of 40 mL / min and a column temperature of 40 °C.

[0637] Analytical chiral SFC separation: Stereoisomeromer mixtures or single enantiomers were analyzed using a Waters UPCC (Waters, USA) or UC (Shimadzu, Japan) column on one of the following: ChiralPak AS-H (4.6 × 100 mm, 3.5 μm), ChiralPak IA (4.6 × 100 mm, 3.5 μm), ChiralPak AD-H (4.6 × 100 mm, 3.5 μm), or ChiralPak IC (4.6 × 100 mm, 3.5 μm); eluted with 0.05% diethylamine / CO2 in MeOH, or 0.05% diethylamine / CO2 in EtOH, or 0.05% diethylamine / CO2 in isopropanol at a flow rate of 1.8 mL / min and a column temperature of 40 °C.

[0638] Scheme for preparing the final target analyte:

[0639] General Option 1:

[0640]

[0641] In general scheme 1, formulas I and II are treated with a suitable base and solvent (e.g., NaH, DMF) to obtain formula III. The protecting group of formula III is removed under suitable conditions (e.g., the Boc group is removed with TFA or HCl) to obtain formula IV. Formula IV is treated under reductive amination conditions (e.g., NaBH3CN, formaldehyde in formic acid, etc.) or alkylation conditions to obtain the final product, formula V.

[0642] General Option 2

[0643]

[0644] In general scheme 2, at SN Ar Formulas I and VI are treated with a suitable base and solvent (e.g., NaH, DMF) under appropriate conditions to obtain Formula VII. Formula III is prepared by reacting Formula VII with a suitable phenylboronic ester under Suzuki coupling conditions (e.g., Pd(dtbpf)Cl2 with a base in a suitable solvent, etc.). The protecting group of Formula III is removed under appropriate conditions (e.g., by removing the Boc group with TFA or HCl) to obtain Formula IV. Formula IV is treated under reductive amination conditions (e.g., NaBH3CN, formaldehyde in formic acid, etc.) or alkylation conditions to obtain the final product, Formula V.

[0645] Examples of preparation of intermediates

[0646] Intermediate 1

[0647] (R)-3-Mercaptopiperidine-1-carboxylic acid tert-butyl ester

[0648]

[0649] Step 1: (S)-3-((methanesulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester

[0650] TEA (8.3 mL, 60 mmol) was added to a solution of (S)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4 g, 20 mmol) in DCM (50 mL), followed by dropwise addition of MsCl (4.6 g, 40 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with ice water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the title compound (5.5 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ 4.72- 4.70 (m, 1H), 3.73 - 3.53 (m, 2H), 3.49 - 3.40 (m, 1H), 3.37 - 3.27 (m,1H), 3.04 (s, 3H), 2.00 - 1.77 (m, 3H), 1.60 - 1.49 (m, 1H), 1.46 (s, 9H).LC / MS (ESI) (m / z): 280 (M+H) + .

[0651] Step 2: (R)-3-(acetylthio)piperidine-1-carboxylic acid tert-butyl ester

[0652] Potassium thioacetate (4.6 g, 40 mmol) was added to a solution of (S)-3-((methanesulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (4.5 g, 16 mmol) in DMF (50 mL) at room temperature, and the mixture was stirred at 100 °C for 1 hour under N2. The mixture was quenched with saturated NH4Cl aqueous solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-10% EtOAc in PE) to give the title compound (1.6 g) as an oil. 1 H NMR (400 MHz, CDCl3) δ 3.83 - 3.74(m, 1H), 3.61 - 3.50 (m, 2H), 3.27 - 3.15 (m, 2H), 2.32 (s, 3H), 2.03 - 1.93(m, 1H), 1.72 - 1.58 (m, 3H), 1.46 (s, 9H). LC / MS (ESI) (m / z): 160 (M-100+H) + .

[0653] Step 3: (R)-3-mercaptopril-1-carboxylic acid tert-butyl ester

[0654] K₂CO₃ (1.1 g, 7.7 mmol) was added to a solution of (R)-3-(acetylthio)piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.9 mmol) in MeOH (10 mL) at 0 °C, and the mixture was stirred at 0 °C for 15 min. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (800 mg) as an oil. LC / MS (ESI) (m / z): 162 (M-56+H) + .

[0655] Intermediate 2a and intermediate 2b

[0656] (R)-3-((6-chloro-5-methylpyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (intermediate 2a) and (R)-3-((6-chloro-4-methylpyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (intermediate 2b)

[0657]

[0658] NaH (1.47 g, 61.3 mmol, 60% dispersion in mineral oil) was added fractionally to a solution of (R)-3-mercaptopril-1-carboxylic acid tert-butyl ester (6.67 g, 30.7 mmol) in DMF (100 mL), and the mixture was stirred at 40 °C under N2 for 30 min. 3,6-Dichloro-4-methyl-1,2-diazine (10 g, 61.35 mmol) was added to the mixture, and the resulting mixture was stirred overnight at room temperature. The mixture was quenched with a saturated aqueous NH4Cl solution at 0 °C and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound as a solid (4.4 g, a mixture of regioisomers). 1 H NMR (400 MHz, CDCl3) δ 7.14 (s, 1H), 4.41 - 4.24 (m, 1H), 3.94 - 3.80(m, 1H), 3.57 - 3.47 (m, 2H), 2.34 & 2.25 (s, 3H), 2.19 - 2.13 (m, 1H), 1.84- 1.77 (m, 2H), 1.65 - 1.59 (m, 2H), 1.41 & 1.40 (s, 9H). LC / MS (ESI) (m / z):344 (M+H) + .

[0659] Intermediates 3 and 4

[0660] 6-Chloro-3-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4-methylpyridazine (intermediate 3) and 3-chloro-6-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4-methylpyridazine (intermediate 4)

[0661]

[0662] Step 1: 4-Bromo-1-chloro-2-(methoxymethoxy)benzene

[0663] NaH (5.12 g, 128 mmol, 60% dispersion in mineral oil) was added fractionally to a solution of 5-bromo-2-chlorophenol (26.5 g, 128 mmol) in THF (300 mL) at 0 °C under N2, and the mixture was stirred at room temperature for 1 hour. MOMCl (12 mL, 153 mmol) was added at 0 °C, and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0 °C and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0–5% EtOAc in PE) to give the title compound (30 g) as an oil. 1 H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4Hz, 1H), 5.23 (s, 2H), 3.52 (s, 3H).

[0664] Step 2: 1-Chloro-4-cyclopropyl-2-(methoxymethoxy)benzene

[0665] At room temperature under N2, Cs2CO3 (38.9 g, 119 mmol), tricyclohexylphosphine (4.2 g, 14.9 mmol), and Pd(OAc)2 (1.3 g, 5.96 mmol) were added to a mixture of 4-bromo-1-chloro-2-(methoxymethoxy)benzene (15 g, 59.6 mmol) and cyclopropylboronic acid (7.7 g, 89.5 mmol) in toluene (150 mL) and water (15 mL). The mixture was degassed three times with N2 and stirred at 85 °C for 16 hours. The mixture was diluted with EtOAc and the layers were separated. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (7.5 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.2Hz, 1H), 6.84 (s, 1H), 6.56 (d, J = 8.2 Hz, 1H), 5.15 (s, 2H), 3.45 (s, 3H),1.79 - 1.76 (m, 1H), 0.91 - 0.86 (m, 2H), 0.65 - 0.51 (m, 2H).

[0666] Step 3: (4-Cyclopropyl-2-(Methoxymethoxy)phenyl)boronic acid

[0667] At 0 °C and N2, TEA (5.9 mL, 42.3 mmol), CyJohn Phos (990 mg, 2.82 mmol), and Ni(NO3)2 (260 mg, 1.41 mmol) were added to a mixture of 1-chloro-4-cyclopropyl-2-(methoxymethoxy)benzene (3 g, 14.1 mmol) and hypodiboric acid (5.1 g, 56.4 mmol) in MeOH (30 mL), and the mixture was stirred at 0 °C and N2 for 1 hour. The mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (670 mg) as an oil.

[0668] Step 4: 6-Chloro-3-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4-methylpyridazine and 3-chloro-6-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4-methylpyridazine

[0669] K₂CO₃ (934 mg, 6.76 mmol) and Pd(dppf)Cl₂ (198 mg, 0.270 mmol) were added to a mixture of (4-cyclopropyl-2-(methoxymethoxy)phenyl)boronic acid (600 mg, 2.70 mmol) and 3,6-dichloro-4-methylpyridazine (440 mg, 2.70 mmol) in 1,4-dioxane (8 mL) and water (2 mL) at room temperature under N₂. The mixture was degassed three times with N₂ and stirred at 90 °C for 3 hours under N₂. After cooling to room temperature, the mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-20% EtOAc in PE) to give intermediate 3 (160 mg), followed by intermediate 4 (650 mg), both as oils. The structure of intermediate 4 was confirmed by NOE. Intermediate 3: LC / MS (ESI) m / z: 305 (M+H) + Intermediate 4: 1H NMR (400MHz, CDCl3) δ 7.82 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.82 (dd,J = 8.0, 1.3 Hz, 1H), 5.20 (s, 2H), 3.44 (s, 3H), 2.44 (s, 3H), 1.98 - 1.88 (m, 1H), 1.05 - 0.97 (m, 2H), 0.80 - 0.71 (m, 2H). LC / MS (ESI) m / z: 305 (M+H) + .

[0670] Intermediate 5

[0671] 3-Chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine

[0672]

[0673] Step 1: 6-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine-3-ol

[0674] Under N2, K2CO3 (1.4 g, 10.38 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (223 mg, 0.35 mmol) were added to a mixture of (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (1.1 g, 5.19 mmol) and 6-chloro-4-methylpyridinium-3-ol (500 mg, 3.46 mmol) in 1,4-dioxane (10 mL) and water (4 mL). The mixture was degassed three times with N2 and stirred at 90 °C for 3 hours under N2. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (650 mg) as a solid. 1 H NMR (400 MHz, CDCl3) δ11.46 (s, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.31 (d, J = 7.8 Hz,1H), 7.19 (s, 1H), 3.93 (s, 3H), 2.28 (s, 3H). LC / MS (ESI) (m / z): 285 (M+H) + .

[0675] Step 2: 3-Chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine

[0676] POCl3 (351 mg, 2.29 mmol) was added to a solution of 6-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazin-3-ol (650 mg, 2.29 mmol) in 1,4-dioxane (7 mL) under N2 conditions, and the mixture was stirred at 60 °C for 3 hours. The mixture was concentrated to dryness under reduced pressure. The residue was diluted with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (370 mg) as a solid. LC / MS (ESI) (m / z): 303 / 305 (M+H) + .

[0677] The intermediates in Table 1 below are prepared from suitable starting materials using a similar process to that described for the preparation of intermediates 3 and 4.

[0678] Table 1. Intermediates prepared using intermediate 5

[0679]

[0680] Intermediate 11

[0681] 6-Chloro-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4-methylpyridazine

[0682]

[0683] Step 1: 2-(6-chloro-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol

[0684] BBr3 (104.8 mL, 1 M, in DCM) was added dropwise to a solution of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (7.90 g, 26.2 mmol) in DCM (50 mL) at -78 °C, and the mixture was stirred at -78 °C to room temperature for 2 hours. The mixture was quenched with a saturated aqueous solution of NaHCO3 at 0 °C and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-70% EtOAc in PE) to give the title compound (5.01 g) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.93 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 2.19 (s, 3H). LC-MS (ESI) (m / z):289.0 (M+H) + .

[0685] Step 2: 6-Chloro-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4-methylpyridazine

[0686] DIPEA (4.50 g, 34.9 mmol) was added to a solution of 2-(6-chloro-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (5.00 g, 17.4 mmol) in DCM (50 mL), followed by dropwise addition of MOMCl (2.11 g, 26.1 mmol) at 0 °C, and the mixture was stirred at room temperature for 3 h. The mixture was quenched with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (2.52 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.48 - 7.42 (m, 3H), 5.14 (s, 2H), 3.38 (s, 3H), 2.23(s, 3H). LC-MS (ESI) (m / z): 333.0 (M+H) + .

[0687] Intermediate 12

[0688] 2-(2-fluoro-6-methoxy-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[0689]

[0690] To a solution of 1-fluoro-3-methoxy-5-(trifluoromethyl)benzene (2.00 g, 10.3 mmol) in THF (20 mL), n-BuLi (6.5 mL, 10.3 mmol, 2.5 M, in hexane) was added dropwise at -78 °C, and the mixture was stirred at -78 °C for 1 h. To the reaction mixture, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (2.3 mL, 11.0 mmol) was added at -78 °C, and the resulting mixture was stirred at -78 °C for 2 h. The mixture was quenched with a saturated aqueous NH4Cl solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (1.8 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ 6.91 (d, J = 8.0 Hz, 1H), 6.82 (s, 1H), 3.85 (s, 3H), 1.39 (s, 12H).

[0691] Intermediate 13

[0692] (R)-3-((6-chloropyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0693]

[0694] Cs₂CO₃ (3.30 g, 10.1 mmol) and tert-butyl (R)-3-mercaptopril-1-carboxylate (1.10 g, 5.07 mmol) were added to a solution of 3,6-dichloropyridazine (500 mg, 3.38 mmol) in MeCN (10 mL) at 0 °C, and the mixture was stirred at 80 °C for 5 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-15% EtOAc in PE) to give the title compound (460 mg) as a solid. 1H NMR (400 MHz, CD3OD) δ 7.56 (s,2H), 4.16 - 4.10 (m, 1H), 3.92 - 3.82 (m, 1H), 3.68 - 3.56 (m, 1H), 3.48 -3.38 (m, 2H), 2.21 - 2.13 (m, 1H), 1.85 - 1.75 (m, 2H), 1.66 - 1.58 (m, 1H), 1.36 (s, 9H). LC-MS (ESI) m / z: 330.2 (M+H) + .

[0695] Example

[0696] Example 1

[0697] (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol, formate (partial)

[0698]

[0699] Step 1: (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0700] NaH (198 mg, 4.95 mmol, 60% dispersion in mineral oil) was added to a solution of (R)-3-mercaptopril-1-carboxylic acid tert-butyl ester (718 mg, 3.3 mmol) in DMF (10 mL) at 0 °C under N2, and the mixture was stirred at 40 °C for 30 min. 6-Chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (500 mg, 1.7 mmol) was added to the above mixture, and the resulting mixture was stirred overnight at 30 °C under N2. The reaction was quenched with ice water and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (750 mg) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.19 (s, 1H), 7.17 (s, 1H), 4.34 - 4.28 (m, 1H), 3.83 (s, 3H), 3.73 - 3.14 (m, 4H), 2.11(s, 3H), 1.85 - 1.71 (m, 3H), 1.66 - 1.60 (m, 1H), 1.40 (s, 9H). LC / MS (ESI)(m / z): 484 (M+H) + .

[0701] Step 2: (R)-2-(4-methyl-6-(piperidin-3-ylthio)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0702] BBr3 (155 mg, 0.62 mmol) was added to a solution of (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.21 mmol) in DCM (3 mL) at -78 °C, and the mixture was stirred at -78 °C for 10 min and then stirred at room temperature for 2 h. The mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (70 mg) as a yellow solid. LC / MS (ESI) (m / z): 370 (M+H) + .

[0703] Step 3: (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol, formate (partial)

[0704] To a solution of (R)-2-(4-methyl-6-(piperidin-3-ylthio)pyridazin-3-yl)-5-(trifluoromethyl)phenol (70 mg, 0.19 mmol) in MeOH (2 mL), 37% HCHO aqueous solution (0.035 mL, 0.95 mmol), AcOH (0.011 mL, 0.19 mmol), and NaBH3CN (36 mg, 0.57 mmol) were added, and the mixture was stirred at room temperature under N2 for 0.5 h. The mixture was quenched with saturated NH4Cl aqueous solution and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250 × 21 mm, 10–90% MeCN in H2O, containing 0.1% FA) to give the title compound (20 mg) as a solid. 1 HNMR (400 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.28 (d, J =8.0 Hz, 1H), 7.25 (s, 1H), 4.26 - 4.19 (m, 1H), 2.95 - 2.92 (m, 2H), 2.36 -2.22 (m, 2H), 2.21 (s, 3H), 2.11 (s, 3H), 2.00 - 1.92 (m, 1H), 1.82 - 1.75(m, 1H), 1.67 - 1.59 (m, 1H), 1.56 - 1.45 (m, 1H). LC / MS (ESI) (m / z): 384 (M+H) + .

[0705] The embodiments listed in Table 2 were prepared from suitable starting materials according to methods and schemes similar to those described for the synthesis of Example 1.

[0706] Table 2. Examples prepared using the process of Example 1

[0707]

[0708]

[0709]

[0710] Example 11

[0711] 2-(4-methyl-6-(((R)-1-methylpiperidin-3-yl)sulfinyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0712]

[0713] Potassium persulfate (Oxone) (72 mg, 0.12 mmol) was added to a solution of (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol (15 mg, 0.039 mmol) in MeCN (2 mL) and water (1 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (YMC-Actus Triart C18, 10–90% MeCN in H2O, containing 0.1% NH4HCO3) to give the title compound (2 mg) as a solid. 1 H NMR(400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.9Hz, 1H), 7.28 (s, 1H), 3.20 - 3.16 (m, 2H), 2.67 - 2.58 LC / MS (ESI) (m / z): 400 (M+H) + .

