Substituted pyridazine compounds as inhibitors of nlrp3 activity and therapeutic uses thereof

Abstract

This application discloses novel substituted pyridazine compounds and analogues, their preparation, pharmaceutical compositions comprising them, and their therapeutic uses as medicaments for treating diseases or disorders associated with modulation of cytokines such as IL-1β and IL-18, modulation of NLRP3, or inhibition of the activation of NLRP3 or related components of the inflammatory process.

Description

[0001]Docket No.: 358117.00008 SUBSTITUTED PYRIDAZINE COMPOUNDS AS INHIBITORS OF NLRP3 ACTIVITY AND THERAPEUTIC USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority and benefits 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. FIELD OF THE DISCLOSURE This application relates to pyridazine compounds and analogues as modulators of cytokines such as IL-1β and IL-18, or NLRP3, and their methods of preparation and therapeutic uses. BACKGROUND OF THE DISCLOSURE Nucleotide-binding oligomerization domain-like receptors (or NOD-like receptors, NLRs) are a family of pattern recognition receptors (PPRs), acting as intracellular sensors of pathogen-associated molecular patterns (PAMPs) and damage- or danger- associated molecular patterns (DAMPs). NLRP3 can be activated by a large assortment of stimuli. Accumulating evidences indicate that NLRs play important roles in innate immune responses against infection and cellular damages. Among numerous NOD-like receptors, Nucleotide-binding oligomerization domain, leucine-rich repeat receptor and pyrin-domain containing protein 3 (NLRP3) has been well characterized to form inflammasome involving its oligomers which recruits the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and the effector zymogen caspase-1. The formation of NLRP3 inflammasome activates caspase-1, which in turn catalyzes proteolytic reactions, releasing pro-inflammatory cytokines such as interleukin-1β (IL-lβ) and IL- 18 [Nat. Rev. Immunol. 2013 June;13(6):397-411]. NLRP3 inflammasome activation also leads to cleavage of Gasdermin D (GSDMD) which causes pyroptosis, a rapid and pro-inflammatory form of cell death resulting from membrane pore-forming fragments from GSDMD. 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 cause hereditary diseases such as Cryopyrin-associated periodic syndrome (CAPS). In addition, aberrant activation of NLRP3 1 160112428.1 Docket No.: 358117.00008 inf1ammasomes exacerbates chronic human diseases such as neurodegenerative disorders (multiple sclerosis, Alzheimer disease and Parkinson disease), metabolic ailments (atherosclerosis and type 2 diabetes), and inflammatory diseases (gout flares and osteoarthritis). More recently, roles of NLRP3 in the initiation and progression of cancers have been documented [Nat. Immunol. 2021 May;22(5):550- 559,doi:10.1038 / s41590-021-00886-5]. A few biologic therapies targeting NLRP3 / IL-1β innate immunity pathway have been approved. They include Anakinra (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, where treatment with Canakinumab resulted in a significantly lower rate of recurrent cardiovascular events, demonstrating a clear benefit of targeting inflammation in high-risk patients with cardiovascular diseases. Targeting NLRP3 activation by small molecules is also feasible as exemplified by CRID3 (also known as MCC950). The direct binding of CRID3 with full-length NLRP3 and one of its analogs with NACHT domain of NLRP3 have been demonstrated by cryo-EM structures [Nature 2022; 604:184-189; J Mol Biol. 2021 Dec 3;433(24);167309]. Potential benefits of targeting NLRP3 using specific small molecule inhibitors instead of targeting IL-1β using biologics include sparing the other IL-1β producing inflammasomes with specific NLRP3 inhibitors and typically much shorter half-life of small molecule drugs compared to biologics (for example, the half-life of Canakinumab in humans is 28 days). The latter enables quick withdrawal when needed, for example, in the event of an infection. CRID3 (CP-456,773) was discovered by researchers at Pfizer in the late 1990s before its target was understood [US patent 6,166,064, 2000 Dec 26; J Pharmacol. Exp Ther 2001;299:187-197]. Its clinical studies were halted, and speculation was due to safety concerns. Since the identification of its biological target as NLRP3 in 2015 [Nat. Med.2015;21:248–255. doi: 10.1038 / nm.3806], several largely peripherally distributed NLRP3 inhibitors have entered clinical trials. However, CRID3 and its derivative have proven to be far from brain penetrant as commonly defined in the field. Although a few NLRP3 inhibitors in early clinical trials were claimed to be CNS penetrant, the CNS penetration of the reported CNS penetrant NLRP3 inhibitors has not been independently confirmed. Thus, there is still a need to develop CNS penetrant, specific, and safe NLRP3 inhibitors for clinical development. 2 160112428.1 Docket No.: 358117.00008 Inhibition of the NLRP3 / IL- lβ innate immunity pathway via small molecule modulators may be a useful and practical approach to treat and prevent many diseases [Na. Rev Drug Disco. 2018;18(5):1141-1160; Pharmacol. Rev 2021 July;73:968-1000]. This list includes, but not limited to, hereditary diseases (Cryopyrin-associated periodic syndrome, CAPS), neurodegenerative disorders (Alzheimer disease, Parkinson disease, traumatic brain injury), metabolic ailments (atherosclerosis and type 2 diabetes), inflammatory diseases (gout flares and osteoarthritis), cancer, among other related human diseases. Various pyridazine derivatives or analogs have been disclosed to be NLRP3 inhibitors. See, e.g., WO2020 / 234715, WO2021 / 193897, WO2022 / 135567, WO2022 / 166890, WO2022 / 216971, US Patent No.11,319,319, US 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 / 131277, WO2023 / 159148, WO2023 / 178099, WO2023 / 183943, WO2023 / 186020, WO2023 / 194964, WO2023 / 220408, WO2023 / 232917, WO2024 / 006559, WO2024.013395, WO2024 / 017924, WO2024 / 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 showed that nitrogen linkers were preferred over oxygen or carbon linkers in pyridazines and related compounds based on the observation that about 95% of examples in the aggregate contained the nitrogen linkers. Wherever direct comparisons were available, oxygen or methylene linkers afforded compounds less potent than analogous compounds having NH linkers. Many of the patents summarized above-described compounds having chemical or physical properties not ideal for CNS penetration perhaps due to, for example, too high a topological polar surface area (tPSA) and / or too many hydrogen bond donors and acceptors. As a result, those compounds can only serve as peripherally restricted NLRP3 inhibitors. Thus, development of CNS penetrating NLRP3 inhibitors is in high demand. Therefore, there is still a need to develop new compounds with robust CNS penetration and suitable pharmacokinetic, safety, and chemical / physical properties as NLRP3 inhibitors useful for treatment of various diseases and conditions. 