[0714] Example 12

[0715] (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)sulfonyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol, trifluoroacetate

[0716]

[0717] Step 1: (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-yl)sulfonyl)piperidine-1-carboxylic acid tert-butyl ester

[0718] To a solution of (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidin-1-carboxylic acid tert-butyl ester (250 mg, 0.52 mmol) in DCM (5 mL), m-CPBA (210 mg, 1.0 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated aqueous Na₂SO₃ and extracted twice with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (130 mg) as a solid. LC / MS (ESI) (m / z): 516 (M+H) + .

[0719] Step 2: (R)-2-(4-methyl-6-(piperidin-3-ylsulfonyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0720] BBr3 (143 mg, 0.59 mmol) was added dropwise to a solution of (R)-2-(4-methyl-6-(piperidin-3-ylsulfonyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (100 mg, 0.19 mmol) in DCM (1 mL) at -78 °C. The mixture was stirred at -78 °C for 10 min under N2 and then stirred at room temperature for 2 h. The mixture was quenched with a saturated aqueous solution of NaHCO3 at 0 °C and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (70 mg) as a solid. LC / MS (ESI) (m / z): 402 (M+H) + .

[0721] Step 3: (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)sulfonyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol, trifluoroacetate

[0722] A solution of (R)-2-(4-methyl-6-(piperidin-3-ylsulfonyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (60 mg, 0.15 mmol) in MeOH (1 mL) was added to a solution of 37% HCHO aqueous solution (0.05 mL), one drop of AcOH, and NaBH3CN (25 mg, 0.39 mmol) at 0 °C, and the mixture was stirred at room temperature for 0.5 h. The mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (YMC-ActusTriart C18, 30–60% MeCN in water, containing 0.1% TFA) to give the title compound (12 mg) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.01 (s, 1H),7.18 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.96 (s, 1H), 3.87 - 3.84(m, 1H), 3.48 - 3.45 (m, 1H), 3.07 - 3.04 (m 1H), 2.97 - 2.91 (m, 1H), 2.64 -2.62 (m, 1H), 2.13 (s, 3H), 1.99 (s, 3H), 1.81 - 1.62 (m, 2H), 1.44 - 1.21(m, 2H). LC / MS (ESI) (m / z): 416 (M+H) + .

[0723] Example 13

[0724] (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol

[0725]

[0726] Step 1: (R)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-(piperidin-3-ylthio)pyridazine hydrochloride

[0727] To a solution of (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (450 mg, 0.9 mmol) in DCM (5 mL), HCl / 1,4-dioxane (5 mL, 4 M) was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure to give the title compound (350 mg) as a solid, which was used directly in the next reaction without further purification. LC / MS (ESI) (m / z): 384 (M+H) + .

[0728] Step 2: (R)-2-(3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidin-1-yl)ethanol-1-ol

[0729] 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (477 mg, 2.7 mmol), AcOH (0.05 mL, 0.9 mmol), and NaBH3CN (169 mg, 2.7 mmol) were added to a solution of (R)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-(piperidin-3-ylthio)pyridazine (350 mg, 0.9 mmol) in MeOH (4 mL) at 0 °C, and the mixture was stirred at room temperature for 0.5 h. The mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the title compound (350 mg) as an oil. LC / MS (ESI) (m / z): 428 (M+H) + .

[0730] Step 3: (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol

[0731] BBr3 (250 mg, 0.7 mmol) was added to a solution of (R)-2-(3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidin-1-yl)ethanol-1-ol (300 mg, 0.7 mmol) in DCM (3 mL) at -78 °C, and the mixture was stirred at 0 °C for 1 hour. The mixture was quenched with MeOH at 0 °C and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18, 40%–95% MeCN in water, containing 0.1% NH3·H2O) to give the title compound (60 mg) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s,1H), 7.53 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.25(s, 1H), 4.54 - 4.30 (m, 1H), 4.27 - 4.15 (m, 1H), 3.55 - 3.46 (m, 2H), 3.13- 2.98 (m, 1H), 2.76 - 2.60 (m, 1H), 2.46 - 2.41 (m, 2H), 2.34 - 2.27 (m,1H), 2.11 (s, 3H), 2.03 - 1.95 (m, 1H), 1.82 - 1.72 (m, 1H), 1.68 - 1.58 (m,1H), 1.56 - 1.46 (m, 1H). LC / MS (ESI) (m / z): 414 (M+H) + .

[0732] Example 14

[0733] (R)-5-methyl-2-(4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)phenol

[0734]

[0735] Step 1: (R)-3-((6-(2-methoxy-4-methylphenyl)-5-methylpyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester and (R)-3-((6-(2-methoxy-4-methylphenyl)-4-methylpyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0736] At room temperature, tert-butyl (2-methoxy-4-methylphenyl)boronic acid (315 mg, 1.89 mmol), Pd(dtbpf)Cl2 (94.2 mg, 0.146 mmol), and K2CO3 (605 mg, 4.38 mmol) were added to a solution of (R)-3-((6-chloro-5-methylpyridazin-3-yl)thio)piperidine-1-carboxylate (500 mg, 1.46 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL). The mixture was degassed three times with N2 and stirred at 90 °C for 4 hours under N2 atmosphere. The mixture was cooled to room temperature, diluted with water, and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel, 0-40% EtOAc in PE) to give compound 2 (110 mg) and compound 2a (60 mg), both solids. Compound 2: 1 H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 7.7 Hz, 1H), 7.13 (s, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.78 (s, 1H), 4.35 - 4.23 (m, 1H), 3.75 (s, 3H), 3.66 - 3.36 (m, 2H), 2.42 (s, 3H), 2.11 (s, 3H), 1.87 - 1.75 (m, 2H), 1.73 -1.57 (m, 4H), 1.39 (s, 9H). LC-MS (ESI) (m / z): 430.2 (M+H) + .

[0737] Step 2: (R)-5-methyl-2-(4-methyl-6-(piperidin-3-ylthio)pyridazin-3-yl)phenol

[0738] BBr3 (2.3 mL, 2.3 mmol, 1 M, in DCM) was added dropwise to a solution of (R)-3-((6-(2-methoxy-4-methylphenyl)-5-methylpyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.233 mmol) in DCM (3 mL) at -78 °C, and the mixture was stirred at -78 °C to room temperature for 2 hours. The mixture was quenched with a saturated aqueous solution of NaHCO3 at 0 °C and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (50 mg) as a solid. LC / MS (ESI) (m / z): 316.1 (M+H) + .

[0739] Step 3: (R)-5-methyl-2-(4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)phenol

[0740] AcOH (19.2 mg, 0.32 mmol) and NaBH3CN (30.2 mg, 0.48 mmol) were added to a mixture of (R)-5-methyl-2-(4-methyl-6-(piperidin-3-ylthio)pyridazin-3-yl)phenol (50 mg, 0.16 mmol) and 37% HCHO aqueous solution (0.1 mL) in MeOH (2 mL) at 0 °C, and the mixture was stirred at room temperature for 20 min. The mixture was quenched with water and extracted twice with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250 × 20 mm, 0-95% acetonitrile in H2O, containing 0.1% NH4OH) to give the title compound (3.6 mg) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H),7.03 (d, J = 7.6 Hz, 1H), 6.67 (s, 1H), 6.58 (d, J = 7.6 Hz, 1H), 4.25 - 4.09(m, 1H), 2.90 - 2.86 (m, 1H), 2.49 - 2.41 (m, 2H), 2.24 (s, 3H), 2.23 - 2.18(m, 1H), 2.17 (s, 3H), 2.13 (s, 3H), 1.99 - 1.91 (m, 1H), 1.82 - 1.73 (m,1H), 1.66 - 1.57 (m,1H), 1.51 - 1.42 (m, 1H). LC-MS (ESI) (m / z): 330.3 (M+H) + .

[0741] Example 15

[0742] (R)-5-chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)phenol

[0743]

[0744] The title compound was prepared according to methods and procedures similar to those described for the synthesis of Example 14. 1 HNMR (400 MHz, DMSO-d6) δ 7.44 (s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 6.84 (s,1H), 6.78 (d, J = 8.1 Hz, 1H), 4.23 - 4.15 (m, 1H), 2.93 - 2.85 (m, 1H), 2.50- 2.39 (m, 2H), 2.28 - 2.20 (m, 1H), 2.17 (s, 3H), 2.13 (s, 3H), 1.99 - 1.91(m, 1H), 1.82 - 1.73 (m, 1H), 1.66 - 1.56 (m, 1H), 1.54 - 1.43 (m, 1H). LC / MS(ESI) m / z: 350 (M+H) + .

[0745] Examples 16 and 17

[0746] 3-Fluoro-2-(4-methyl-6-(((R)-1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol (Example 16) and (R)-3-fluoro-2-(5-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol (Example 17)

[0747]

[0748] Except for the final step in which the regioisomers were separated by preparative HPLC (YMC-Actus Triart C18 250×20mm, 5-95% MeCN in H2O, containing 0.1% FA) to obtain Example 16, and then Example 17 (both solids), the title compound was prepared according to methods and protocols similar to those described for the synthesis of Example 14. Example 16: 1 H NMR (400 MHz, CD3OD) δ 7.55 (d, J = 0.8 Hz, 1H), 7.08 - 7.06 (m, 2H), 4.32 - 4.24 (m, 1H), 3.36 - 3.33 (m, 1H), 2.90 - 2.85 (m, 1H), 2.56 - 2.50(m, 1H), 2.44 (s, 3H), 2.43 - 2.36 (m, 1H), 2.19 (s, 3H), 2.17 - 2.10 (m,1H), 1.96 - 1.91 (m, 1H), 1.86 - 1.77 (m, 1H), 1.66 - 1.58 (m, 1H). LC-MS(ESI) (m / z): 402.3 (M+H) + Example 17: 1 H NMR (400 MHz, CD3OD) δ 7.82 (s, 1H),7.08 (s, 1H), 7.03 (d, J = 11.2 Hz, 1H), 4.46 - 4.40 (m, 1H), 3.42 - 3.35 (m,1H), 2.94 - 2.82 (m, 1H), 2.62 - 2.45 LC-MS (ESI) (m / z): 402.4 (M+H) + .

[0749] Example 18

[0750] 2-(6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol

[0751]

[0752] Step 1: 2,2-Dimethyltetrahydro-2H-pyran-4-ylmethanesulfonate

[0753] MsCl (1.76 g, 15.4 mmol) was added to a solution of 2,2-dimethyltetrahydropyran-4-ol (1.0 g, 7.68 mmol) and TEA (3.2 mL, 23 mmol) in DCM (5 mL) at 0 °C under N2. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted twice with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the title compound (1.5 g) as an oil. 1 H NMR (400 MHz, CDCl3) δ 5.02 -4.79 (m, 1H), 3.85 - 3.74 (m, 1H), 3.63 - 3.57 (m, 1H), 2.96 (s, 3H), 2.03 -1.89 (m, 2H), 1.76 - 1.66 (m, 1H), 1.62 - 1.56 (m, 1H), 1.22 (s, 3H), 1.16 (s, 3H).

[0754] Step 2: S-(2,2-dimethyltetrahydro-2H-pyran-4-yl)thioacetate

[0755] Potassium thioacetate (2.1 g, 18.2 mmol) was added to a solution of 2,2-dimethyltetrahydro-2H-pyran-4-ylmethanesulfonate (1.5 g, 7.28 mmol) in DMF (10 mL), and the reaction mixture was stirred at 100 °C for 3 hours under N2. The mixture was diluted with saturated aqueous NH4Cl solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (508 mg) as an oil. LC / MS (ESI) m / z: 189 (M+H) + .

[0756] Step 3: 2,2-Dimethyltetrahydro-2H-pyran-4-thiol

[0757] At room temperature, K₂CO₃ (1.1 g, 8.09 mmol) was added to a solution of S-(2,2-dimethyltetrahydropyran-4-yl)thioacetate (508 mg, 2.70 mmol) in MeOH (10 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title compound (298 mg) as an oil. LC / MS (ESI) m / z: 147 (M+H) + .

[0758] Step 4: 6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)thio)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine

[0759] NaH (204 mg, 5.10 mmol, 60% dispersion in mineral oil) was added to a solution of 2,2-dimethyltetrahydro-2H-pyran-4-thiol (298 mg, 2.04 mmol) in DMF (10 mL) at 0 °C, and the reaction mixture was stirred at 40 °C for 30 min. 6-Chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (514 mg, 1.70 mmol) was added to the mixture, and the resulting mixture was stirred overnight at 30 °C. The mixture was quenched with a saturated aqueous NH4Cl solution at 0 °C and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (240 mg) as a solid. LC / MS (ESI) m / z: 413 (M+H) + .

[0760] Step 5: 2-(6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol

[0761] BBr3 (577 mg, 2.3 mmol) was added to a solution of 6-((2,2-dimethyltetrahydro-2H-pyran-4-yl)thio)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (190 mg, 0.461 mmol) in DCM (5 mL) at -78 °C under N2, and the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice-cooled saturated NaHCO3 aqueous solution and extracted twice with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Triart C18, 40–50% MeCN in water, containing 0.1% FA) to give the title compound (10.3 mg) as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.55 (d, J= 7.8 Hz, 1H), 7.42 - 7.34 (m, 2H), 4.01 - 3.94 (m, 1H), 3.67 - 3.63 (m, 2H), 2.73 - 2.69 (m, 1H), 2.40 - 2.34 (m, 1H), 2.32 (s, 3H), 2.06 - 1.98 (m, 1H), 1.94 - 1.85 (m, 1H), 1.74 (s, 3H), 1.62 (s, 3H). LC / MS ESI (m / z): 399 (M+H) + .

[0762] Example 19

[0763] (Rac)-2-(4-methyl-6-(((1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-2-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol, formate

[0764]

[0765] Step 1: 2-Hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0766] NaBH4 (336 mg, 8.9 mmol) was added to a solution of tert-butyl 2-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1 g, 4.4 mmol) in MeOH (20 mL), and the mixture was stirred at 0 °C for 1 hour under a N2 atmosphere. The mixture was quenched with ice water and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (800 mg) as a solid. LC-MS (ESI) (m / z): 228.2 (M+H) + .

[0767] Step 2: 2-((methanesulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0768] DIPEA (853 mg, 6.6 mmol) was added to a solution of tert-butyl 2-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (750 mg, 3.3 mmol) in DCM (10 mL), followed by dropwise addition of MsCl (570 mg, 5.0 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The mixture was diluted with saturated aqueous NaHCO3 solution and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (800 mg) as a solid. LC-MS (ESI) (m / z): 306.1 (M+H) + .

[0769] Step 3: 2-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0770] Potassium thioacetate (450 mg, 3.93 mmol) was added to a solution of tert-butyl 2-((methanesulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (800 mg, 2.62 mmol) in DMF (15 mL), and the mixture was stirred at 60 °C for 2 h under N2 atmosphere. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (700 mg) as a solid. LC-MS (ESI) (m / z): 286.1 (M+H) + .

[0771] Step 4: 2-Mercapto-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0772] K₂CO₃ (1.02 g, 7.35 mmol) was added to a solution of tert-butyl 2-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylate (700 mg, 2.45 mmol) in MeOH (15 mL), and the mixture was stirred at 40 °C for 4 hours under a N₂ atmosphere. o C. The mixture was quenched with an aqueous HCl solution (30 mL, 0.5 M) and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness to give the title compound as a solid (550 mg). LC-MS (ESI) (m / z): 244.1 (M+H) + .

[0773] Step 5: (Rac)-(1R,2R,5S)-2-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0774] Cs₂CO₃ (1.07 g, 3.28 mmol) and 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (595 mg, 1.97 mmol) were added to a solution of 2-mercapto-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (400 mg, 1.64 mmol) in MeCN (20 mL), and the mixture was stirred at 80 °C for 3 h under a N₂ atmosphere. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (400 mg) as a solid. LC-MS (ESI) (m / z): 510.2 (M+H) + .

[0775] Step 6: (Rac)-2-(6-(((1R,2R,5S)-8-azabicyclo[3.2.1]octane-2-yl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol

[0776] BBr3 (3 mL, 3 mmol, 1 M, in DCM) was added dropwise to a solution of (rac)-(1R,2R,5S)-2-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (400 mg, 0.78 mmol) in DCM (20 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with a saturated aqueous solution of NaHCO3 at 0 °C and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-9% MeOH in DCM) to give the title compound (250 mg) as a solid. LC-MS (ESI) m / z: 396.1 (M+H) + .

[0777] Step 7: (Rac)-2-(4-methyl-6-(((1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-2-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0778] Formaldehyde (40 mg, 1.33 mmol), acetic acid (0.1 mL), and NaBH3CN (200 mg, 3.18 mmol) were added to a solution of (rac)-2-(6-(((1R,2R,5S)-8-azabicyclo[3.2.1]octane-2-yl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (250 mg, 0.63 mmol) in MeOH (10 mL) at 0 °C, and the mixture was stirred at room temperature for 30 min. The mixture was quenched with saturated NH4Cl aqueous solution and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250×21mm, 5%~95% MeCN in H2O, containing 0.1% FA) to obtain the title compound as a solid (150 mg). 1HNMR (400 MHz, CD3OD) δ 7.52 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.29 (d, J =7.4 Hz, 1H), 7.22 (s, 1H), 4.62 - 4.55 (m, 1H), 4.16 - 4.11 (m, 1H), 3.92 -3.85 (m, 1H), 2.81 (s, 3H), 2.37 - 2.25 (m, 3H), 2.22 (s, 3H), 2.10 - 1.99(m, 3H), 1.93 - 1.87 (m, 1H), 1.84 - 1.75 (m, 1H). LC-MS (ESI) m / z: 410.1 (M+H) + .

[0779] Examples 20 and 21

[0780] 2-(4-methyl-6-(((1S,2S,5R)-8-methyl-8-azabicyclo[3.2.1]octane-2-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol (Example 20) and

[0781] 2-(4-Methyl-6-(((1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-2-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol (Example 21)

[0782]

[0783] Example 19 was resolved by chiral SFC to obtain Example 20 (peak 1, Rt = 3.403 min) and Example 21 (peak 2, Rt = 4.225 min) as solids. Configuration assignment was based on bioactivity compared to similar analogs prepared from chiral starting materials. Chiral SFC conditions: Column: ChiralPak C-IG, 250 × 30 mm ID, 5 µm; Mobile phase: A = CO2 and B = MeOH (0.1% DEA in MeOH); Isocratic ratio: B 20%; Flow rate: 60 mL / min. Example 20: 1H NMR (400 MHz, CD3OD) δ 7.49 (s, 1H), 7.44 (d, J = 7.9 Hz, 3H), 7.27 (d, J = 7.9 Hz, 1H), 7.21 (s, 1H), 4.54 - 4.41 (m, 1H), 3.84 - 3.74 (m, 1H), 3.56 - 3.48 (m, 1H), 2.57 (s, 3H), 2.29 - 2.23 (m, 1H), 2.21 (s, 3H), 2.15 - 2.09 (m, 2H), 2.04 -1.95 (m, 2H), 1.88 - 1.77 (m, 1H), 1.75 - 1.65 (m, 2H). LC / MS (ESI) m / z: 410(M+H) + Example 21: 1 H NMR (400 MHz, CD3OD) δ 7.49 (s, 1H), 7.44 (d, J = 7.9 Hz,1H), 7.27 (d, J = 7.9 Hz, 1H), 7.21 (s, 1H), 4.54 - 4.43 (m, 1H), 3.86 - 3.80(m, 1H), 3.59 - 3.52 (m, 1H), 2.59 (s, 3H), 2.30 - 2.22 (m, 1H), 2.21 (s,3H), 2.17 - 2.10 (m, 2H), 2.07 - 1.96 (m, 2H), 1.88 - 1.78 (m, 1H), 1.77 -1.63 (m, 2H). LC-MS (ESI) m / z: 410 (M+H) + .

[0784] Example 22

[0785] 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol

[0786]

[0787] Step 1: (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid ethyl ester hydrochloride

[0788] SOCl₂ (19.05 g, 160 mmol) was added dropwise to a solution of (2S,4S)-4-hydroxytetrahydropyrrole-2-carboxylic acid (20 g, 152.5 mmol) in EtOH (180 mL) at 0 °C, and the mixture was stirred at 80 °C for 6 hours. The mixture was concentrated to dryness under reduced pressure to give the title compound (22 g) as a solid. LC-MS (ESI) (m / z): 160 (M+H) + .

[0789] Step 2: (2S,4S)-1-benzyl-4-hydroxypyrrolidine-2-carboxylic acid ethyl ester

[0790] TEA (34.93 mL, 251.3 mmol) was added to a solution of (2S,4S)-4-hydroxytetrahydropyrrole-2-carboxylate hydrochloride (22 g, 112 mmol) in DCM (500 mL), followed by dropwise addition of benzyl bromide (15.69 mL, 131.9 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (25 g) as a solid. LC-MS (ESI) (m / z): 250 (M+H) + .

[0791] Step 3: (2S,4S)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid ethyl ester

[0792] TBSCl (13.0 g, 86.3 mmol) was added fractionally to a mixture of (2S,4S)-1-benzyl-4-hydroxytetrahydropyrrole-2-carboxylate (20.0 g, 80.2 mmol) and imidazole (8.61 g, 126 mmol) in DMF (150 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-18% EtOAc in PE) to give the title compound (23 g) as an oil. LC-MS (ESI) (m / z): 364.5 (M+H) + .

[0793] Step 4: ((2S,4S)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-yl)methanol

[0794] LiBHEt3 (110.5 mL, 1 M, in THF) was added dropwise to a solution of (2S,4S)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid ethyl ester (20 g, 55.0 mmol) in THF (300 mL) at 0 °C, and the mixture was stirred at 25 °C for 24 h under a nitrogen atmosphere. The mixture was quenched with a saturated aqueous NH4Cl solution at 0 °C and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (13.6 g) as an oil. LC / MS (ESI) m / z: 322.5 (M+H) + .

[0795] Step 5: (3R,5S)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidine-3-ol

[0796] TFAA (6.53 mL, 46.7 mmol) was added dropwise to a solution of ((2S,4S)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-yl)methanol (10.0 g, 31.1 mmol) in anhydrous THF (120 mL) at -78 °C, and the mixture was stirred at -78 °C for 1 hour. Then, TEA (4.32 mL, 31.1 mmol) was added dropwise to the above mixture at -78 °C, and the resulting mixture was stirred at 70 °C for 16 hours. The mixture was cooled to room temperature and quenched with an aqueous solution of NaOH (100 mL, 2.5 M). The resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (7.0 g) as an oil. 1H NMR (400 MHz, CDCl3) δ7.32 - 7.21 (m, 5H), 3.95 - 3.88 (m, 1H), 3.85 - 3.76 (m, 1H), 3.63 (d, J =13.4 Hz, 1H), 3.41 (d, J = 13.4 Hz, 1H), LC-MS (ESI) m / z: 322.5 (M+H) + .

[0797] Step 6: (3S,5S)-1-benzyl-3-((tert-butyldimethylsilyl)oxy)-5-fluoropiperidine

[0798] Bis(2-methoxyethyl)aminosulfur trifluoride (2.46 mL, 18.7 mmol) was added dropwise to a solution of (3R,5S)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidine-3-ol (5.0 g, 15.6 mmol) in DCM (60 mL) at -78 °C, and the mixture was stirred at -78 °C for 5 hours. o C. The mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted twice with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (3.23 g) as an oil. 1 H NMR (400 MHz, CDCl3) δ 7.32 - 7.16 (m, 5H), 4.63 - 4.38 (m, 1H), 3.78 - 3.66 (m, 1H), 3.60 (d, J = 13.2 Hz, 1H), 3.49 (d, J = 13.2 Hz, 0.00 (s, 3H), -0.02 (s, 3H). LC-MS (ESI) m / z: 324.4 (M+H) +.

[0799] Step 7: (3S,5S)-3-((tert-butyldimethylsilyl)oxy)-5-fluoropiperidine

[0800] At 0 °C, Pd / C (200 mg, 10 wt%), Pd(OH)₂ (100 mg, 10 wt%), and AcOH (0.042 mL, 0.730 mmol) were added to a solution of (3S,5S)-1-benzyl-3-((tert-butyldimethylsilyl)oxy)-5-fluoropiperidine (1.8 g, 5.58 mmol) in THF (20 mL). The mixture was degassed three times with N₂ and stirred at 40 °C for 16 hours under an H₂ balloon. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (940 mg) as an oil. LC-MS (ESI) m / z: 234.4 (M+H) + .

[0801] Step 8: (3S,5S)-3-((tert-butyldimethylsilyl)oxy)-5-fluoropiperidine-1-carboxylic acid tert-butyl ester

[0802] Boc₂O (1.46 g, 6.74 mmol) and TEA (1.56 mL, 11.23 mmol) were added to a solution of (3S,5S)-3-((tert-butyldimethylsilyl)oxy)-5-fluoropiperidine (940 mg, 4.02 mmol) in DCM (15 mL) at 0 °C, and the mixture was stirred at 25 °C for 4 h. The mixture was diluted with water and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-28% EtOAc in PE) to give the title compound as a solid (1.16 g). LC-MS (ESI) m / z: 278.4 (M+H-56) + .

[0803] Step 9: (3S,5S)-3-fluoro-5-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0804] TBAF (3.24 mL, 3.24 mmol, 1 M, in THF) was added to a solution of (3S,5S)-3-((tert-butyldimethylsilyl)oxy)-5-fluoropiperidine-1-carboxylic acid tert-butyl ester (900 mg, 2.70 mmol) in DMF (2 mL) at 0 °C, and the mixture was stirred at 25 °C for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NH4Cl solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0–23% MeOH in DCM) to give the title compound (450 mg) as an oil. LC-MS (ESI) m / z: 242.3 (M+Na) + .

[0805] Step 10: (3S,5S)-3-fluoro-5-((methanesulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester

[0806] TEA (0.44 mL, 3.22 mmol) was added to a solution of (3S,5S)-3-fluoro-5-hydroxypiperidine-1-carboxylic acid tert-butyl ester (350 mg, 1.60 mmol) in DCM (5 mL), followed by dropwise addition of MsCl (274 mg, 2.40 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hours under a N2 atmosphere. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0–13% MeOH in DCM) to give the title compound (250 mg) as a solid. LC-MS (ESI) m / z: 242.2 (M-56+H) + .

[0807] Step 11: (3R,5S)-3-(acetylthio)-5-fluoropiperidine-1-carboxylic acid tert-butyl ester

[0808] Potassium thioacetate (192 mg, 1.68 mmol) was added to a solution of (3S,5S)-3-fluoro-5-((methanesulfonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.67 mmol) in DMA (2 mL) at 25 °C, and the mixture was stirred at 100 °C for 1 h under a N2 atmosphere. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-25% EtOAc in PE) to give the title compound (160 mg) as an oil. LC-MS (ESI) (m / z): 278.3 (M+H) + .

[0809] Step 12: (3S,5R)-3-fluoro-5-mercaptopril-1-carboxylic acid tert-butyl ester

[0810] K₂CO₃ (159 mg, 1.15 mmol) was added to a solution of (3R,5S)-3-(acetylthio)-5-fluoropiperidine-1-carboxylic acid tert-butyl ester (160 mg, 0.58 mmol) in MeOH (3 mL) at 0 °C, and the mixture was stirred at 0 °C for 15 min under a N₂ atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title compound (110 mg) as an oil, which was used directly in the next reaction without purification.

[0811] Step 13: (3S,5R)-3-fluoro-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0812] Cs₂CO₃ (214 mg, 0.66 mmol) and 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (75 mg, 0.31 mmol) were added to a solution of (R)-3-mercaptopril-1-carboxylic acid tert-butyl ester (80 mg, 0.26 mmol) in MeCN (3 mL), and the mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (40 mg) as a solid. LC-MS (ESI) m / z: 502.5 (M+H) + .

[0813] Step 14: 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol

[0814] BBr3 (49.9 mg, 0.20 mmol) was added dropwise to a solution of (3S,5R)-3-fluoro-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.08 mmol) in DCM (3 mL) at -78 °C, and the mixture was stirred at 25 °C for 2 hours. oThe reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a solid (15 mg). LC-MS (ESI) m / z: 388.4 (M+H) + .

[0815] Step 15: 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol

[0816] Paraformaldehyde (10.8 mg, 0.36 mmol) and AcOH (0.01 mL, 0.04 mmol) were added to a solution of 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (15 mg, 0.04 mmol) in MeOH (1 mL) at 0 °C, followed by the addition of sodium cyanoborohydride (7.9 mg, 0.12 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 h. The mixture was quenched with a saturated aqueous solution of NaHCO3 at 0 °C and extracted twice with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250×20mm, 20-95% MeCN in H2O, containing 0.1% NH4OH) to give the title compound as a solid (1.13 mg). 1 H NMR (400 MHz, CD3OD) δ 7.46 (s, 1H),7.36 (d, J = 8.2 Hz, 1H), 7.13 - 7.11 (m, 2H), 4.58 - 4.33 (m, 3H), 3.74 -3.62 (m, 1H), 2.92 - 2.79 (m, 1H), 2.46 (s, 3H), 2.45 - 2.41 (m, 1H), 2.40 -2.34 (m, 1H), 2.22 (s, 3H), 2.10 - 2.00 (m, 1H). LC / MS (ESI) (m / z): 402.2 (M+H) + .

[0817] Example 23

[0818] 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol

[0819]

[0820] Step 1: (3S,5S)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl-4-nitrobenzene ester

[0821] PPh3 (4.9 g, 18.7 mmol) and 4-nitrobenzoic acid (1.7 g, 10.3 mmol) were added to a solution of (3R,5S)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol (3 g, 9.33 mmol) in THF (30 mL) at 0 °C under a N2 atmosphere, and the mixture was stirred at this temperature for 30 min. DIAD (3.8 g, 18.7 mmol) was added to the above mixture, and the resulting mixture was stirred at 0 °C for 30 min and then at 50 °C for 16 h. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (3 g) as a solid. LC-MS (ESI) (m / z): 471.3 (M+H) + .

[0822] Step 2: (3S,5S)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidine-3-ol

[0823] LiOH·H₂O (536 mg, 12.8 mmol) was added to a solution of (3S,5S)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-yl-4-nitrobenzoate (3 g, 6.37 mmol) in THF (30 mL) and water (30 mL), and the mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (1.5 g) as an oil, which was used directly in the next reaction without purification. LC-MS (ESI) (m / z): 322.3 (M+H) + .

[0824] Step 3-12: 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol

[0825] The title compound was prepared as a solid according to the methods and procedures described in steps 6-15 of Example 22. 1HNMR (400 MHz, DMSO-d6) δ 7.52 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.19 - 7.16(m, 2H), 4.99 - 4.83 (m, 1H), 4.46 - 4.37 (m, 1H), 3.00 - 2.95 (m, 1H), 2.77- 2.69 (m, 1H), 2.42 - 2.32 (m, 1H), 2.30 - 2.24 (m, 1H), 2.22 (s, 3H), 2.13(s, 3H), 2.06 - 1.77 (m, 2H). LC-MS (ESI) m / z: 402.0 (M+H) + .

[0826] Example 24

[0827] (R)-3-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazine

[0828]

[0829] Sodium dichlorofluoroacetate (40 mg, 0.26 mmol) and Cs₂CO₃ (60 mg, 0.18 mmol) were added to a solution of (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol (20 mg, 0.052 mmol) in DMF (4 mL) and water (1 mL), and the mixture was stirred at 100 °C for 16 h under N₂ atmosphere. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18, 10–60% MeCN in water, containing 0.1% FA) to give the title compound (1.4 mg) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 7.80(d, J = 8.1 Hz, 1H), 7.75 - 7.73 (m, 2H), 7.62 (s, 1H), 7.40 (t, J = 73.0 Hz,1H), 4.27 - 4.19 (m, 1H), 2.88 - 2.86 (m, 1H), 2.47 - 2.39 (m, 1H), 2.35 -2.19 (m, 2H), 2.18 (s, 3H), 2.07 (s, 3H), 1.99 - 1.93 (m, 1H), 1.82 - 1.74(m, 1H), 1.67 - 1.58 (m, 1H), 1.55 - 1.48 (m, 1H). LC / MS (ESI) (m / z): 434 (M+H) + .

[0830] Examples 25 and 26

[0831] (R)-2-(4-((1-methylpiperidin-3-yl)thio)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (Example 25) and (R)-2-(1-((1-methylpiperidin-3-yl)thio)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (Example 26)

[0832]

[0833] Step 1: 4-Chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine and 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine

[0834] Pd(dtbpf)Cl2 (237 mg, 0.36 mmol) and K2CO3 (1.50 g, 10.9 mmol) were added to a mixture of (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (800 mg, 3.64 mmol) and 1,4-dichloropyrido[3,4-d]pyridazine (1.45 g, 7.27 mmol) in 1,4-dioxane (15 mL) and water (5 mL). The mixture was degassed three times with N2 and stirred at 50 °C for 3 h under N2. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (800 mg) as a solid, a mixture of regioisomers. LC / MS (ESI) (m / z): 340 (M+H) + .

[0835] Step 2: 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine-4-ol and 4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine-1-ol

[0836] t-BuOK (374 mg, 3.06 mmol) was added to a solution of 4-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine and 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine (520 mg, 1.53 mmol) in THF (10 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the title compound (490 mg) as a solid, a mixture of regioisomers. LC / MS (ESI) (m / z): 322 (M+H) + .