3 160112428.1 Docket No.: 358117.00008 SUMMARY OF THE DISCLOSURE The present disclosure aims to meet the foregoing need by providing pyridazine compounds and their derivatives as NLRP3 inhibitors, in particular CNS penetrant NLRP3 inhibitors. In one aspect, the present disclosure provides a compound having the structure of Formula I: , or a stereoisomer, a acceptable salt or prodrug thereof, wherein: represents a single or double bond; X is NR1, CH2, O, S or a bond; R1is H, alkyl, cycloalkyl, alkyl-CO-, or heterocyclyl, wherein the alkyl, cycloalkyl, alkyl-CO, heterocyclyl are each optionally substituted with one to five groups independently selected from R7; R2at each occurrence is independently selected from R7, or two R2groups and the intervening connecting atoms form a 3- to 6-membered ring optionally comprising one or two heteroatoms independently selected from O, N, and S, wherein said ring is optionally substituted with one to five groups independently selected from R7; or two nonadjacent R2groups taken together form a 1- to 3-membered bridge optionally comprising one heteroatom selected from O, N, and S, wherein the bridge is optionally substituted by one to three substituents independently selected from R7; or alternatively, R1and an adjacent R2and the intervening connecting atoms form a 5- or 6- membered heterocyclyl optionally comprising one additional heteroatom independently selected from O, N, and S, wherein the heterocyclyl is optionally substituted with one to three groups independently selected from R7; 4 160112428.1 Docket No.: 358117.00008 W1and W2are together selected from: (i) both nothing, (ii) both O, (iii) nothing and O, and (iv) NR3and O, wherein R3is H, alkyl, cycloalkyl, alkyl-CO-, CN, NO2, aryl, or heteroaryl, wherein alkyl, cycloalkyl, alkyl-CO-, aryl, and heteroaryl are each optionally substituted with one to five groups independently selected from R8; or alternatively, R3and an R2together with their intervening connecting atoms form a 5- to 8- membered heterocyclic ring optionally comprising one additional heteroatom independently selected from O, N, and S and optionally substituted with 1 to 3 groups independently selected from R7; Y is CR4a, N, or C=O; Z is CR4b, N, or N-R9, with the provisos that Y and Z are not both N; and if Y is C=O, then Z is N-R9; or alternatively, Y and Z taken together is S; or alternatively, Y and Z taken together is part of a 5- to 7-membered carbocylic, 5- to 7-membered heterocyclic, six-membered aromatic or heteroaromatic, or 5-membered heteroaromatic ring fused to the existing ring containing N-N, each optionally substituted by one to three substituents independently selected from R4a, R4b, R9, R10, and R11; R4aand R4bare independently selected from H, alkyl, cycloalkyl, CN, haloalkyl, phenyl, -C1-6alkyl-OR9, -C1-6alkyl-NHR9, and -C1-6alkyl-N(R9)2; R5 is OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy; R6 at each occurrence is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6haloalkoxyl, C3-6cycloalkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, halo, CN, SF5, NHR9, N(R9)2, OR9, and SR9; or alternatively, two adjacent R6groups together with their intervening connecting atoms form a 5- or 6-membered carbocyclic, heterocyclic, aromatic, or heteroaromatic ring fused to the existing phenyl ring; R7 at each occurrence is independently selected from H, C1-6 alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9; R8at each occurrence is independently selected from H, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl CN, phenyl, and halo; R9at each occurrence is independently H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; 5 160112428.1 Docket No.: 358117.00008 R10at each occurrence is independently H, C1-6alkyl, C3-6cycloalkyl, halo, or CF3; R11at each occurrence is independently H, C1-6alkyl, C3-6cycloalkyl, or =O; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4, with the proviso that m+n≥2; i is 0, 1, 2, 3, 4; and j is 0, 1, 2, 3, 4. In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the embodiments disclosed, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers. In another aspect, the present disclosure provides a method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of the embodiments disclosed, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof. In another aspect, the present disclosure provides a method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound according to any one of the embodiments disclosed, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides use of a compound according to any embodiment disclosed, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of a disease or condition responsive to inhibition of NLRP3 in a subject in need thereof. In another aspect, the present disclosure provides use of a compound according to any embodiment disclosed, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, for use in the manufacture of a medicament for treatment or prevention of a disease or condition responsive to inhibition of NLRP3 in a subject in need thereof. 