[0837] Step 3: (R)-3-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)thio)piperidine-1-carboxylic acid tert-butyl ester and (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0838] (R)-3-mercaptopril-1-carboxylic acid tert-butyl ester (497 mg, 2.29 mmol) was added to a solution of 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-ol and 4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-ol (490 mg, 1.52 mmol) in DMF (10 mL) at 0 °C, followed by the addition of DBU (464 mg, 3.05 mmol) and BOP (1.35 g, 3.05 mmol), and the mixture was stirred at 80 °C for 3 h. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (300 mg) as a solid, a mixture of regioisomers. LC / MS (ESI) (m / z): 521 (M+H) + .

[0839] Step 4: (R)-2-(4-(piperidin-3-ylthio)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol and (R)-2-(1-(piperidin-3-ylthio)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol

[0840] BBr3 (286 mg, 1.14 mmol) was added dropwise to a solution of (R)-3-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido-[3,4-d]pyridazin-4-yl)thio)piperidine-1-carboxylic acid tert-butyl ester and (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido-[3,4-d]pyridazin-1-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.57 mmol) in DCM (5 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with MeOH (2 mL) at -60 °C, poured into ice-cooled saturated NaHCO3 aqueous solution, and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title compound (210 mg) as a solid, a mixture of regioisomers. LC / MS (ESI) (m / z): 407 (M+H) + .

[0841] Step 5: (R)-2-(4-((1-methylpiperidin-3-yl)thio)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (Example 25) and (R)-2-(1-((1-methylpiperidin-3-yl)thio)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (Example 26)

[0842] At 0 °C, a solution of (R)-2-(4-(piperidin-3-ylthio)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol and (R)-2-(1-(piperidin-3-ylthio)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (200 mg, 0.49 mmol) in MeOH (5 mL) was added with AcOH (0.1 mL) and 37% HCHO aqueous solution (0.18 mL, 2.45 mmol), followed by the addition of NaBH3CN (93 mg, 1.48 mmol), and the mixture was stirred at room temperature for 30 min. The mixture was quenched with saturated NaHCO3 aqueous solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18, 10-90% MeCN in H2O, containing 0.1% NH4OH) to obtain Example 25 (second eluent, 25 mg) and Example 26 (first eluent, 28 mg), both solids. The regional chemistry was confirmed by NOE. Example 25: 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.00 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.50 (dd, J = 5.6, 0.8 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.32 (s, 1H), 4.67- 4.55 (m, 1H), 2.93 - 2.91 (m, 1H), 2.46 - 2.29 (m, 3H), 2.22 (s, 3H), 2.07- 1.97 (m, 1H), 1.91 - 1.81 (m, 1H), 1.77 - 1.63 (m, 2H). LC / MS (ESI) (m / z):421 (M+H) + Example 26: 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 9.03 (d, J =5.7 Hz, 1H), 8.02 (dd, J = 5.7, 0.7 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.37(d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 4.61 - 4.48 (m, 1H), 2.91 - 2.89 (m, 1H), 2.46 - 2.30 (m, 3H), 2.21 (s, 3H), 2.06 - 1.97 (m, 1H), 1.91 - 1.82 (m, 1H),1.78 - 1.62 (m, 2H). LC / MS (ESI) (m / z): 421 (M+H) + .

[0843] Examples 27 and 28

[0844] (R)-2-(4-((1-methylpiperidin-3-yl)thio)pyrido[3,4-d]pyridazin-1-yl)-5-(2H-1,2,3-triazol-2-yl)phenol (Example 27) and (R)-2-(1-((1-methylpiperidin-3-yl)thio)pyrido[3,4-d]pyridazin-4-yl)-5-(2H-1,2,3-triazol-2-yl)phenol (Example 28)

[0845]

[0846] Step 1: 4-Chloro-1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)pyrido[3,4-d]pyridazine and 1-chloro-4-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)pyrido[3,4-d]pyridazine

[0847] Under a nitrogen atmosphere, Pd(dtbpf)Cl2 (177 mg, 0.27 mmol) and K2CO3 (1.14 g, 8.22 mmol) were added to a mixture of (2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)boronic acid (prepared according to the process in intermediate B8 from WO2020163541, 600 mg, 2.74 mmol) and 1,4-dichloropyrido[3,4-d]pyridazine (1.10 g, 5.48 mmol) in 1,4-dioxane (15 mL) and water (3 mL). The reaction mixture was degassed three times with nitrogen and stirred at 90 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-60% EtOAc in PE) to give the title compound (500 mg) as a solid, a mixture of regioisomers. LC-MS (ESI) (m / z): 339.0 (M+H) + .

[0848] Step 2: (R)-3-((1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)pyrido[3,4-d]pyridazin-4-yl)thio)piperidine-1-carboxylic acid tert-butyl ester and (R)-3-((4-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)pyrido[3,4-d]pyridazin-1-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0849] (R)-3-mercaptopril-1-carboxylic acid tert-butyl ester (289 mg, 1.33 mmol) and Cs₂CO₃ (866 mg, 2.66 mmol) were added to a solution of 4-chloro-1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)pyrido[3,4-d]pyridazine (450 mg, 1.33 mmol) in MeCN (8 mL) at room temperature, and the mixture was stirred at 90 °C for 2 h under N₂ atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0–2% MeOH in DCM) to give the title compound (300 mg) as a solid. LC-MS (ESI) (m / z): 520.3 (M+H) + .

[0850] Step 3: (R)-2-(4-(piperidin-3-ylthio)pyrido[3,4-d]pyridazin-1-yl)-5-(2H-1,2,3-triazol-2-yl)phenol and (R)-2-(1-(piperidin-3-ylthio)pyrido[3,4-d]pyridazin-4-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0851] BBr3 (0.96 mL, 0.96 mmol, 1 M, in DCM) was added dropwise to a solution of (R)-3-((1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)pyrido[3,4-d]pyridazin-4-yl)thio)piperidin-1-carboxylic acid tert-butyl ester (250 mg, 0.48 mmol) in DCM (3 mL) at -78 °C, and the mixture was stirred at -78 °C to room temperature for 2 hours. The mixture was quenched with a saturated aqueous solution of NaHCO3 at 0 °C and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (200 mg) as a solid. LC-MS (ESI) (m / z): 406.1 (M+H) + .

[0852] Step 4: (R)-2-(4-((1-methylpiperidin-3-yl)thio)pyrido[3,4-d]pyridazin-1-yl)-5-(2H-1,2,3-triazol-2-yl)phenol and (R)-2-(1-((1-methylpiperidin-3-yl)thio)pyrido[3,4-d]pyridazin-4-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0853] At room temperature, a solution of (R)-2-(4-(piperidin-3-ylthio)pyrido[3,4-d]pyridazin-1-yl)-5-(2H-1,2,3-triazol-2-yl)phenol (200 mg, 0.48 mmol) in MeOH (5 mL) was mixed with 0.2 mL of 37% HCHO aqueous solution and 0.05 mL of AcOH, followed by the addition of NaBH3CN (90 mg, 1.43 mmol). The mixture was stirred at room temperature under a N2 atmosphere for 0.5 hours. oC. The mixture was quenched with a saturated aqueous NH4Cl solution and extracted twice with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250 × 21 mm, 10–90% MeCN in H2O, containing 0.1% FA) to give the title compound (80 mg) as a solid. The mixture was resolved by chiral SFC to give Example 27 (peak 1, Rt = 2.248 min) and Example 28 (peak 2, Rt = 3.141 min) as solids, and the configuration assignment was confirmed by NOE. Chiral SFC conditions: column: ChiralPak IB, 250 × 20 mm ID, 5 µm; mobile phase: A = CO2 and B = MeOH (0.1% 2MNH3 in MeOH); isocratic strength: B 40%; flow rate: 60 mL / min.

[0854] Example 27: 1 H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.59 (s, 1H),9.02 (d, J = 5.6 Hz, 1H), 8.18 (s, 2H), 7.776 & 7.771 (s, 1H), 7.686 & 7.681(d, J = 8.3, 1H), 7.61 - 7.56 (m, 1H), 4.64 - 4.57 (m, 1H), 3.00 - 2.89 (m,1H), 2.47 - 2.39 (m, 2H), 2.37 - 2.30 (m, 1H), 2.22 (s, 3H), 2.06 - 1.99 (m,1H), 1.92 - 1.82 (m, 1H), 1.75 - 1.64 (m, 2H). LC-MS (ESI) m / z: 434.1 (M+H) + .

[0855] Example 28: 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.13 (s, 1H),9.02 (d, J = 5.7 Hz, 1H), 8.19 (s, 2H), 8.01 (d, J = 5.7 Hz, 1H), 7.796 &7.790 (s, 1H), 7.720 & 7.715 (d, J = 8.3, 1H), 7.65 (d, J = 8.3 Hz, 1H), 4.59- 4.49 (m, 1H), 2.95 - 2.88 (m, 1H), 2.47 - 2.38 (m, 2H), 2.36 - 2.30 (m,1H), 2.22 (s, 3H), 2.05 - 1.98 (m, 1H), 1.89 - 1.81 (m, 1H), 1.73 - 1.64 (m,2H). LC-MS (ESI) m / z: 434.1 (M+H) + .

[0856] Example 29

[0857] (R)-2-(4-((1-methylpiperidin-3-yl)thio)phthalazin-1-yl)-5-(trifluoromethyl)phenol

[0858]

[0859] Step 1: 4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazine-1-ol

[0860] Under a nitrogen atmosphere, K₂CO₃ (942 mg, 6.82 mmol) and Pd(dtbpf)Cl₂ (147 mg, 0.23 mmol) were added to a mixture of (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (500 mg, 2.27 mmol) and 4-chlorophthalazine-1-ol (411 mg, 2.27 mmol) in 1,4-dioxane (5 mL) and water (2 mL). The mixture was degassed three times with nitrogen and stirred at 90 °C for 3 hours under a nitrogen atmosphere. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (350 mg) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 8.33 - 8.26 (m, 1H), 7.89- 7.81 (m, 2H), 7.60 (d, J = 7.7 Hz, 1H), 7.52 -7.42 (m, 2H), 7.31- 7.20 (m,1H), 3.79 (s, 3H). LCMS (ESI) (m / z): 321.1 (M+H) + .

[0861] Step 2: 1-Chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazine

[0862] POCl3 (670 mg, 4.37 mmol) was added to a solution of 4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazine-1-ol (350 mg, 1.09 mmol) in 1,4-dioxane (4 mL), and the mixture was stirred at 60 °C for 3 hours. The mixture was then concentrated to dryness under reduced pressure. o C. The residue was neutralized with a saturated aqueous solution of NaHCO3 and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (150 mg) as a solid. LC-MS (ESI) (m / z): 339.1 / 341.1 (M+H) + .

[0863] Step 3: (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0864] NaH (53 mg, 1.33 mmol, 60% dispersion in mineral oil) was added to a solution of (R)-3-mercaptopril-1-carboxylic acid tert-butyl ester (192 mg, 0.89 mmol) in DMF (2 mL) at 0 °C under a N2 atmosphere, and the mixture was stirred at 40 °C for 30 min. A solution of 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazine (150 mg, 0.44 mmol) in DMF (2 mL) was added to the mixture, and the resulting mixture was stirred at 30 °C for 3 h under a N2 atmosphere. The mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NH4Cl solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound (120 mg) as a yellow solid. LC / MS (ESI) (m / z): 520.3 (M+H) + .

[0865] Step 4: (R)-2-(4-(piperidin-3-ylthio)phthalazin-1-yl)-5-(trifluoromethyl)phenol

[0866] BBr3 (116 mg, 0.46 mmol) was added dropwise to a solution of (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.23 mmol) in DCM (2 mL) at -78 °C under a N2 atmosphere, and the mixture was stirred at room temperature for 30 min. The mixture was quenched at 0 °C with a saturated aqueous solution of NaHCO3 and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (70 mg) as a solid. LC / MS (ESI) (m / z): 406.1 (M+H) + .

[0867] Step 5: (R)-2-(4-((1-methylpiperidin-3-yl)thio)phthalazin-1-yl)-5-(trifluoromethyl)phenol

[0868] A solution of (R)-2-(4-(piperidin-3-ylthio)phthalazin-1-yl)-5-(trifluoromethyl)phenol (70 mg, 0.17 mmol) in MeOH (2 mL) was added to a solution of 37% HCHO aqueous solution (0.27 mL) at 0 °C, followed by the addition of sodium cyanoborohydride (33 mg, 0.52 mmol), and the mixture was stirred at room temperature for 20 min. The mixture was quenched with ice water and filtered. The filtrate was purified by preparative HPLC (YMC-Actus Triart C18 250 × 20 mm, 10%–95% MeCN in H₂O containing 0.1% NH₄OH) to give the title compound (2 mg) as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (d,J = 8.1 Hz, 1H), 7.98 (t, J = 7.1 Hz, 1H), 7.91 (t, J = 7.2 Hz, 1H), 7.63 (d,J = 8.0 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 8.2 Hz, 2H), 4.56 -4.47 (m, 1H), 2.95 (d, J = 9.6 Hz, 1H), 2.46 - 2.33 (m, 2H), 2.31 - 2.23 (m,1H), 2.20 (s, 3H), 2.04 - 1.98 (m, 1H), 1.88 - 1.79 (m, 1H), 1.71 - 1.61 (m,2H). LC / MS (ESI) m / z: 420.2 (M+H) + .

[0869] Example 30

[0870] (R)-2-(4-((1-methylpiperidin-3-yl)thio)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0871]

[0872] Step 1: 1-Chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopentano[d]pyridazine

[0873] Under a nitrogen atmosphere, Pd(dtbpf)Cl2 (37 mg, 0.06 mmol) and K2CO3 (2.2 g, 15.87 mmol) were added to a mixture of 1,4-dichloro-6,7-dihydro-5H-cyclopentano[d]pyridazine (1 g, 5.29 mmol) and (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (1.4 g, 6.35 mmol) in 1,4-dioxane (10 mL) and water (2 mL). The reaction mixture was degassed three times with nitrogen and stirred at 90 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (500 mg) as a solid. LC-MS (ESI) (m / z): 329.0 (M+H) + .

[0874] Step 2: (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazine-1-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0875] NaH (110 mg, 2.74 mmol, 60% dispersion in mineral oil) was added to a solution of (R)-3-mercaptopril-1-carboxylic acid tert-butyl ester (397 mg, 1.83 mmol) in DMF (2 mL) at 0 °C under a N2 atmosphere, and the mixture was stirred at room temperature under a N2 atmosphere for 30 min. A solution of 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopentano[d]pyridazine (300 mg, 0.91 mmol) in DMF (3 mL) was added to the above mixture at 0 °C, and the resulting mixture was stirred at 30 °C under a N2 atmosphere for 16 h. The mixture was quenched with saturated NH4Cl aqueous solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (350 mg) as a solid. LC-MS (ESI) (m / z): 510.1 (M+H) + .

[0876] Step 3: (R)-2-(4-(piperidin-3-ylthio)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol

[0877] BBr3 (0.2 mL, 2.06 mmol) was added dropwise to a solution of (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (350 mg, 0.69 mmol) in DCM (3 mL) at -78 °C, and the mixture was stirred at -78 °C for 10 min and then at room temperature for 2 h. The mixture was quenched with a saturated aqueous solution of NaHCO3 at 0 °C and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (250 mg) as a solid. LC-MS (ESI) (m / z): 370 (M+H) + .

[0878] Step 4: (R)-2-(4-((1-methylpiperidin-3-yl)thio)-6,7-dihydro-5H-cyclopenta[d]pyridazine-1-yl)-5-(trifluoromethyl)phenol

[0879] To a mixture of (R)-2-(4-(piperidin-3-ylthio)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (100 mg, 0.25 mmol) and an aqueous solution of HCHO (0.13 mL, 1.26 mmol, 37 wt%) in MeOH (1.5 mL), NaBH3CN (48 mg, 0.76 mmol) was added, and the mixture was stirred at room temperature for 30 min. The mixture was quenched with a saturated aqueous solution of NH4Cl and extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250 × 21 mm, 20–95% MeCN in H2O, containing 0.1% FA) to give the title compound as a solid (27.9 mg). 1H NMR(400 MHz, DMSO-d6) δ 7.61 (d, J = 8.3 Hz, 1H), 7.28 - 7.26 (m, 2H), 4.44 -4.36 (m, 1H), 2.99 - 2.91 (m, 3H), 2.84 - 2.78 (m, 2H), 2.59 - 2.51 (m, 1H),2.44 - 2.36 (m, 1H), 2.33 - 2.26 (m, 1H), 2.23 (s, 3H), 2.09 - 2.02 (m, 2H),2.00 - 1.92 (m, 1H), 1.84 - 1.76 (m, 1H), 1.68 - 1.53 (m, 2H) LC-MS (ESI) m / z: 410.3 (M+H) + .

[0880] The examples listed in Table 3 were prepared from suitable starting materials according to methods and schemes similar to those described for the synthesis of Example 30.