6 160112428.1 Docket No.: 358117.00008 In some embodiments, the present disclosure provides a method for treating or preventing a disease or condition in a subject in need thereof, comprising administering an effective amount of a compound according to any one of the embodiments disclosed, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising the foregoing compound, wherein the disease or condition is a neurodegenerative disorder, a metabolic ailment, an inflammatory syndrome, an autoinflammatory disease, cancer, or a hereditary disease. In any aspects or embodiments disclosed, the compound includes, but is not limited to, any compound of formula (I), (I-a), (I-a-1), (I-b), (I-b-1), (I-c), (I-c-1), (I-d), (I-d-1), (I-e), (I- e-1), (I-f), (I-f-1), (I-f-2), (I-f-2-a), (I-g), (I-g-1), (I-g-2), (I-g-3), (I-h), (I-h-1), (I-i), (I-i-1), (I- j), (I-j-1), (I-k), (I-k-1), (I-k-2), (I-k-3), (I-l), (I-l-1), (I-m), (I-n), or (I-n-1), among others, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof. Other aspects and advantages of the present disclosure will be better appreciated by those skilled in the in view of the following detailed description, examples, and claims. DETAILED DESCRIPTION OF THE DISCLOSURE The present disclosure provides novel sulfur linked pyridazines that have unexpected and superior combinations of potency, selectivity, safety, brain penetration, and pharmacokinetic profiles compared to known pyridazines with any linkers which are prerequisites for the selection of a candidate in preparation for human trials. As of this filing, the present inventors are not aware of any sulfide-linked pyridazine compounds disclosed below to be potent and brain penetrant NLRP3 inhibitors. More importantly, we have discovered that the sulfur-linked pyridazine compounds have unexpected and superior combinations of potency, selectivity, safety, brain penetration, and pharmacokinetic profiles compared to known pyridazines with any linkers which are prerequisites for the selection of a candidate in preparation for human trials. In one aspect, the present disclosure provides a compound having the structure of Formula I: 7 160112428.1 Docket No.: 358117.00008 , or a stereoisomer, a acceptable salt or prodrug thereof, wherein: represents a single or double bond; X is NR1, CH2, O, S or a bond; R1is H, alkyl, cycloalkyl, alkyl-CO-, or heterocyclyl, wherein the alkyl, cycloalkyl, alkyl-CO, heterocyclyl are each optionally substituted with one to five groups independently selected from R7; R2at each occurrence is independently selected from R7, or two R2groups and the intervening connecting atoms form a 3- to 6-membered ring optionally comprising one or two heteroatoms independently selected from O, N, and S, wherein said ring is optionally substituted with one to five groups independently selected from R7; or two nonadjacent R2groups taken together form a 1- to 3-membered bridge optionally comprising one heteroatom selected from O, N, and S, wherein the bridge is optionally substituted by one to three substituents independently selected from R7; or alternatively, R1and an adjacent R2and the intervening connecting atoms form a 5- or 6- membered heterocyclyl optionally comprising one additional heteroatom independently selected from O, N, and S, wherein the heterocyclyl is optionally substituted with one to three groups independently selected from R7; W1and W2are together selected from: (i) both nothing, (ii) both O, (iii) nothing and O, and (iv) NR3and O, wherein R3is H, alkyl, cycloalkyl, alkyl-CO-, CN, NO2, aryl, or heteroaryl, wherein alkyl, cycloalkyl, alkyl-CO-, aryl, and heteroaryl are each optionally substituted with one to five groups independently selected from R8; or alternatively, R3and an R2together with their intervening connecting atoms form a 5- to 8- membered heterocyclic ring optionally comprising one additional heteroatom independently selected from O, N, and S and optionally substituted with 1 to 3 groups 8 160112428.1 Docket No.: 358117.00008 independently selected from R7; Y is CR4a, N, or C=O; Z is CR4b, N, or N-R9, with the provisos that Y and Z are not both N; and if Y is C=O, then Z is N-R9; or alternatively, Y and Z taken together is S; or alternatively, Y and Z taken together is part of a 5- to 7-membered carbocylic, 5- to 7-membered heterocyclic, six-membered aromatic or heteroaromatic, or 5-membered heteroaromatic ring fused to the existing ring containing N-N, each optionally substituted by one to three substituents independently selected from R4a, R4b, R9, R10, and R11; R4aand R4bare independently selected from H, alkyl, cycloalkyl, CN, haloalkyl, phenyl, -C1-6alkyl-OR9, -C1-6alkyl-NHR9, and -C1-6alkyl-N(R9)2; R5is OH, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or C1-6haloalkoxy; R6at each occurrence is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxyl, C3-6cycloalkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, halo, CN, SF5, NHR9, N(R9)2, OR9, and SR9; or alternatively, two adjacent R6groups together with their intervening connecting atoms form a 5- or 6-membered carbocyclic, heterocyclic, aromatic, or heteroaromatic ring fused to the existing phenyl ring; R7at each occurrence is independently selected from H, C1-6alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9; R8at each occurrence is independently selected from H, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl CN, phenyl, and halo; R9at each occurrence is independently H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; R10at each occurrence is independently H, C1-6alkyl, C3-6cycloalkyl, halo, or CF3; R11at each occurrence is independently H, C1-6alkyl, C3-6cycloalkyl, or =O; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4, with the proviso that m+n≥2; i is 0, 1, 2, 3, 4; and j is 0, 1, 2, 3, 4. 9 160112428.1 Docket No.: 358117.00008 In some embodiments, in the compounds of formula (I), or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof: X is NR1, CH2, O, S or a bond; R1is H, C1-6alkyl, C3-6cycloalkyl, C1-6alkyl-CO-, 4-6 membered heterocyclyl, wherein the C1-5alkyl, C3-6cycloalkyl, C1-4alkyl-CO-, and 4-6 membered heterocyclyl are each optionally substituted with one to three groups independently selected from R7; R2at each occurrence is independently selected from R7, or two R2groups and the intervening connecting atom(s) form a 3- to 6-membered ring optionally comprising a heteroatom selected from O, N, and S, and the ring is optionally substituted with one or two groups independently selected from R7; or two nonadjacent R2groups taken together form a 1- to 3-membered bridge optionally comprising one heteroatom selected from O, N, and S, wherein the bridge is optionally substituted by one to three substituents independently selected from