[0881] Table 3. Examples prepared using the process of Example 30

[0882]

[0883] Example 33

[0884] (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)thio)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0885]

[0886] Step 1: 6-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione

[0887] At room temperature under a nitrogen atmosphere, (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (5.5 g, 25.0 mmol), K₂CO₃ (8.7 g, 63.0 mmol), and Pd(dppf)Cl₂·CH₂Cl₂ (1.7 g, 2.08 mmol) were added to a solution of 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione (4 g, 20.9 mmol) in 1,4-dioxane (40 mL). The mixture was degassed three times with nitrogen and stirred at 80 °C for 6 hours under a nitrogen atmosphere. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-70% EtOAc in PE) to give the title compound (4.5 g) as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 12.11 (s,1H), 7.49 (d, J = 8.1 Hz, 1H), 7.39 - 7.37 (m, 2H), 3.83 (s, 3H). LC / MS (ESI)(m / z): 288.0 (M+H) + .

[0888] Step 2: 3,5-Dichloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine

[0889] DIEA (4 mL) was added to a solution of 6-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (4.0 g, 13.9 mmol) in POCl3 (40 mL), and the mixture was stirred overnight at 100 °C. The mixture was concentrated to dryness under reduced pressure. The residue was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-20% EtOAc in PE, containing 5% DCM) to give the title compound (2.1 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.26 (s, 1H), 3.91 (s, 3H). LC / MS (ESI) m / z: 323.9 (M+H) + .

[0890] Step 3: 3-Chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazine

[0891] MeMgBr (3.1 mL, 9.3 mmol, 3 M, in 2-methyl-THF) was added dropwise to a solution of 3,5-dichloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine (2 g, 6.19 mmol) in 10 mL of THF at -60 °C. The mixture was stirred at -60 °C for 30 min under N2 atmosphere and then at -20 °C for 1 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution at -20 °C and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (355 mg) as a solid. LC / MS (ESI) (m / z): 303.9 (M+H) + .

[0892] Step 4: (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazine-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0893] Cs₂CO₃ (646 mg, 1.98 mmol) and 3-chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazine (200 mg, 0.66 mmol) were added to a solution of (R)-3-mercaptopril-1-carboxylic acid tert-butyl ester (143 mg, 0.66 mmol) in MeCN (5 mL), and the mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (150 mg) as a solid. LC / MS (ESI) (m / z): 485.3 (M+H) + .

[0894] Step 5: (R)-2-(5-methyl-3-(piperidin-3-ylthio)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0895] BBr3 (1.45 mL, 1.45 mmol, 1 M, in DCM) was added dropwise to a solution of (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.289 mmol) in DCM (5 mL) at -78 °C, and the mixture was stirred at room temperature for 2 hours. oC. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-20% MeOH in DCM) to give the title compound (52 mg) as a solid. LC / MS (ESI) (m / z): 371.1 (M+H) + .

[0896] Step 6: (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)thio)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol

[0897] AcOH (2 drops) and NaBH3CN (17 mg, 0.270 mmol) were added to a mixture of (R)-2-(5-methyl-3-(piperidin-3-ylthio)-1,2,4-triazin-6-yl)-5-(trifluoromethyl)phenol (50 mg, 0.135 mmol) and 37% HCHO aqueous solution (0.08 mL) in MeOH (2 mL) at 0 °C, and the mixture was stirred at room temperature for 20 min. The mixture was quenched with water and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Triart C18, 250 × 20 mm, 5 μm, 5 ~ 95% MeCN in H2O, containing 0.1% NH4HCO3) to give the title compound (5 mg) as a solid. 1 H NMR (400 MHz, CD3OD) δ 7.54 (d,J = 7.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 4.29 - 4.19 (m, 1H),3.67 - 3.59 (m, 1H), 3.22 - 3.14 (m, 1H), 2.95 - 2.87 (m, 1H), 2.80 - 2.74(m, 1H), 2.68 (s, 3H), 2.45 (s, 3H), 2.25 - 2.18 (m, 1H), 2.08 - 2.02 (m,1H), 1.96 - 1.87 (m, 1H), 1.78 - 1.68 (m, 1H). LC / MS (ESI) m / z: 385.2 (M+H) + .

[0898] Example 34

[0899] (R)-2-(4-((1-methylpiperidin-3-yl)thio)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol

[0900]

[0901] Step 1: 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione

[0902] Phosphorus pentasulfide (431 mg, 0.92 mmol) was added to a stirred solution of 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (prepared according to the procedure of Example 11, WO2024013395, 150 mg, 0.48 mmol) in pyridine (3 mL), and the mixture was stirred in a sealed tube at 150 °C for 6 hours. The reaction mixture was poured into ice water and stirred at 0 °C for 10 minutes. The precipitated solid was filtered, washed with water, and dried under vacuum to give the title compound (110 mg) as a solid. LC-MS (ESI) (m / z): 326.2 (M+H).

[0903] Step 2: 2-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)thio)ethyl acetate

[0904] Ethyl 2-bromoethyl (105 mg, 0.614 mmol) and K₂CO₃ (212 mg, 1.537 mmol) were added to a stirred, degassed solution of 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-4(3H)-thione (100 mg, 0.307 mmol) in THF (4 mL) and water (2 mL), and the mixture was stirred at 25 °C for 3 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (90 mg) as a solid. LC-MS (ESI) (m / z): 412.2 (M+H).

[0905] Step 3: (R)-3-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0906] DIPEA (66 mg, 0.51 mmol) and (R)-3-mercaptopiridine-1-carboxylic acid tert-butyl ester (184 mg, 0.85 mmol) were added to a solution of ethyl 2-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)thio)ethyl acetate (70 mg, 0.17 mmol) in DMF (2 mL), and the mixture was stirred at 100 °C for 16 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-8% MeOH in DCM) to give the title compound (39 mg) as a solid. LC-MS (ESI) m / z: 509.2 (M+H) + .

[0907] Step 4: (R)-2-(4-(piperidin-3-ylthio)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol

[0908] BBr3 (0.2 mL, 0.20 mmol, 1 M, in DCM) was added dropwise to a solution of (R)-3-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (39 mg, 0.076 mmol) in DCM (3 mL). The mixture was stirred at -78 °C for 10 min and then at room temperature for 2 h. The mixture was quenched at 0 °C with a saturated aqueous solution of NaHCO3 and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (20 mg) as a solid, which was used directly in the next reaction without purification. LC / MS (ESI) m / z: 395.1 (M+H) + .

[0909] Step 5: (R)-2-(4-((1-methylpiperidin-3-yl)thio)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol

[0910] At room temperature, a solution of (R)-2-(4-(piperidin-3-ylthio)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5-(trifluoromethyl)phenol (20 mg, 0.05 mmol) in MeOH (1 mL) was mixed with HCHO aqueous solution (0.1 mL, 37 wt%), AcOH (0.05 mL), and then NaBH3CN (15.8 mg, 0.24 mmol). The mixture was stirred at room temperature under a N2 atmosphere for 0.5 hours. o C. The mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted twice with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (Welch xbidge xb-C18 250×21.2mm, 20–95% MeCN in H2O, containing 0.1% FA) to give the title compound as a solid (3.5 mg). 1 H NMR (400 MHz, CD3OD) δ 8.07 (d, J = 8.0 Hz, 1H),7.73 (s, 1H), 7.32 - 7.22 (m, 3H), 7.18 - 7.13 (m, 1H), 4.61 - 4.49 (m, 2H),2.76 - 2.58 (m, 2H), 2.52 - 2.42 (m, 1H), 2.38 (s, 3H), 2.22 - 2.15 (m, 1H), 2.01 - 1.93 (m, 1H), 1.86 - 1.71 (m, 2H). LC-MS (ESI) (m / z): 409.1 (M+H) + .

[0911] Example 35

[0912] (R)-2-(2-methyl-7-((1-methylpiperidin-3-yl)thio)pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol

[0913]

[0914] Step 1: 3-Methyl-1H-pyrazole-5-carbonylhydrazide

[0915] N₂H₄·H₂O (3 mL) was added to a solution of methyl 3-methyl-1H-pyrazole-5-carboxylate (10 g, 19.21 mmol) in EtOH (30 mL) at 25 °C, and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was ground together with a 1 / 1 mixture of water / MeOH and filtered. The filter cake was washed with water and dried under vacuum to give the title compound (6.4 g) as a solid. LC-MS (ESI) (m / z): 141.1 (M+H) + .

[0916] Step 2: 2-Methylpyrazolo[1,5-d][1,2,4]triazine-4(5H)-one

[0917] Triethoxymethane (6.1 mL, 54.8 mmol) was added to a solution of 3-methyl-1H-pyrazole-5-carbonylhydrazine (6.4 g, 45.67 mmol) in DMF (20 mL) at 25 °C, and the mixture was stirred at 165 °C for 1 h in a CEM microwave reactor. The mixture was cooled to room temperature and filtered. The filter cake was washed with EtOH and dried under vacuum to give the title compound (3.8 g) as a solid. LC-MS (m / z): 151.1 (M+H) + .

[0918] Step 3: 7-Bromo-2-methylpyrazolo[1,5-d][1,2,4]triazine-4(5H)-one

[0919] At 0 °C, benzyltrimethylammonium tribromide (4.58 g, 11.72 mmol) was added to a mixture of 2-methylpyrazolo[1,5-d][1,2,4]triazine-4(5H)-one (3.8 g, 10.66 mmol) and t-Bu-TMG (10.80 g, 21.31 mmol) in 1,4-dioxane (50 mL), and the mixture was stirred at 25 °C for 16 h. The mixture was then quenched with a mixture of saturated aqueous Na₂S₂O₃ and saturated aqueous NaHCO₃, and extracted twice with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (1.5 g) as a solid. LC-MS (m / z): 229 / 231 (M+H) + .

[0920] Step 4: (R)-3-((2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-d][1,2,4]triazine-7-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0921] (R)-3-mercaptopril-1-carboxylic acid tert-butyl ester (2.13 g, 6.13 mmol) was added to a mixture of 7-bromo-2-methylpyrazolo[1,5-d][1,2,4]triazine-4(5H)-one (1.5 g, 10.09 mmol) and K₂CO₃ (5.4 g, 10.52 mmol) in NMP (10 mL) at 0 °C, and the mixture was stirred at 120 °C for 16 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-50% EtOAc in PE) to give the title compound (800 mg) as a solid. LC-MS (m / z): 366.2 (M+H) + .

[0922] Step 5: (R)-3-((2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-d][1,2,4]triazine-7-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0923] Pyridine (346 mg, 0.11 mmol) was added to a solution of (R)-3-((2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-d][1,2,4]triazin-7-yl)thio)piperidin-1-carboxylic acid tert-butyl ester (800 mg, 0.21 mmol) in DCM (5 mL), followed by dropwise addition of Tf₂O (925 mg, 0.28 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h. The mixture was quenched with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-35% EtOAc in PE) to give the title compound (400 mg) as a solid. LC-MS (m / z): 498.1 (M+H) + .

[0924] Step 6: (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylpyrazolo[1,5-d][1,2,4]triazine-7-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0925] Under a nitrogen atmosphere at 25°C, tert-butyl (2-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-d][1,2,4]triazin-7-yl)thio)piperidine-1-carboxylate (280 mg, 0.56 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added with (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (185 mg, 0.84 mmol), K₂CO₃ (233 mg, 1.68 mmol), and Pd(dtbpf)Cl₂ (37 mg, 0.06 mmol). The mixture was degassed three times with nitrogen and stirred overnight at 50°C. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-20% EtOAc in PE) to give the title compound as a solid (112 mg). LC-MS (ESI) (m / z): 524.2 (M+H) + .

[0926] Step 7: (R)-2-(2-methyl-7-(piperidin-3-ylthio)pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol

[0927] A solution of BBr3 (1 mL, 1 mmol, 1 M, in DCM) was added dropwise to a solution of (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylpyrazolo[1,5-d][1,2,4]triazin-7-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (112 mg, 0.21 mmol) in DCM (3 mL), and the mixture was stirred at room temperature for 50 min. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 at 0 °C and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the title compound (80 mg) as a solid, which was used directly in the next reaction without purification. LC-MS (ESI) m / z: 410.1 (M+H) + .

[0928] Step 8: (R)-2-(2-methyl-7-((1-methylpiperidin-3-yl)thio)pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol

[0929] A solution of (R)-2-(2-methyl-7-(piperidin-3-ylthio)pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5-(trifluoromethyl)phenol (80 mg, 0.19 mmol) in MeOH (3 mL) was added to an aqueous solution of HCHO (30 mg, 0.38 mmol, 37 wt%), one drop of AcOH, and NaBH3CN (18 mg, 0.29 mmol), and the mixture was stirred at 25 °C for 30 min. The mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250 × 21 mm, 10–95% MeCN in H2O, containing 0.1% NH4HCO3) to give the title compound (20 mg) as a solid. 1 HNMR (400 MHz, CD3OD) δ 8.08 (d, J = 8.5 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.16(s, 1H), 4.50 - 4.40 (m, 1H), 3.27 - 3.19 (m, 1H), 2.75 - 2.63 (m, 1H), 2.58(s, 3H), 2.51 - 2.40 (m, 1H), 2.33 (s, 3H), 2.31 - 2.26 (m, 1H), 2.23 - 2.15(m, 1H), 1.99 - 1.91 (m, 1H), 1.87 - 1.71 (m, 2H). LC-MS (ESI) m / z: 424.1 (M+H) + .

[0930] Example 36

[0931] (R)-2-(5-(hydroxymethyl)-4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0932]

[0933] Step 1: 4-((benzyloxy)methyl)-3-chloro-6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazine

[0934] Under a nitrogen atmosphere, 2-(benzyloxy)acetic acid (200 mg, 1.20 mmol), AgNO3 (20 mg, 0.12 mmol), and K2S2O8 (244 mg, 0.902 mmol) were added to a solution of 6-chloro-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4-methylpyridazine (200 mg, 0.60 mmol) in MeCN (4 mL) and water (4 mL), and the mixture was stirred overnight at 70 °C under a nitrogen atmosphere. The mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (184 mg) as a solid. LC-MS (ESI) (m / z): 453.2 (M+H) + .

[0935] Step 2: (R)-3-((4-cyano-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0936] To a solution of 4-((benzyloxy)methyl)-3-chloro-6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazine (184 mg, 0.41 mmol) in MeCN (5 mL), tert-butyl (R)-3-mercaptopril-1-carboxylate (176 mg, 0.81 mmol) and Cs₂CO₃ (397 mg, 1.22 mmol) were added, and the mixture was stirred at 90 °C for 3 h under a N₂ atmosphere. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (206 mg) as a solid. LC-MS (ESI) (m / z): 634.3 (M+H) + .

[0937] Step 3: (R)-2-(5-(hydroxymethyl)-4-methyl-6-(piperidin-3-ylthio)pyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride

[0938] BCl3 (1 mL, 1 M, in hexane) was added to a solution of (R)-3-((4-((benzyloxy)methyl)-6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidin-1-carboxylic acid tert-butyl ester (194 mg, 0.306 mmol) in DCM (3 mL) under a N2 atmosphere at 0 °C, and the mixture was stirred at room temperature for 3 h. The mixture was quenched with MeOH at 0 °C and concentrated to dryness under reduced pressure to give the title compound (150 mg) as a solid, which was used directly in the next reaction without purification. LC-MS (ESI) (m / z): 400.2 (M+H) + .

[0939] Step 4: (R)-2-(5-(hydroxymethyl)-4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0940] To a solution of (R)-2-(5-(hydroxymethyl)-4-methyl-6-(piperidin-3-ylthio)pyridazin-3-yl)-5-(trifluoromethyl)phenol hydrochloride (150 mg, 0.306 mmol) in MeOH (2 mL), HCHO aqueous solution (0.2 mL, 37 wt%), NaBH3CN (87 mg, 1.382 mmol), and AcOH (0.05 mL, 0.873 mmol) were added, and the mixture was stirred at room temperature under N2 atmosphere for 1 hour. The mixture was quenched with saturated NH4Cl aqueous solution and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250 × 20 mm, 20–60% MeCN in H2O, containing 0.1% NH4HCO3) to give the title compound as a solid (22.6 mg). 1H NMR (400 MHz, CD3OD) δ 7.42 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.9Hz, 1H), 7.19 (s, 1H), 4.76 (s, 2H), 4.40 - 4.27 (m, 1H), 3.24 - 3.14 (m,1H), 2.76 - 2.63 (m, 1H), 2.42 - 2.32 (m, 1H), 2.30 (s, 3H), 2.27 (s, 3H),2.25 - 2.18 (m, 1H), 2.17 - 2.10 (m, 1H), 1.93 - 1.84 (m, 1H), 1.82 - 1.71(m, 1H), 1.65 - 1.53 (m, 1H). LC-MS (ESI) (m / z): 414.1 (M+H) + .

[0941] Example 37

[0942] (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3-yl)thio)pyridazine-4-carboxynitrile

[0943]

[0944] Step 1: (R)-3-((6-chloro-4-cyano-5-methylpyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0945] To a solution of 3,6-dichloro-5-methyl-1,2-diazine-4-carboxynitrile (100 mg, 0.53 mmol) in MeCN (3 mL), tert-butyl (R)-3-mercaptopril-1-carboxylate (173 mg, 0.80 mmol) and DIPEA (206 mg, 1.60 mmol) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0–15% EtOAc in PE) to give the title compound (116 mg) as a solid. LC / MS (ESI) (m / z): 369.0 (M+H) + .

[0946] Step 2: (R)-3-((4-cyano-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0947] At room temperature under a nitrogen atmosphere, tert-butyl piperidine-1-carboxylate (116 mg, 0.31 mmol) in a mixture of (R)-3-((6-chloro-4-cyano-5-methylpyridazin-3-yl)thio)piperidine-1-carboxylate (6 mL) and water (0.6 mL) were added to (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (97 mg, 0.47 mmol), K3PO4 (200 mg, 0.94 mmol), and SPhos Pd G2 (45 mg, 0.063 mmol), and the mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (88 mg) as a solid. LC / MS (ESI) (m / z): 495.1 (M+H) + .

[0948] Step 3: (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3-ylthio)pyridazine-4-carboxynitrile hydrochloride

[0949] To a solution of (R)-3-((4-cyano-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidin-1-carboxylic acid tert-butyl ester (88 mg, 0.16 mmol) in 1,4-dioxane (2 mL), HCl / 1,4-dioxane (2 mL, 4 M) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure to give the title compound (80 mg) as a solid, which was used directly in the next reaction without purification. LC / MS (ESI) (m / z): 395.2 (M+H) + .

[0950] Step 4: (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3-yl)thio)pyridazine-4-carboxynitrile

[0951] To a solution of (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3-ylthio)pyridazine-4-carboxynitrile hydrochloride (80 mg, 0.16 mmol) in MeOH (2 mL), HCHO aqueous solution (0.2 mL, 37 wt%), NaBH3CN (40 mg, 0.63 mmol), and AcOH (0.05 mL) were added sequentially, and the mixture was stirred at room temperature under N2 atmosphere for 1 hour. The mixture was quenched with saturated NH4Cl aqueous solution and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250 × 20 mm, 20–60% MeCN in H2O, containing 0.1% NH4HCO3) to give the title compound as a solid (12.6 mg). 1 H NMR (400MHz, DMSO-d6) δ 10.74 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.0 Hz,1H), 7.27 (s, 1H), 4.58 - 4.34 (m, 1H), 2.90 - 2.74 (m, 1H), 2.49 - 2.44 (m,1H), 2.42 - 2.32 (m, 2H), 2.31 (s, 3H), 2.20 (s, 3H), 1.99 - 1.90 (m, 1H),1.87 - 1.78 (m, 1H), 1.72 - 1.58 (m, 2H). LC / MS (ESI) (m / z): 409.1 (M+H) + .

[0952] Example 38

[0953] (R)-2-(4-methyl-5-((methylamino)methyl)-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0954]

[0955] Step 1: (R)-3-((6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0956] At room temperature, (R)-3-mercaptopril-1-carboxylic acid tert-butyl ester (588 mg, 2.71 mmol) and Cs₂CO₃ (1.76 g, 5.41 mmol) were added to a solution of 6-chloro-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4-methylpyridazine (600 mg, 1.80 mmol) in MeCN (15 mL), and the mixture was stirred at 90 °C for 16 h under a N₂ atmosphere. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-30% EtOAc in PE) to give the title compound (350 mg) as a solid. LC-MS (ESI) m / z: 514.2 (M+H) + .

[0957] Step 2: (R)-3-((4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0958] K₂S₂O₈ (212 mg, 1.17 mmol) and AgNO₃ (20 mg, 0.12 mmol) were added to a mixture of (R)-3-((6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidin-1-carboxylic acid tert-butyl ester (350 mg, 0.58 mmol) in MeCN (5 mL) and water (5 mL) at room temperature under a nitrogen atmosphere. The mixture was degassed three times with nitrogen and stirred overnight at 60 °C. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-40% EtOAc in PE) to give the title compound (280 mg) as a solid. LC-MS (ESI) m / z: 690.7 (M+H) + .

[0959] Step 3: (R)-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3-ylthio)pyridazin-4-yl)methyl)(methyl)carbamate benzyl ester

[0960] To a solution of (R)-3-((4-(((((benzyloxy)carbonyl)(methyl)amino)methyl)-6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidin-1-carboxylic acid tert-butyl ester (280 mg, 0.41 mmol) in 1,4-dioxane (3 mL), HCl / 1 mL, 4 M was added and the mixture was stirred at room temperature for 1 hour. The mixture was alkalized with saturated aqueous NaHCO3 solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (210 mg) as a solid. LC-MS (ESI) m / z: 547.2 (M+H) + .

[0961] Step 4: (R)-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3-yl)thio)pyridazin-4-yl)methyl)(methyl)carbamate benzyl ester

[0962] NaBH3CN (72 mg, 1.15 mmol) was added to a mixture of (R)-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3-ylthio)pyridazin-4-yl)methyl)(methyl)carbamate (210 mg, 0.38 mmol), HCHO aqueous solution (0.2 mL, 37 wt%), and AcOH (46 mg, 0.77 mmol) in MeOH (2 mL) at 0 °C, and the mixture was stirred at room temperature for 30 min. The mixture was quenched with saturated NaHCO3 aqueous solution and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (160 mg) as a solid. LC-MS (ESI) m / z: 560.9 (M+H) + .

[0963] Step 5: (R)-2-(4-methyl-5-((methylamino)methyl)-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0964] BBr3 (1.25 mL, 1 M, in DCM) was added dropwise to a solution of (R)-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3-yl)thio)pyridazin-4-yl)methyl)(methyl)carbamate (140 mg, 0.25 mmol) in DCM (3 mL) at -78 °C, and the mixture was stirred at -78 °C to room temperature for 3 hours. The mixture was quenched with EtOH at -78 °C and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250 × 21 mm, 10 ~ 95% MeCN in H2O, containing 0.1% NH4HCO3) to give the title compound (29 mg) as a solid. 1 H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 7.9Hz, 1H), 7.20 (s, 1H), 4.44 - 4.31 (m, 1H), 3.86 (s, 2H), 3.24 - 3.14 (m,1H), 2.75 - 2.62 (m, 1H), 2.47 (s, 3H), 2.43 - 2.33 (m, 1H), 2.31 (s, 3H),2.25 (s, 3H), 2.24 - 2.22 (m, 1H), 2.17 - 2.11 (m, 1H), 1.93 - 1.85 (m, 1H),1.82 - 1.73 (m, 1H), 1.70 - 1.54 (m, 1H). LC / MS (ESI) m / z: 427.2 (M+H) + .

[0965] Example 39

[0966] (R)-3-chloro-2-(6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol (VS-6959)

[0967]

[0968] Step 1: 3-Chloro-2-iodo-5-(trifluoromethyl)phenol and 5-chloro-2-iodo-3-(trifluoromethyl)phenol

[0969] NaH (4.08 g, 102 mmol, 60% dispersion in mineral oil) was added fractionally to a solution of 3-chloro-5-(trifluoromethyl)phenol (10 g, 51.0 mmol) in toluene (100 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Iodine (12.9 g, 51.0 mmol) was then added fractionally to the mixture at 0 °C, and the mixture was stirred at room temperature for 3 h. The mixture was quenched with a saturated aqueous NH4Cl solution at 0 °C, acidified to pH 5 with 2 M HCl, and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-10% EtOAc in PE) to give a mixture of the title compounds as a solid (13 g). LC-MS (ESI) m / z: 321 (MH) - .

[0970] Step 2: 1-Chloro-2-iodine-3-(methoxymethoxy)-5-(trifluoromethyl)benzene and 5-chloro-2-iodine-1-(methoxymethoxy)-3-(trifluoromethyl)benzene

[0971] DIEA (15.6 g, 121 mmol) was added to a mixture of 3-chloro-2-iodo-5-(trifluoromethyl)phenol and 5-chloro-2-iodo-3-(trifluoromethyl)phenol (13 g, 40.3 mmol) in DCM (150 mL), followed by dropwise addition of MOMCl (4.87 g, 60.5 mmol) at 0 °C. The mixture was stirred at room temperature under a N2 atmosphere for 2 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0–5% EtOAc in PE) to give the title compound (14 g) as an oil in a ratio of approximately 3:1. 1 ¹H NMR (400MHz, CDCl₃) δ 7.39 (d, J = 1.2 Hz, 1H, major), 7.33 (d, J = 2.2 Hz, 1H, minor), 7.25 (d, J = 2.1 Hz, 1H, minor), 7.16 (d, J = 1.4 Hz, 1H, major), 5.30 (s, 2H, major), 5.28 (s, 2H, minor), 3.52 (s, 3H, major and minor).

[0972] Step 3: 2-(2-chloro-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane and 2-(4-chloro-2-(methoxymethoxy)-6-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane

[0973] Under a nitrogen atmosphere, TEA (26.9 mL, 192 mmol), CyJohn Phos (1.34 g, 3.83 mmol), and Pd(OAc)₂ (0.86 g, 3.83 mmol) were added sequentially to a mixture of 1-chloro-2-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzene and 5-chloro-2-iodo-1-(methoxymethoxy)-3-(trifluoromethyl)benzene (14 g, 38.3 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (24.5 g, 192 mmol) in 1,4-dioxane (150 mL). The mixture was degassed three times with nitrogen and stirred overnight at 95 °C under a nitrogen atmosphere. The mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-8% EtOAc in PE) to give the title compound (4.6 g) as an oil in a ratio of approximately 5:2. 1 ¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, J = 1.2 Hz, 1H, minor), 7.24 (s, 1H, major), 7.22 (d, J = 1.2 Hz, 1H, minor), 7.15 (s, 1H, major), 5.18 (s, 2H, major), 5.17 (s, 2H, minor), 3.47 (s, 3H, major and minor), 1.40 (s, 9H, major), 1.38 (s, 9H, minor).

[0974] Step 4: 3-Chloro-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)phenol and 5-Chloro-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3-(trifluoromethyl)phenol

[0975] TFA (30 mL) was added to a mixture of 2-(2-chloro-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane and 2-(4-chloro-2-(methoxymethoxy)-6-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (3.5 g, 9.56 mmol) in DCM (50 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in EtOAc. The mixture was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-25% EtOAc in PE) to give the title compound (0.8 g) as an oil. LC-MS (ESI) m / z: 321 (MH) - .

[0976] Step 5: (R)-3-((6-(2-chloro-6-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester and (R)-3-((6-(4-chloro-2-hydroxy-6-(trifluoromethyl)phenyl)pyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester

[0977] Under a nitrogen atmosphere, a mixture of 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-5-(trifluoromethyl)phenol and 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3-(trifluoromethyl)phenol (614 mg, 1.91 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added to (R)-3-((6-chloropyridazin-3-yl)thio)piperidine-1-carboxylic acid tert-butyl ester (350 mg, 1.06 mmol), Na2CO3 (337 mg, 3.18 mmol), and Pd(PPh3)4 (119 mg, 0.106 mmol). The mixture was degassed three times with nitrogen and stirred at 120 °C for 2 hours under a nitrogen atmosphere. Another portion of 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-5-(trifluoromethyl)phenol and 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3-(trifluoromethyl)phenol (170 mg, 0.53 mmol) and Pd(PPh3)4 (59 mg, 0.053 mmol) were added, and the resulting mixture was further stirred at 120 °C for 16 hours. The mixture was cooled to room temperature, diluted with water, and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, 0-20% EtOAc in PE) to give compound 6 (50 mg), followed by compound 6-1 (200 mg), both solids. Compound 6: 1 HNMR (400 MHz, CD3OD) δ 7.67 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.33 (s, 1H), 7.16 (s, 1H), 4.30 - 4.21 (m, 1H), 3.91 - 3.77 (m, 1H), 3.63 -3.53 (m, 1H), 3.39 - 3.35 (m, 1H), 2.25 - 2.17 (m, 1H), 1.96 - 1.77 (m, 2H),1.68 - 1.61 (m, 1H), 1.45 - 1.30 (m, 10H). LC-MS (ESI) m / z: 490.1 (M+H) + Compound 6-1: 1H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 8.9Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 4.29 - 4.21 (m,1H), 3.86 - 3.79 (m, 1H), 3.60 - 3.52 (m, 1H), 3.41 - 3.35 (m, 1H), 2.23 -2.18 (m, 1H), 1.92 - 1.77 (m, 2H), 1.68 - 1.60 (m, 1H), 1.40 - 1.29 (m, 10H). The structures of compounds 6 and 6-1 are based on their 1 H observed 19 Assigned by F. Hosey spectroscopy, NOE effects were observed between the relevant aromatic protons and CF3 groups for both compounds. LC-MS (ESI) m / z: 490.1 (M+H) + .

[0978] Step 6: (R)-3-chloro-2-(6-(piperidin-3-ylthio)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0979] To a solution of (R)-3-((6-(2-chloro-6-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)thio)piperidin-1-carboxylic acid tert-butyl ester (50 mg, 0.10 mmol) in DCM (1 mL), HCl / 1,4-dioxane (1 mL, 4 M) was added and the mixture was stirred at room temperature for 20 min. The mixture was neutralized with saturated aqueous NaHCO3 solution and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (35 mg) as an oil. LC-MS (ESI) (m / z): 390.0 (M+H) + .

[0980] Step 7: (R)-3-chloro-2-(6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0981] AcOH (10.8 mg, 0.18 mmol) and NaBH3CN (17.0 mg, 0.27 mmol) were added to a mixture of (R)-3-chloro-2-(6-(piperidin-3-ylthio)pyridazin-3-yl)-5-(trifluoromethyl)phenol (35 mg, 0.090 mmol) and HCHO aqueous solution (0.1 mL, 37 wt%) in MeOH (1 mL) at 0 °C, and the mixture was stirred at room temperature for 20 min. The mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250 × 20 mm, 10%–95% MeCN in H2O, containing 0.1% NH4HCO3) to give the title compound (8 mg) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 7.64 (d, J = 8.9 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.29 (s, 1H), 7.14 (s, 1H), 4.33 - 4.26 (m, 1H), 3.26 - 3.23 (m, 1H), 2.77 - 2.74 (m, 1H),2.44 - 2.37 (m, 1H), 2.35 (s, 3H), 2.32 - 2.28 (m, 1H), 2.19 - 2.12 (m, 1H),1.93 - 1.87 (m, 1H), 1.84 - 1.75 (m, 1H), 1.64 - 1.56 (m, 1H). LC-MS (ESI)(m / z): 404 (M+H) + The structure of the title compound was also confirmed by HOESY spectroscopy.

[0982] Example 40

[0983] (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-3-(trifluoromethyl)phenol (VS-6960)

[0984]

[0985] The title compound was prepared according to methods and procedures similar to those described for the synthesis of Example 39. 1HNMR (400 MHz, CD3OD) δ 7.60 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H), 4.32 - 4.25 (m, 1H), 3.25- 3.22 (m, 1H), 2.76 - 2.73 (m, 1H), 2.43 - 2.38 (m, 1H), 2.34 (s, 3H), 2.31- 2.26 (m, 1H), 2.17 - 2.12 (m, 1H), 1.93 - 1.86 (m, 1H), 1.83 - 1.80 (m,1H), 1.63 - 1.54 (m, 1H). LC-MS (ESI) (m / z): 404 (M+H) + The structure of the title compound was also confirmed by HOESY spectroscopy.

[0986] Reference Example

[0987] Reference Example 1

[0988] (R)-2-(4-Methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol

[0989]

[0990] The title compound was prepared according to the procedure in US20200361898. LC / MS (ESI) m / z: 367 (M+H) + .

[0991] See Example 2

[0992] (R)-2-(4-(3-hydroxybutyl)-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol

[0993]

[0994] The title compound was prepared according to the procedure in WO2023003002. LC / MS (ESI) m / z: 367 (M+H) + .

[0995] Reference Examples 3 to 5 in Table 4 were prepared according to the process in WO2022216971. Reference Examples 6 and 7 were prepared according to the processes in WO2023028534 (Compound I-97) and US Patent 11,618,751 (Example 4), respectively.

[0996] Table 4. Reference Examples 3-7

[0997]

[0998] Biological assay examples

[0999] The compounds of the present invention were evaluated in a variety of assays to assess their suitability for potential development. It should be understood that successful development candidates require a combination of potency, pharmacokinetic, and safety properties. Because the inventors are interested in CNS indications, compounds intended for these applications should also have sufficient exposure in brain tissue. While superior properties in one aspect (e.g., potency) may, to some extent, compensate for poor performance in another aspect (e.g., pharmacokinetics), in most cases, superior properties do not guarantee the success of a compound. The key to success is a balance of properties among all relevant parameters. The inventors believe that they have achieved a good balance of properties from some of the compounds disclosed herein.

[1000] Biological assay Example 1: IL-1β inhibition assay in THP-1 cells

[1001] The following protocol was used to evaluate the ability of the test compound to inhibit IL-1β formation in human THP-1 cells:

[1002] 1. Maintain THP-1 cells (ATCC #TIB-202) in complete RPMI-1640 (Gibco A1049101) medium containing 10% heat-inactivated FBS (Gibco 10099141C), 1% L-glutamine (Gibco 25030149), and 1% Pen / Strep (Gibco 15140122).