R7; or alternatively, R1and an adjacent R2and the intervening connecting atoms form a 5- or 6- membered heterocyclyl optionally comprising one additional heteroatom selected from O, N, and S, wherein the heterocyclyl is optionally substituted with one to three groups independently selected from R7; W1and W2are together selected from: (i) both nothing, (ii) both O, (iii) nothing and O, and (iv) NR3and O, wherein R3is H, C1-5alkyl, C3-6cycloalkyl, C1-4alkyl-CO, CN, NO2, C6aryl, or 5- or 6-membered heteroaryl optionally substituted with one to three groups independently selected from R8; or alternatively, R3and R2taken together with the intervening connecting atoms form a 5- to 8- membered heterocyclic ring optionally comprising one additional heteroatom selected from O, N, and S as part of this ring and optionally substituted with one or two groups independently selected from R7Y is CR4a, N, or C=O; Z is CR4b, N, or N-R9; with the provisos that Y and Z are not both N, and if Y is C=O, then Z is N-R9; or alternatively, Y and Z taken together is S; or alternatively, Y and Z taken together is part of a 5- to 7-membered carbocyclic, 5- to 7-membered heterocyclic, six-membered aromatic or heteroaromatic, or 5-membered 10 160112428.1 Docket No.: 358117.00008 heteroaromatic ring optionally substituted by one or two substituents independently selected from R4a, R4b, R9, R10, and R11; R4aand R4bare independently selected from H, C1-4alkyl, C3-6cycloalkyl, CN, CF3, or phenyl; R5is OH, OCHF2, OCF3, CHF2, CF3, CF3CH2, or OMe; R6at each occurrence is independently selected from H, CF3, CF2CF3, OCF3, C3-6cycloalkyl, C1-4alkyl, CHF2, OCHF2, halo, CN, SF5, NHR9, N(R9)2, OR9, and SR9; or alternatively, two R6 groups together with intervening connecting atoms form a 5- or 6-membered carbocyclic, heterocyclic, aromatic, or heteroaromatic ring fused to the existing phenyl ring; R7 at each occurrence is independently selected from H, C1-4 alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9; R8at each occurrence is independently selected from H, C1-4alkyl, cyclopropyl, CF3, CHF2, CN, phenyl, and halo; R9at each occurrence is independently H, C1-4alkyl, or cyclopropyl; R10at each occurrence is independently H, C1-4alkyl, cyclopropyl, halo, or CF3; R11at each occurrence is independently H, C1-4alkyl, cyclopropyl or =O; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4, with the proviso that m+n≥2; i is 0, 1, 2, or 3; and j is 0, 1, or 2. In some embodiments, in the compounds of formula (I), or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof: X is NR1or O; R1is hydrogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkyl-CO-, -C1-6alkyl-OR9, -C1-6alkyl- C(O)OR9, or 4- to 6-membered heterocyclyl, each, except hydrogen, optionally substituted with one to three groups independently selected from C1-4alkyl, halo, CN, =O, OR9, SR9, NHR9, and N(R9)2; 11 160112428.1 Docket No.: 358117.00008 R2at each occurrence is independently selected from C1-6alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9, or two adjacent R2groups and the intervening connecting atoms form a 5- or 6-membered ring optionally comprising one or two heteroatoms independently selected from O, N, and S, wherein said ring is optionally substituted with one to three groups independently selected from C1-4alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9; or two nonadjacent R2groups taken together form a C1-3alkylene bridge optionally substituted by one or two substituents independently selected from C1-4 alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9; W1and W2together are selected from: (i) both nothing, (ii) both O, and (iii) nothing and O; Y is CR4aor N; Z is CR4bor N, provided that Y and Z are not both N; or alternatively, Y and Z taken together is part of a 5- or 6-membered carbocyclic, 5- or 6-membered heterocyclic, six-membered aromatic or heteroaromatic, or 5-membered heteroaromatic ring, each fused to the existing ring containing N-N and each optionally substituted by one to three substituents independently selected from halo, CN, =O (excluding aromatic and heteroaromatic), C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, phenyl, -C1-6alkyl- OR9, -C1-6alkyl-NHR9, and -C1-6alkyl-N(R9)2; R4aand R4bare independently selected from H, C1-6alkyl, C3-6cycloalkyl, CN, C1-6haloalkyl, phenyl, -C1-6alkyl-OR9, -C1-6alkyl-NHR9, and -C1-6alkyl-N(R9)2; R5is OH, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6at each occurrence is independently selected from hydrogen, C1-4alkyl, C1-4haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, halo, CN, NHR9, N(R9)2, OR9, or SR9; R9at each occurrence is independently H, C1-4alkyl, or C1-4haloalkyl, or C3-6cycloalkyl; m is 1, or 2; n is 1, 2, or 3; i is 0, 1, 2, 3; and j is 1, 2, 3. 12 160112428.1 Docket No.: 358117.00008 In some embodiments, the present disclosure provides a compound having a structure of formula (I-a): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein X, m, n, R2, Y, Z, R5, and R6are as defined in any one of the embodiments disclosed. In some embodiments, in the compounds of formula (I) or (I-a), or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein is selected from: Z1, Z2, Z3, and Z4are independently selected from CR10and N, with the proviso that at most one of them is N; Z5is O, NR9, S, SO, or SO2; 13 160112428.1 Docket No.: 358117.00008 Y1is a bond, CHR11, or SO2; o and p are selected from the following combinations among the columns: o = 0 0 0 2 3 4 1 1 2 2 3 1 all the other groups are as defined in any one of the embodiments disclosed. In some embodiments, the present disclosure provides a compound having a structure of formula (I-a-1): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is NR1or O; Y and Z are as defined in any embodiment of disclosed; R5is independently selected from OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, and C1-2haloalkoxy; R6ais independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; R9at each occurrence is independently H or C1-4alkyl. In some embodiments, the present disclosure provides a compound having a structure of formula (I-b): 14 160112428.1 Docket No.: 358117.00008 , or a stereoisomer, a acceptable salt or prodrug thereof, wherein n1=0, 1, or 2; and R1, R2, Y, Z, R5, and R6are as defined in any one