[1003] 2. On the day of the experiment, THP-1 cells (~5.5 × 10⁻⁶) were... 5 Cells were seeded at 1,000 cells / mL into 384-well plates, with 45 μL of RPMI-1640 medium (FBS-free) per well. Pre-stimulation was performed by adding 1.0 μg / mL LPS (SIGMA, L6529).

[1004] 3. Add 5 μL of serially diluted compound (10 doses starting at 5 μM, 1:3 dilution) or solvent (0.05% DMSO in the culture medium) to the appropriate wells.

[1005] 4. Incubate the cells at 37°C and 5% CO2 for 3 hours. Add 5 μL of Nigeria mycin (MEC, HY-100381) (final concentration 5 μM) to the sample wells and positive control wells to stimulate the cells; add 5 μL of RPMI-1640 medium (without FBS) to the negative control wells.

[1006] 5. After incubating at 37°C and 5% CO2 for 1 hour, transfer 8 μL of the supernatant to a 384-well plate and add 8 μL of RPMI-1640 medium (without FBS) to each well; prepare standard solutions in parallel.

[1007] 6. IL-1β levels were measured using a human IL-1β kit (PerkinElmer, 62HIL1BPEH) according to the manufacturer's instructions; at HTRF ® Reading plates on a compatible plate reader (PE Nivo).

[1008] 7. Data Analysis: The concentration of IL-1β in the treated wells was calculated using a standard curve. IC50 was then used. 50 The data was fitted to a nonlinear regression equation (log inhibitor vs. response-variable slope four-parameter).

[1009] 8. The IC50 or geometric mean of IC50 obtained from THP-1 cells are shown in Table 5. Data >300 nM are listed as +, data 100–300 nM as ++, data 30–100 nM as +++, data 10–30 nM as ++++, data 3–10 nM as +++++, data 1–3 nM as ++++++, and data <1 nM as +++++++. These results indicate that the compounds disclosed herein exhibit potent inhibition of IL-1β formation in THP-1 cells.

[1010] Table 5. Inhibition of IL-1β in THP-1 cells

[1011]

[1012]

[1013] Biological assay Example 2: hERG assay

[1014] The following protocol was used to evaluate the inhibitory potential of compounds on the hERG (human Ether-à-go-go related gene) channel in CHO-hERG cells using the QPatch automated patch-clamp system.

[1015] Methods: CHO cells stably expressing the hERG transcript were studied using the QPatch system (Sophion) via automated whole-cell patch-clamp technique. Cells were incubated at 37°C, 5% CO2 in F12 medium supplemented with serum at 175 cm⁻¹. 2 Cells were grown in flasks. Two days after plating (at 70-80% confluence), the culture medium was removed and the cells were washed with 7 mL of PBS (phosphate-buffered saline), then treated with 3 mL of Detachin at 37°C for 2 minutes. Subsequently, 7 mL of serum-free medium was added, and the cells were cultured at 2-5 × 10⁶ cells / mL. 6 Cells were resuspended in growth medium at a density of 10 cells / mL. The cell suspension was then transferred to a QPatch system and centrifuged; the cells were washed and resuspended in extracellular fluid (mM): 140 NaCl, 5 KCl, 1 CaCl2, 1.25 MgCl2, 10 HEPES, and 10 glucose, adjusted to pH 7.4 with NaOH. The intracellular fluid composition (mM) was: 140 KCl, 1 MgCl2, 1 CaCl2, 10 EGTA, and 10 HEPES, adjusted to pH 7.2 with KOH. Cells were held at -80 mV and activated by a pre-pulse of +40 mV for 5 s, followed by a step to -50 mV for 5 s. The voltage protocol was repeated every 15 seconds, and the peak tail current induced by the -50 mV step was recorded and measured as the test parameter. After a 5-minute baseline recording in the extracellular fluid, the solution containing the compound was applied to the cells for 2.5 minutes. Each cell was subjected to six incremental concentrations. Each concentration was tested on at least three cells (n≥3). The reference compound, cisapride, was administered at the end of the test compound addition.

[1016] Data Analysis: Data were extracted and analyzed using measurement software v5.6.4, GraphPad Prism 8, and Excel provided by Sophion. The concentration of the compound that blocked 50% of the hERG current (IC50) was determined. 50 This is obtained by fitting the normalized concentration-inhibition relationship to the following equation in Prism 8 software:

[1017]

[1018] Where Y is the inhibition percentage corresponding to X, [X] is the logarithm of the compound concentration in the external solution, and Hill Slope is the Hill coefficient. The inhibition rate is calculated using the following equation: Inhibition = (1 - I / Io) × 100%, where Io and I are the hERG current amplitudes measured at -50 mV with and without the test compound.

[1019] The results of the hERG determination are shown in Table 6. The results show that the compounds from this disclosure exhibit more favorable hERG properties compared to compounds from the prior art.

[1020] Table 6. Inhibitory potential of compounds on hERG channels

[1021]

[1022] #Data from WO2023 / 066377

[1023] Biological assay Example 3: Brain permeation (K) of the compound in mice p and K p,uu )

[1024] The total brain / plasma ratio was assessed in C57BL / 6 mice following oral administration of the compound at a dose of 30 mg / kg. For each time point, a cohort of three male C57BL / 6 mice (6–9 weeks old, approximately 30 g, from Vital River, Shanghai, China) were administered the compound orally by gavage after an overnight fast. If the endpoint time point was more than 4 hours post-administration, food was provided 4 hours after administration. The test compound was prepared at 3.0 mg / mL in a 1:1 PEG400 and saline solution, administered at a volume of 10 mL / kg. At the designed time points, approximately 40.0 µL of whole blood was collected via the facial vein into EDTA-K2 tubes and placed on ice. Blood samples were centrifuged at 12,000 rpm for 10 min at 4 °C to obtain plasma, which was then immediately frozen and stored at -75 ± 15 °C prior to analysis. After the last whole blood collection, animals were euthanized with CO2 and perfused with saline via the left ventricle. Whole brain tissue was then collected and rinsed with cold saline, dried on filter paper, weighed, and flash-frozen on dry ice. The brain tissue samples were then transferred to a freezer at -75±15°C until analysis. For analysis, the brain samples were homogenized with buffer (methanol:15mM PBS = 1:2) at a ratio of 1:4 tissue weight (g) to buffer volume (mL). The samples were then processed using an AB Sciex Triple Quad buffer. TM On a 4500 instrument, plasma and brain drug levels were quantified by LC-MS / MS using a ZORBAX Eclipse XDB-C18 column, 3.5µm (or 5µm) 2.1×50 mm. Quantification was performed using calibration curves prepared in blank plasma or blank brain homogenate. Brain / plasma ratio (K0.05) was also used. p The total brain drug concentration is typically calculated as the total plasma drug concentration divided by the total brain drug concentration, both expressed as the area under the curve (AUC). In this case, the inventors also use K... pThe ratio of total brain drug concentration to total plasma drug concentration at each time point is used as a measure of brain penetration.

[1025] Plasma protein binding and brain homogenate protein binding were measured using equilibrated dialysis using a 96-well equilibrated dialysis plate (HTDialysis) fitted with a dialysis membrane with a molecular weight cutoff of 12-14 kDa. The dialysis membrane was immersed in ultrapure water for 60 minutes to separate the strip, then in 20% ethanol for 20 minutes, and finally in ultrapure water for 20 minutes. The dialysis apparatus was assembled according to the manufacturer's instructions. Each cell received 150 μL of plasma or brain homogenate (1 g brain tissue + 4 mL dialysis buffer) supplemented with 1 μM of the test compound, and dialyzed with an equal volume of dialysis buffer (100 mM sodium phosphate and 150 mM sodium chloride, pH 7.4 ± 0.1). The dialysis plate was sealed and incubated at 37°C and 5% CO2 at 100 rpm for 4 hours. At the end of the incubation, after separation on a ZORBAX Eclipse XDB-C18, 3.5 μm (or 5 μm) 2.1 × 50 mm column, the sample was transferred to a Triple Quad column from ABSciex. TM The concentrations of the compound in both chambers were measured by LC-MS / MS at a 4500. The peak area ratio between the test compound and the internal standard in the buffer (receiving cell) chamber (F) or the plasma or brain homogenate chamber (T) was calculated. The free fraction in plasma (f) was calculated using the following equation. u,pl ) or the free fraction in the brain (f u,br ), where D is the dilution factor used to prepare brain homogenate, which is 5 in this case.

[1026]

[1027] K p,uu The ratio of free brain to free plasma concentration is generally defined as the ratio of unbound (free) AUC between brain and plasma: AUC br × f u,br / AUC pl × f u,pl In this case, the inventor will also include K. p,uu The ratio of the drug concentration in the brain to the drug concentration in the plasma at various time points is used as a measure of brain penetration.

[1028] The results of the selected compounds in mouse brain permeation assays are shown in Table 7. These data indicate that some compounds of the present invention exhibit surprisingly higher free brain exposure and much higher free brain / free plasma concentration ratios compared to most compounds from the prior art. The higher free brain exposure from the compounds of the present invention is even more advantageous when considering their potency. Some SARs are also quite surprising and unexpected. For example, the significant changes in the relative protein binding between plasma and brain in Examples 1 and 6 resulted in Example 6 having a significantly higher K0 than Example 1. p,uu The ratio, even if the overall brain / plasma ratio shows the opposite trend.

[1029] Table 7. CNS permeability of the compound in C57BL / 6 mice after oral administration

[1030]

[1031] Biological assay Example 4: Pharmacokinetic characteristics of the compound in rats

[1032] The pharmacokinetic characteristics of the compound administered intravenously (iv) and orally (po) were evaluated in male SD rats (6-9 weeks old, 200-250 g body weight, from Vital River, Shanghai, China). Six rats were randomly assigned to two groups (N=3 / group): an IV (1 mg / kg) administration group and a PO (2 mg / kg) administration group. Appropriate amounts of the compound were weighed, and PEG400 and saline were added in a 1:1 mixture to prepare drug solutions at concentrations of 0.5 mg / mL for IV administration or 0.2 mg / mL for PO administration. Animals in the PO group were fasted overnight but allowed free access to water, and were provided with food 4 hours after administration. Animals in the IV group had free access to food and water. Blood was collected at several time points up to 24 hours later. Approximately 150 μL of whole blood was collected via the jugular or tail vein into EDTA-K2 tubes and placed on ice. The whole blood samples were then centrifuged at 4°C and 12,000 rpm for 10 minutes within 30 minutes of collection. Take approximately 50 µL of plasma and place it in a labeled 1.5 mL tube. Store the tube at -75 ± 15°C before analysis. After separation on a ZORBAX Eclipse XDB-C18 column (3.5 µm 2.1 × 50 mm or 5 µm 4.6 × 50 mm), analyze using a Triple Quad column from ABSciex. TM Plasma concentrations of the test compounds were determined using liquid chromatography-tandem mass spectrometry (LC-MS / MS) on a 4500 plasma. Quantification was performed using calibration curves prepared in blank plasma. Pharmacokinetic analysis (t-time) was performed using WinNonlin software (Phoenix) via statistical moments with a non-compartmental model from concentration-time data. 1 / 2AUC last C max T max and MRT last wait).

[1033] Alternatively, brain samples were collected at the final time point, and drug concentrations were analyzed using methods similar to those described in the mouse experiments above. Similarly, the free fractions in rat plasma and brain were also determined to provide K+ from the rats. p and K p,uu In another screening mode, multiple compounds are administered as a mixture to the same group of rats to obtain a set of pharmacokinetic profiles of the compounds to be compared in the same animals.

[1034] The results of the pharmacokinetic characteristics of the selected compounds of the present invention in rats are shown in Table 8. These data indicate that some of the compounds of the present invention exhibit attractive pharmacokinetic characteristics in rats. Some results were unexpected. For example, due to the higher lipophilicity and the addition of three metabolically unstable benzyl hydrogens, Example 6 was expected to have a higher clearance rate than Example 1. However, a significant decrease in clearance rate and an increase in half-life and exposure were observed.

[1035] Table 8. Pharmacokinetic characteristics of the selected compounds in SD rats

[1036]

[1037] The combined results of the compounds in this invention demonstrate an excellent combination of properties in terms of potency, safety, brain penetration, and preclinical pharmacokinetics. Therefore, they show potential for further development.

[1038] Although this disclosure includes references to various embodiments or examples, it should be understood that these embodiments and examples are merely illustrative of certain aspects of the principles and applications of the invention. Many modifications may be made to the illustrative embodiments, and other configurations may be designed that are intended to be covered by this disclosure, without departing from the spirit and scope of the invention. All patent or non-patent references cited in this application are incorporated herein by reference in their entirety, without acknowledging any of them as prior art.

Claims

1. A compound having the structure of Formula I or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof: , (I) in: Indicates a single bond or a double bond; X is NR1, CH2, O, S, or a bond; R1 is H, alkyl, cycloalkyl, alkyl-CO- or heterocyclic, wherein each of the alkyl, cycloalkyl, alkyl-CO- or heterocyclic group is optionally substituted by 1 to 5 groups independently selected from R7; R2 is independently selected from R7 each time it appears, or two R2 groups and the connecting atom between them form a 3- to 6-membered ring optionally containing one or two heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted by one to five groups independently selected from R7; or two non-adjacent R2 groups together form a 1- to 3-membered bridge optionally containing a heteroatom selected from O, N, and S, wherein the bridge is optionally substituted by one to three substituents independently selected from R7; Alternatively, R1 and the adjacent R2 and the connecting atom in between form a 5- or 6-membered heterocyclic group that optionally includes an additional heteroatom independently selected from O, N and S, wherein the heterocyclic group is optionally substituted by 1 to 3 groups independently selected from R7. W1 and W2 together are selected from: (i) both are empty, (ii) both are O, (iii) empty and O, and (iv) NR3 and O, wherein R3 is H, alkyl, cycloalkyl, alkyl-CO-, CN, NO2, aryl or heteroaryl, wherein each of the alkyl, cycloalkyl, alkyl-CO-, aryl and heteroaryl is optionally substituted by 1 to 5 groups independently selected from R8; Alternatively, R3 and R2 together with the connecting atoms between them form a 5- to 8-membered heterocycle, which optionally contains an additional heteroatom independently selected from O, N, and S and optionally is substituted by 1 to 3 groups independently selected from R7. Y is CR 4a N or C=O; Z is CR 4b The value of Y is N or N-R9, provided that Y and Z are not both N; and if Y is C=O, then Z is N-R9. Alternatively, Y and Z together form S; Alternatively, Y and Z together form part of an existing 5- to 7-membered carbon ring, 5- to 7-membered heterocycle, 6-membered aromatic ring, or heteroaromatic ring, or 5-membered heteroaromatic ring, fused with an existing ring containing NN, each ring optionally being composed of 1 to 3 independently selected from R. 4a R 4b R9, R 10 and R 11 Substituents of the substituents; R 4a and R 4b Independently selected from H, alkyl, cycloalkyl, CN, haloalkyl, phenyl, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-NHR 9 and -C 1-6 Alkyl-N(R) 9 )2; R5 represents OH and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R6 is independently selected from hydrogen and C each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5- or 6-membered heterocyclic, 5- or 6-membered heteroaryl, halogen, CN, SF5, NHR9, N(R9)2, OR9, and SR9; Alternatively, two adjacent R6 groups together with the connecting atom between them form a 5- or 6-membered carbon ring, heterocycle, aromatic ring, or heteroaromatic ring that is fused with the existing benzene ring; R7 is selected independently from H and C each time it appears. 1-6 Alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2 and CO2R9; R8 is selected independently from H and C each time it appears. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl halogens, CN, phenyl groups, and halogens; R9 is independently H or C each time it appears. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl; R 10 Each occurrence is independently H or C. 1-6 Alkyl, C 3-6 cycloalkyl, halogen, or CF3; R 11 Each occurrence is independently H or C. 1-6 Alkyl, C 3-6 cycloalkyl or =O; m is 0, 1, or 2; n can be 0, 1, 2, 3 or 4, provided that m + n ≥ 2; i is 0, 1, 2, 3, or 4; and j is 0, 1, 2, 3, or 4.