of the embodiments disclosed. In some embodiments, the present disclosure provides a compound having a structure of formula (I-b-1): (R2)i,or a stereoisomer, a acceptable salt or prodrug thereof, wherein: Y and Z are as defined in any embodiment disclosed; n1is 0 or 1; R5 is independently selected from OH, halo, C1-2 alkyl, C1-2 haloalkyl, C1-2 alkoxy, and C1-2haloalkoxy; R6ais independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4 haloalkyl; R9at each occurrence is independently H or C1-4alkyl. In some embodiments, the present disclosure provides a compound having a structure 15 160112428.1 Docket No.: 358117.00008 of formula (I-c): R R 75R2N N j or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: r is 0, 1, or 2; and Y, Z, R1, R2, j, R6, and R7 are as defined in any one of the embodiments disclosed. In some embodiments, the present disclosure provides a compound having a structure of formula (I-c-1): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: r is 0 or 1; Y and Z are as defined in any embodiment disclosed; R5is independently selected from OH,2 2haloalkyl, C1-2alkoxy, and C1-2haloalkoxy; R6a is independently selected from halo, CN, OR9, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6 at each occurrence is independently selected from hydrogen, halo, OR9, C1-4 alkyl, and C1-4haloalkyl; and R9at each occurrence is independently H or C1-4alkyl. In some embodiments, the present disclosure provides a compound having a structure of formula (I-d): 16 160112428.1 Docket No.: 358117.00008 , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein X, R2, m, n, Y, Z, and R6are as defined in any one of the embodiments disclosed. In some embodiments, the present disclosure provides a compound having a structure of formula (I-d-1): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is NR1or O; Y and Z are as defined in any embodiment disclosed; R6ais independently selected from halo,4C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6 at each occurrence is independently selected from hydrogen, halo, OR9, C1-4 alkyl, and C1-4haloalkyl; and R9at each occurrence is independently H or C1-4alkyl. In some embodiments, the present disclosure provides a compound having a structure of formula (I-e): 17 160112428.1 Docket No.: 358117.00008 , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; and R1, R2, Y, Z, and R6are as defined in any one of the embodiments disclosed. In some embodiments, the present disclosure provides a compound having a structure of formula (I-e-1): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; Y and Z are as defined in any embodiment disclosed; R6ais independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; and R9at each occurrence is independently H or C1-4alkyl. 18 160112428.1 Docket No.: 358117.00008 In some embodiments, the present disclosure provides a compound having a structure of formula (I-f): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; and R1, R2, i, j, R4a, R4b, and R6 are as defined in any one of the embodiments disclosed. In some embodiments, in the compounds of formula (I-f), or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof: n1is 1; i is 0, 1, or 2; j is 1 or 2; R1 is hydrogen, C1-6alkyl, C1-6alkyl-CO-, -C1-6alkyl-OR9, or -C1-6alkyl-C(O)OR9; R2at each occurrence is independently hydrogen, C1-6alkyl, or halo; or two nonadjacent R2groups taken together form a C1-3alkylene bridge optionally substituted by one or two substituents independently selected from R7; R4aand R4bare independently selected from H, C1-6alkyl, CN, C1-6haloalkyl, -C1-6alkyl-OR9, -C1-6alkyl-NHR9, and -C1-6alkyl-N(R9)2; R5is OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6at each occurrence is independently selected from hydrogen, halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5- membered heteroaryl; R7 is hydrogen, C1-4 alkyl, halo, or OR9; and R9at each occurrence is independently H or C1-4alkyl. In some embodiments, the present disclosure provides a compound having a structure 19 160112428.1 Docket No.: 358117.00008 of formula (I-f-1): , or a stereoisomer, a acceptable salt or prodrug thereof, wherein: R1is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2OH; R2is H or F; R4ais H, CN, -CH3, -CH2OH, or -CH2NHCH3; R4bis H or -CH3; R5is -OH, -CF3, or -OCHF2; R6is H, F, Cl, -CF3, or -CH3; and R6ais -CF3, -CH3, cyclopropyl, Cl, or . In some embodiments, the present disclosure provides a compound having a structure of formula (I-f-2): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: r is 0, 1, or 2; R1is hydrogen, C1-6alkyl, C1-6alkyl-CO-, -C1-6alkyl-OR9, or -C1-6alkyl-C(O)OR9; R2is hydrogen, C1-6alkyl, or halo; 20 160112428.1 Docket No.: 358117.00008 R4aand R4bare independently selected from H, C1-6alkyl, CN, C1-6haloalkyl, -C1-6alkyl-OR9, -C1-6alkyl-NHR9, and -C1-6alkyl-N(R9)2; R5is OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6at each occurrence is independently selected from hydrogen, halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5- membered heteroaryl; R7is C1-4alkyl, halo, and OR9; and R9 at each occurrence is independently H or C1-4 alkyl. In some embodiments, the present disclosure provides a compound having a structure of formula (I-f-2-a): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2OH; R4ais H, CN, -CH3, -CH2OH, or -CH2NHCH3; R4bis H or -CH3; R5is -OH, -CF3, or -OCHF2; R6is H, F, Cl, -CF3, or -CH3; and R6ais -CF3, -CH3, cyclopropyl, Cl, or . In some embodiments, the present disclosure provides a compound having a structure of formula (I-g): 21 160112428.1 Docket No.: 358117.00008 , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; R1, R2, R5, R6and R10are as defined in any one of embodiments disclosed; and Z1, Z2, Z3, and Z4are each independently CR10or N, with the proviso that no more than one of them are N. In some embodiments, the present disclosure provides a compound having a structure of formula (I-g-1), (I-g-2), or (I-g-3): , or prodrug thereof, wherein: i is 0, 1, or 2; R1at each occurrence is independently hydrogen, C1-6alkyl, C1-6alkyl-CO-, -C1-6alkyl- OR9, or -C1-6alkyl-C(O)OR9; R2at each occurrence is independently hydrogen, C1-6alkyl, or halo; R5at each occurrence is independently OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6aat each occurrence is independently selected from halo, CN, OR9, C1-4alkyl, C1-422 160112428.1 Docket No.: 358117.00008 haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; R9at each occurrence is independently H or C1-4alkyl; and R10at each occurrence is independently H, C1-4alkyl, cyclopropyl, halo, or CF3. In some embodiments, in the compounds of formula (I-g), (I-g-1), (I-g-2), or (I-g-3), or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof: i is 0; R1is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2OH; R5is -OH, -CF3, or -OCHF2; R6is H, F, or -CH3; and R6a is -CF3, -CH3, cyclopropyl, Cl, or ; and R10is H. In some embodiments, the present disclosure provides a compound having a structure of formula (I-h), (I-i), or (I-j): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; and R1, R2, R5, R6, and R10are as defined in any one of the embodiments disclosed. In some embodiments, the present disclosure provides a compound having a structure of formula (I-h-1), (I-i-1), or (I-j-1): 23 160112428.1 Docket No.: 358117.00008 , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0, 1, or 2; R1at each occurrence is independently hydrogen, C1-6alkyl, C1-6alkyl-CO-, -C1-6alkyl- OR9, or -C1-6alkyl-C(O)OR9; R2at each occurrence is independently hydrogen, C1-6alkyl, or halo; R5at each occurrence is independently OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6aat each occurrence is independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; R9at each occurrence is independently H or C1-4alkyl; and R10at each occurrence is independently H, C1-4alkyl, cyclopropyl, halo, or CF3. In some embodiments, in the compounds of formula (I-h), (I-i), (I-j), (I-h-1), (I-i-1), or (I-j-1), or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof: i is 0; R1is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2OH; R5is -OH, -CF3, or -OCHF2; R6is H, F, Cl, -CF3, or -CH3; and R6ais -CF3, -CH3, 24 160112428.1 Docket No.: 358117.00008 R10is H or -CH3. In some embodiments, the present disclosure provides a compound having a structure of formula (I-k): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; i is 0, 1, or 2; q is 0 or 1; Y1is -CH2- or -S(O)2-; and R1, R2, R5, R6, and R11are as defined in any one of the embodiments disclosed. In some embodiments, the present disclosure provides a compound having a structure of formula (I-k-1), (I-k-2), or (I-k-3): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0, 1, or 2; 25 160112428.1 Docket No.: 358117.00008 R1at each occurrence is independently hydrogen, C1-6alkyl, C1-6alkyl-CO-, -C1-6alkyl- OR9, or -C1-6alkyl-C(O)OR9; R2at each occurrence is independently hydrogen, C1-6alkyl, or halo; R5at each occurrence is independently OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6aat each occurrence is independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; R9 at each occurrence is independently H or C1-4 alkyl; and R11at each occurrence is independently H, C1-4alkyl, cyclopropyl, halo, or CF3. In some embodiments, in the compounds of formula (I-k), (I-k-1), (I-k-2), or (I-k-3), or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof: i is 0; R1is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2OH; R5is -OH, -CF3, or -OCHF2; R6is H, F, Cl, -CF3, or -CH3; and R6ais -CF3, -CH3, cyclopropyl, Cl, or ; and R11at each occurrence is independently H, C1-4alkyl, cyclopropyl, or =O. In some embodiments, the present disclosure provides a compound having a structure of formula (I-l): , 160112428.1 Docket No.: 358117.00008 (I-l) or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; and R1, R2, R4b, R5, and R6are as defined in any one of the embodiments disclosed. In some embodiments, the present disclosure provides a compound having a structure of formula (I-l-1): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0, 1, or 2; R1at each occurrence is independently hydrogen, C1-6alkyl, C1-6alkyl-CO-, -C1-6alkyl- OR9, or -C1-6alkyl-C(O)OR9; R2at each occurrence is independently hydrogen, C1-6alkyl, or halo; R4bis H, C1-6alkyl, CN, or C1-6haloalkyl, R5at each occurrence is independently OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6aat each occurrence is independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4 haloalkyl; and R9 at each occurrence is independently H or C1-4 alkyl. 27 160112428.1 Docket No.: 358117.00008 In some embodiments, in the compounds of formula (I-l) or (I-l-1), or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof: i is 0; R1is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2OH; R4bis H or -CH3; R5is -OH, -CF3, or -OCHF2; R6is H, F, Cl, -CF3, or -CH3; and R6ais -CF3, -CH3, . In some embodiments, the provides a compound having a structure of formula (I-m): (R2)ij,or a stereoisomer, a acceptable salt or prodrug thereof, wherein: n=0 or 1; and R1, R2, R6, and R9 are as defined in any one of embodiments disclosed. In some embodiments, the present disclosure provides a compound having a structure of formula (I-n): , 160112428.1 Docket No.: 358117.00008 (I-n) or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein Y, Z, R2, m, n, i, and R6are as defined in any one of the embodiments disclosed. In some embodiments, the present disclosure provides a compound having a structure of formula (I-n-1): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0, 1, 2, or 3; R2is H, F, or -CH3; R4ais H, CN, -CH3, -CH2OH, or -CH2NHCH3; R4bis H or -CH3; R5is -OH, -CF3, or -OCHF2; R6 is H, F, Cl, -CF3, or -CH3; and R6ais -CF3, -CH3, . In some embodiments, the provides a compound selected from: N HO N HO , , Docket No.: 358117.00008 , , , , 5 , 10 Docket No.: 358117.00008 , acceptable salt or prodrug thereof. In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the embodiments disclosed, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers. In another aspect, the present disclosure provides a method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of the embodiments disclosed, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof. In another aspect, the present disclosure provides a method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound according to any one of the embodiments disclosed, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides use of a compound according to any embodiment disclosed, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment or prevention