2. The compound according to claim 1, or its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs, wherein: X is NR1, CH2, O, S, or a bond; R1 represents H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 alkyl-CO-, 4-6 membered heterocyclic group, wherein the C 1-5 Alkyl, C 3-6 cycloalkyl, C 1-4 The alkyl-CO- and 4-6-membered heterocyclic groups are each optionally substituted by 1 to 3 independently selected groups from R7; R2 is independently selected from R7 each time it appears, or two R2 groups and the connecting atom between them form a 3- to 6-membered ring that optionally contains a heteroatom selected from O, N and S, and the ring is optionally substituted by one or two groups independently selected from R7; or two non-adjacent R2 groups together form a 1- to 3-membered bridge that optionally contains a heteroatom selected from O, N and S, wherein the bridge is optionally substituted by one to three substituents independently selected from R7; Alternatively, R1 and the adjacent R2 and the connecting atom in between form a 5- or 6-membered heterocyclic group that optionally includes an additional heteroatom selected from O, N and S, wherein the heterocyclic group is optionally substituted by 1 to 3 groups independently selected from R7. W1 and W2 are selected together from: (i) both are empty, (ii) both are 0, (iii) empty and 0, and (iv) NR3 and 0, where R3 is H and C. 1-5 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkyl-CO, CN, NO2, C6 aryl, or optionally substituted with 1 to 3 groups independently selected from R8, 5- or 6-membered heteroaryl; Alternatively, R3 and R2 together with the connecting atoms in between form a 5- to 8-membered heterocycle, which optionally includes an additional heteroatom selected from O, N, and S as part of the ring, and optionally is substituted by one or two groups independently selected from R7. Y is CR 4a N or C=O; Z is CR 4b The value of Y is N or N-R9, provided that Y and Z are not both N; and if Y is C=O, then Z is N-R9. Alternatively, Y and Z together form S; Alternatively, Y and Z together are a 5- to 7-membered carbon ring, a 5- to 7-membered heterocyclic ring, a 6-membered aromatic ring, or a heterocyclic ring, or a 5-membered heterocyclic ring, wherein the ring is optionally selected independently by one or two of R. 4a R 4b R9, R 10 and R 11 Substituents of the substituents; R 4a and R 4b Independently selected from H and C 1-4 Alkyl, C 3-6 cycloalkyl, CN, CF3 or phenyl; R5 is OH, OCHF2, OCF3, CHF2, CF3, CF3CH2, or OMe; R6 is independently selected from H, CF3, CF2CF3, OCF3, and C each time it appears. 3-6 cycloalkyl, C 1-4 Alkyl, CHF2, OCHF2, halogen, CN, SF5, NHR9, N(R9)2, OR9 and SR9; Alternatively, the two R6 groups together with the connecting atom between them form a 5- or 6-membered carbon ring, heterocycle, aromatic ring, or heteroaromatic ring that fused with the existing benzene ring; R7 is selected independently from H and C each time it appears. 1-4 Alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2 and CO2R9; R8 is selected independently from H and C each time it appears. 1-4 Alkyl, cyclopropyl, CF3, CHF2, CN, phenyl, and halogens; R9 is independently H or C each time it appears. 1-4 Alkyl or cyclopropyl; R 10 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, halogen, or CF3; R 11 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, or =O; m is 0, 1, or 2; n can be 0, 1, 2, 3 or 4, provided that m + n ≥ 2; i can be 0, 1, 2, or 3; and j can be 0, 1, or 2.

3. The compound according to claim 1, or its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts or prodrugs, wherein: X is NR1 or O; R1 is hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-C(O)OR 9 Or 4- to 6-membered heterocyclic groups, each group other than hydrogen is optionally composed of 1 to 3 independently selected C 1-4 Substitution with alkyl, halogen, CN, =O, OR9, SR9, NHR9 and N(R9)2 groups; R2 is selected independently from C each time it appears. 1-6 Alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9, or two adjacent R2 groups and a connecting atom between them, form a 5- or 6-membered ring optionally comprising one or two heteroatoms independently selected from O, N, and S, wherein the ring is optionally surrounded by one to three heteroatoms independently selected from C. 1-4 The groups are substituted with alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9 groups; or two non-adjacent R2 groups are optionally formed by one or two independent groups selected from C. 1-4 C substituents of alkyl, halogen, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9 1-3 Alkyl bridges; W1 and W2 together are selected from: (i) both are empty, (ii) both are 0, and (iii) empty and 0; Y is CR 4a Or N; Z is CR 4b Or N, provided that Y and Z are not both N at the same time; Alternatively, Y and Z together are a 5- or 6-membered carbon ring, a 5- or 6-membered heterocyclic ring, a 6-membered aromatic ring or heteroaromatic ring, or a 5-membered heteroaromatic ring, each of which is fused with an existing ring comprising N and N, and each is optionally composed of 1 to 3 independently selected from halogens, CN, =O (excluding aromatic and heteroaromatic rings), C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl, phenyl, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-NHR 9 and -C 1-6 Alkyl-N(R) 9 Substitution of )2 by substituents; R 4a and R 4b Independently selected from H and C 1-6 Alkyl, C 3-6 cycloalkyl, CN, C 1-6 Halogenated alkyl, phenyl, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-NHR 9 and -C 1-6 Alkyl-N(R) 9 )2; R5 represents OH and C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups; R6 is independently selected from hydrogen and C each time it appears. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5- or 6-membered heterocyclic, 5- or 6-membered heteroaryl, halogen, CN, NHR9, N(R9)2, OR9 or SR9; R9 is independently H or C each time it appears. 1-4 Alkyl, or C 1-4 Halogenated alkyl, or C 3-6 cycloalkyl; m is 1 or 2; n is 1, 2, or 3; i is 0, 1, 2, or 3; and j is 1, 2, or 3.

4. The compound according to any one of claims 1-3, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Ia): ， (Ia) Wherein X, m, n, R2, Y, Z, R5 and R6 are as defined in any one of claims 1-3.

5. The compound according to any one of claims 1-4, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein... Selected from: in: Z1, Z2, Z3, and Z4 are independently selected from CR 10 and N, provided that at most one of them is N; Z5 is O, NR9, S, SO or SO2; Y 1 For key, CHR 11 Or SO2; o and p are selected from the following combinations: q = 0, 1, or 2; and All other groups are as defined in any one of claims 1-3.

6. The compound according to claim 4 or 5, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Ia-1): ， (Ia-1) in: X is NR1 or O; Y and Z are as defined in claim 5; R5 is independently selected from OH, halogen, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy and C 1-2 Halogenated alkoxy groups; R 6a Independently selected from halogen, CN, OR9, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl; R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; R9 is either H or C each time it appears. 1-4 alkyl.

7. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Ib): ， (Ib) Where n1 = 0, 1 or 2; and R1, R2, Y, Z, R5 and R6 are as defined in any one of claims 1-5.

8. The compound according to claim 7, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Ib-1): ， (Ib-1) in: Y and Z are as defined in claim 5; n1 is either 0 or 1; R5 is independently selected from OH, halogen, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy and C 1-2 Halogenated alkoxy groups; R 6a Independently selected from halogen, CN, OR9, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl; R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; R9 is either H or C each time it appears. 1-4 alkyl.

9. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Ic): (Ic) in: r is 0, 1, or 2; and Y, Z, R1, R2, j, R6, and R7 are as defined in claim 4 or 5.

10. The compound according to claim 9, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Ic-1): ， (Ic-1) in: r is 0 or 1; Y and Z are as defined in claim 5; R5 is independently selected from OH, halogen, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy and C 1-2 Halogenated alkoxy groups; R 6a Independently selected from halogen, CN, OR9, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl; R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and R9 is either H or C each time it appears. 1-4 alkyl.

11. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Id): ， (Id) X, R2, m, n, Y, Z and R6 are defined as in any one of claims 1-4.

12. The compound according to claim 11, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Id-1): ， (Id-1) in: X is NR1 or O; Y and Z are as defined in claim 5; R 6a Independently selected from halogen, CN, OR9, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl; R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and R9 is either H or C each time it appears. 1-4 alkyl.

13. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Ie): ， (Ie) in: n1 = 0 or 1; and R1, R2, Y, Z and R6 are as defined in any one of claims 1-5.

14. The compound according to claim 13, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Ie-1): ， (Ie-1) in: n1 = 0 or 1; Y and Z are as defined in claim 5; R 6a Independently selected from halogen, CN, OR9, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl; R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and R9 is either H or C each time it appears. 1-4 alkyl.

15. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (If): ， (If) in: n1 = 0 or 1; and R1, R2, i, j, R 4a R 4b R6 is as defined in any one of claims 1-5.

16. The compound according to claim 15, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein: n1 is 1; i is 0, 1, or 2; j is 1 or 2; R1 is hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 or -C 1-6 Alkyl-C(O)OR 9 ; R2 is independently hydrogen or C each time it appears. 1-6 Alkyl or halogen; or two non-adjacent R2 groups together forming a C group optionally substituted with one or two independent substituents selected from R7. 1-3 Alkyl bridges; R 4a and R 4b Independently selected from H and C 1-6 Alkyl, CN, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-NHR 9 and -C 1-6 Alkyl-N(R) 9 )2; R5 represents OH, halogen, or C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups; R6 is independently selected from hydrogen, halogen, CN, OR9, and C each time it appears. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl; R7 is hydrogen, C 1-4 Alkyl, halogen, or OR9; and R9 is either H or C each time it appears. 1-4 alkyl.

17. The compound according to claim 15 or 16, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (If-1): ， (If-1) in: R1 is -CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2OH; R2 is either H or F; R 4a It can be H, CN, -CH3, -CH2OH or -CH2NHCH3; R 4b It is H or -CH3; R5 is -OH, -CF3, or -OCHF2; R6 can be H, F, Cl, -CF3, or -CH3; and R 6a -CF3, -CH3, cyclopropyl, Cl or .

18. The compound according to claim 15 or 16, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (If-2): ， (If-2) in: r is 0, 1, or 2; R1 is hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 or -C 1-6 Alkyl-C(O)OR 9 ; R2 is hydrogen, C 1-6 Alkyl or halogen; R 4a and R 4b Independently selected from H and C 1-6 Alkyl, CN, C 1-6 Halogenated alkyl, -C 1-6 Alkyl-OR 9 -C 1-6 Alkyl-NHR 9 and -C 1-6 Alkyl-N(R) 9 )2; R5 represents OH, halogen, or C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups; R6 is independently selected from hydrogen, halogen, CN, OR9, and C each time it appears. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl; R7 is C 1-4 Alkyl, halogen, and OR9; and R9 is either H or C each time it appears. 1-4 alkyl.

19. The compound according to claim 18, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (If-2-a): ， (If-2-a) in: R1 is -CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2OH; R 4a It can be H, CN, -CH3, -CH2OH or -CH2NHCH3; R 4b It is H or -CH3; R5 is -OH, -CF3, or -OCHF2; R6 can be H, F, Cl, -CF3, or -CH3; and R 6a -CF3, -CH3, cyclopropyl, Cl or .

20. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Ig): ， (Ig) in: n1 = 0 or 1; R1, R2, R5, R6 and R 10 As defined in any one of claims 1-5; and Z1, Z2, Z3, and Z4 are each independently CR 10 Or N, provided that no more than one of them is N.

21. The compound of claim 20, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has a structure of formula (Ig-1), (Ig-2), or (Ig-3): ， in: i is 0, 1, or 2; R1 is independently hydrogen or C each time it appears. 1-6 Alkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 or -C 1-6 Alkyl-C(O)OR 9 ; R2 is independently hydrogen or C each time it appears. 1-6 Alkyl or halogen; R5 is independently OH, halogen, or C each time it appears. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups; R 6a Each occurrence is independently selected from halogen, CN, OR9, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl; R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; R9 is either H or C each time it appears. 1-4 Alkyl; and R 10 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, halogen, or CF3.

22. The compound according to claim 20 or 21, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0; R1 is -CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2OH; R5 is -OH, -CF3, or -OCHF2; R6 can be H, F, Cl, -CF3, or -CH3; and R 6a -CF3, -CH3, cyclopropyl, Cl or ;and R 10 For H.

23. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has a structure of formula (Ih), (Ii), or (Ij): ， in: n1 = 0 or 1; and R1, R2, R5, R6 and R 10 As defined in any one of claims 1-4.

24. The compound according to claim 23, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has a structure of formula (Ih-1), (Ii-1), or (Ij-1): ， in: i is 0, 1, or 2; R1 is independently hydrogen or C each time it appears. 1-6 Alkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 or -C 1-6 Alkyl-C(O)OR 9 ; R2 is independently hydrogen or C each time it appears. 1-6 Alkyl or halogen; R5 is independently OH, halogen, or C each time it appears. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups; R 6a Each occurrence is independently selected from halogen, CN, OR9, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl; R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; R9 is either H or C each time it appears. 1-4 Alkyl; and R 10 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, halogen, or CF3.

25. The compound according to claim 24, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0; R1 is -CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2OH; R5 is -OH, -CF3, or -OCHF2; R6 can be H, F, Cl, -CF3, or -CH3; and R 6a -CF3, -CH3, cyclopropyl, Cl or ;and R 10 It can be H or -CH3.

26. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Ik): ， (Ik) in: n1 = 0 or 1; i is 0, 1, or 2; q is 0 or 1; Y 1 For -CH2- or -S(O)2-; and R1, R2, R5, R6 and R 11 As defined in any one of claims 1-5.

27. The compound according to claim 26, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Ik-1), (Ik-2), or (Ik-3): ， in: i is 0, 1, or 2; R1 is independently hydrogen or C each time it appears. 1-6 Alkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 or -C 1-6 Alkyl-C(O)OR 9 ; R2 is independently hydrogen or C each time it appears. 1-6 Alkyl or halogen; R5 is independently OH, halogen, or C each time it appears. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups; R 6a Each occurrence is independently selected from halogen, CN, OR9, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl; R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; R9 is either H or C each time it appears. 1-4 Alkyl; and R 11 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, halogen, or CF3.

28. The compound according to claim 27, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0; R1 is -CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2OH; R5 is -OH, -CF3, or -OCHF2; R6 can be H, F, Cl, -CF3, or -CH3; and R 6a -CF3, -CH3, cyclopropyl, Cl or ;and R 11 Each occurrence is independently H or C. 1-4 Alkyl, cyclopropyl, or =O.

29. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Il): ， (I-l) in: n1 = 0 or 1; and R1, R2, R 4b R5 and R6 are as defined in any one of claims 1-5.

30. The compound according to claim 29, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (11-1): ， (I-l-1) in: i is 0, 1, or 2; R1 is independently hydrogen or C each time it appears. 1-6 Alkyl, C 1-6 Alkyl-CO-, -C 1-6 Alkyl-OR 9 or -C 1-6 Alkyl-C(O)OR 9 ; R2 is independently hydrogen or C each time it appears. 1-6 Alkyl or halogen; R 4b For H, C 1-6 Alkyl, CN or C 1-6 Halogenated alkyl groups, R5 is independently OH, halogen, or C each time it appears. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy or C 1-2 Halogenated alkoxy groups; R 6a Each occurrence is independently selected from halogen, CN, OR9, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, 5-membered heterocyclic and 5-membered heteroaryl; R6 is independently selected from hydrogen, halogen, OR9, and C each time it appears. 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and R9 is either H or C each time it appears. 1-4 alkyl.

31. The compound according to claim 30, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0; R1 is -CH3, -CH2CH3, -CH(CH3)2 or -CH2CH2OH; R 4b It is H or -CH3; R5 is -OH, -CF3, or -OCHF2; R6 can be H, F, Cl, -CF3, or -CH3; and R 6a -CF3, -CH3, cyclopropyl, Cl or .

32. The compound according to claim 1 or 2, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (Im): ， (Im) in: n = 0 or 1; and R1, R2, R6 and R9 are as defined in claim 1 or 2.

33. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (In): ， (In) Wherein Y, Z, R2, m, n, i and R6 are as defined in any one of claims 1-5.

34. The compound according to claim 33, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the structure of formula (In-1): ， (In-1) in: i can be 0, 1, 2, or 3; R2 is H, F, or -CH3; R 4a It can be H, CN, -CH3, -CH2OH or -CH2NHCH3; R 4b It is H or -CH3; R5 is -OH, -CF3, or -OCHF2; R6 can be H, F, Cl, -CF3, or -CH3; and R 6a -CF3, -CH3, cyclopropyl, Cl or .

35. The compound according to claim 1 or 2, or a stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt or prodrug thereof, wherein the compound is selected from Examples 1-40.

36. A pharmaceutical composition comprising a therapeutically effective amount of the compound or its stereoisomers, tautomers, isotopic derivatives, pharmaceutically acceptable salts or prodrugs according to any one of claims 1 to 35, and one or more pharmaceutically acceptable carriers.

37. A method for treating or preventing a disease or condition that responds to inhibition of NLRP3 in a subject in need, the method comprising administering to the subject an effective amount of a compound or stereoisomer, tautomer, isotopic derivative, pharmaceutically acceptable salt or prodrug, or pharmaceutical composition according to claim 36.

38. A method for treating or preventing a disease or condition in a subject in need, the method comprising administering to the subject an effective amount of a compound or stereoisomer, tautomer, isotope derivative, pharmaceutically acceptable salt or prodrug, or pharmaceutical composition according to any one of claims 1 to 35, wherein the disease or condition is a neurodegenerative disease, a metabolic disease, an inflammatory syndrome, an autoinflammatory disease, cancer, or a genetic disease.

39. The method of claim 28, wherein the neurodegenerative disease is Parkinson's disease or Alzheimer's disease; the metabolic disease is type 2 diabetes or atherosclerosis; the inflammatory disease is gout or osteoarthritis; the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis; the cancer is lung cancer; and the hereditary disease is cryopyridine-associated periodic syndrome.

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