of a disease or condition responsive to inhibition of NLRP3 in a subject in need thereof. In another aspect, the present disclosure provides use of a compound according to any embodiment disclosed, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, for use in the manufacture of a medicament for treatment or 31 160112428.1 Docket No.: 358117.00008 prevention of a disease or condition responsive to inhibition of NLRP3 in a subject in need thereof. In some embodiments, the present disclosure provides a method for treating or preventing a disease or condition in a subject in need thereof, comprising administering an effective amount of a compound according to any of the embodiments disclosed, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition comprising the foregoing compound, wherein the disease or condition is a neurodegenerative disorder, a metabolic ailment, an inflammatory syndrome, an autoinflammatory disease, cancer, or a hereditary disease. In some embodiments of the present disclosure, the neurodegenerative disorder is Parkinson’s disease or Alzheimer’s disease. In some embodiments of the present disclosure, the metabolic ailment is type 2 diabetes or atherosclerosis. In some embodiments of the present disclosure, the inflammatory disease is gout flares or osteoarthritis. In some embodiments of the present disclosure, the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis. In some embodiments of the present disclosure, the cancer is lung cancer. In some embodiments of the present disclosure, the hereditary disease is Cryopyrin- associated periodic syndrome. In any aspects or embodiments disclosed, the compound includes, but is not limited to, any compound of formula (I), (I-a), (I-a-1), (I-b), (I-b-1), (I-c), (I-c-1), (I-d), (I-d-1), (I-e), (I- e-1), (I-f), (I-f-1), (I-f-2), (I-f-2-a), (I-g), (I-g-1), (I-g-2), (I-g-3), (I-h), (I-h-1), (I-i), (I-i-1), (I- j), (I-j-1), (I-k), (I-k-1), (I-k-2), (I-k-3), (I-l), (I-l-1), (I-m), (I-n), or (I-n-1), among others, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof. In addition, any reasonable combinations of the embodiments disclosed as apparent to those of ordinary skill in the art are also encompassed by the present disclosure. 32 160112428.1 Docket No.: 358117.00008 In one aspect, the present disclosure provides compounds having the following structure of formula (I): , and stereoisomers, and prodrug thereof, wherein: X is NR1, CH2, O, S or a bond; R1is H, alkyl, cycloalkyl, alkyl-CO, heterocyclyl, wherein the alkyl, cycloalkyl, alkyl- CO, heterocyclyl are each optionally substituted with 1-5 groups independently selected from R7; R2at each occurrence is independently selected from R7, or two R2groups or one R1and one R2and the intervening connecting atom(s) can form a 3-6 membered ring containing 0-3 heteroatom, wherein said ring is optionally substituted with one to five groups of R7;W1and W2are either both nothing, O and nothing, O and O, or NR3and O, respectively, wherein R3is H, alkyl, cycloalkyl, alkyl-CO, CN, NO2, aryl, or heteroaryl, wherein alkyl, cycloalkyl, alkyl-CO, aryl, and heteroaryl are each optionally substituted with 1-5 groups of R8; or alternatively, R3and R2taken together with the intervening connecting atoms form a 5-8 membered heterocyclic ring containing optional one or two additional heteroatoms independently selected from O, N, and S as part of this ring and optionally substituted with 1 to 3 groups of R7Y is CR4’, N, or C=O; Z is CR4, N, or N-R9with the proviso that if Y is C=O, then Z is N-R9and Y and Z are not both N; or alternatively, Y and Z taken together is S; or alternatively, Y and Z taken together is part of a 5-7 membered carbocylic, 5-7 membered heterocyclic, six-membered aromatic or heteroaromatic, and 5-membered heteroaromatic rings, each optionally substituted by 1-3 substituents independently selected 33 160112428.1 Docket No.: 358117.00008 from R4, R4’, R9, R10, and R11; R4and R4’are independently selected from H, alkyl, cycloalkyl, CN, CF3, or phenyl; R5is OH, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, or C1-4haloalkoxy; R6at each occurrence is independently selected from C1-4alkyl, C1-4haloalkyl, cycloalkyl, halo, CN, SF5, NHR9, N(R9)2, OR9, or SR9; or alternatively, two R6 together with intervening connecting atoms form a 5-6 membered carbocyclic, heterocyclic, aromatic, or heteroaromatic ring fused to the existing phenyl ring; R7at each occurrence is independently selected from H, alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9; R8at each occurrence is independently selected from H, C1-4alkyl, cyclopropyl, CF3, CHF2, CN, phenyl, and halo; R9at each occurrence is independently H, C1-4alkyl, C1-4haloalkyl, or cyclopropyl; R10at each occurrence is independently H, C1-4alkyl, cyclopropyl, halo, or CF3; R11at each occurrence is independently H, C1-4alkyl, cyclopropyl or =O; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4, with the proviso that m+n≥2; i is 0, 1, 2, 3, 4; and j is 0, 1, 2, 3, 4. In some embodiments of this aspect: X is NR1, CH2, O, S or a bond; R1is H, C1-5alkyl, C3-6cycloalkyl, C1-4alkyl-CO, 4-6 membered heterocyclyl, wherein the C1-5alkyl, C3-6cycloalkyl, C1-4alkyl-CO, and 4-6 membered heterocyclyl are each optionally substituted with 1-3 groups independently selected from R7; R2at each occurrence is independently selected from R7, or two R2groups or one R1and one R2and the intervening connecting atom(s) can form a 3-6 membered ring containing 0-1 heteroatom and the said ring is optionally substituted with 0-2 groups of R7;W1and W2are either both nothing, O and nothing, O and O, or NR3and O, wherein R334 160112428.1 Docket No.: 358117.00008 is H, C1-5alkyl, C3-6cycloalkyl, C1-4alkyl-CO, CN, NO2, phenyl, or 5- or 6-membered heteroaryl optionally substituted with 1-3 groups of R8; or alternatively, R3and R2taken together with the intervening connecting atoms form a 5-8 membered heterocyclic ring containing optional one additional heteroatom independently selected from O, N, and S as part of this ring and optionally substituted with 0-2 groups of R7Y is CR4’, N, or C=O; Z is CR4, N, or N-R9with the provision that if Y is C=O, Z is N-R9and Y and Z is not both N; or alternatively, Y and Z taken together is S; or alternatively, Y and Z taken together is part of a 5-7 membered carbocylic, 5-7 membered heterocyclic, six-membered aromatic or heteroaromatic, and 5-membered heteroaromatic rings with 1-2 optional substitutions independently selected from R4, R4’, R9, R10, and R11; R4and R4’are independently selected from H, C1-4alkyl, C3-5cycloalkyl, CN, CF3, or phenyl; R5is OH, OCHF2, OCF3, CHF2, CF3, CF3CH2, or OMe; R6at each occurrence is independently selected from CF3, OCF3, C3-6cycloalkyl, C1-4alkyl, CHF2, OCHF2, halo, CN, SF5, NHR9, N(R9)2, OR9, and SR9; or alternatively, two R6together with intervening connecting atoms form a 5-6 membered carbocyclic, heterocyclic, aromatic, or heteroaromatic ring fused to the existing phenyl ring; R7at each occurrence is independently selected from H, C1-4alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9; R8at each occurrence is independently independently selected from H, C1-4alkyl, cyclopropyl, CF3, CHF2, CN, phenyl, and halo; R9at each occurrence is independently H, C1-4alkyl, or cyclopropyl; R10at each occurrence is independently H, C1-4alkyl, cyclopropyl, halo, or CF3; R11at each occurrence is independently H, C1-4alkyl, cyclopropyl or =O; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4, with the proviso that m+n≥2; 35 160112428.1 Docket No.: 358117.00008 i is 0, 1, 2, or 3; and j is 0, 1, or 2. In some embodiments of this aspect, the disclosure provides a compound of following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: wherein X, m, n, i, j, R2, Y, Z, R5, and R6are as defined in formula (I). In some embodiments, the disclosure provides a compound of formula (I), or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, wherein one of them is N; Z5is O, NR9, S, SO, SO2; o and p are selected from the following combinations among the columns: o = 0 0 0 2 3 4 1 1 2 2 3 1 In some embodiments, the disclosure provides a compound of following formula, or a 36 160112428.1 Docket No.: 358117.00008 stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: , wherein n=0 or 1; and defined in formula (I). In some embodiments, the disclosure provides a compound of the following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: , wherein X, R2, m, n, Y, (I). In some embodiments, the disclosure provides a compound of the following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: wherein n=0 or 1; Y ; and i, j, R1, R2, R5, and R6are as defined in formula (I). In some embodiments, the disclosure provides a compound of the following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: 37 160112428.1 Docket No.: 358117.00008 , wherein Y and Z are as i, j, X, R2, m, n, and R6are as defined in formula (I). In some embodiments, the disclosure provides a compound of following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: , wherein n=0 or 1; and in formula (I). In some embodiments, the disclosure provides a compound of following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: , wherein n=0 or 1; Y and Z are as R6are as defined in formula (I). 38 160112428.1 Docket No.: 358117.00008 In some embodiments, the disclosure provides a compound of following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: , wherein n=0 or 1; and in formula (I). In some embodiments, the disclosure provides a compound of following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: , wherein n=0 or 1; i, in formula (I); and Z1, Z2, Z3, and Z4are as defined . In some provides a compound of following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: (R2)ij, 160112428.1 Docket No.: 358117.00008 (I-h) wherein n=0 or 1; and i, j, R1, R2, R6, and R10are as defined in formula (I). In some embodiments, the disclosure provides a compound of the following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: , wherein n=0 or 1; and in formula (I). In some embodiments, the disclosure provides a compound of the following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: , wherein n=0 or 1; in formula (I). In some embodiments, the disclosure provides a compound of the following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: , 160112428.1 Docket No.: 358117.00008 (I-k) wherein n=0 or 1; and i, j, R1, R2, R6, and R11are as defined in formula (I). In some embodiments, the disclosure provides a compound of the following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: , wherein n=0 or 1; and in formula (I). In some embodiments, the disclosure provides a compound of the following formula, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof: , wherein n=0 or 1; and i, j, R1, R2, R6, and R9are as defined in formula (I). In some embodiments, the disclosure provides a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, wherein R1is methyl, ethyl, isopropyl or 2-hydroxylethyl In some embodiments, the disclosure provides a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, wherein R2is absent, OH, or NH2. In some embodiments, the disclosure provides a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, wherein R4and R4’are independently selected from H, CH3, CF3, and CN. 41 160112428.1 Docket No.: 358117.00008 In some embodiments, the disclosure provides a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, wherein R8is H or methyl. In some embodiments, the disclosure provides a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, wherein R6is CF3, Cl, CH3, cyclopropyl, or OCF3. In some embodiments, the disclosure provides a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound is selected from Examples 1-19. In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers. In another aspect, the present disclosure provides a method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering an effective amount of a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof to the subject. In another aspect, the present disclosure provides a method for treating or preventing a disease or condition in a subject in need thereof, comprising administering an effective amount of a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition thereof to the subject, wherein the disease or condition is a neurodegenerative disorder, a metabolic ailment, an inflammatory syndrome, an autoinflammatory disease, cancer, or a hereditary disease. In some embodiments, the neurodegenerative disorder is Parkinson’s disease, Alzheimer’s disease; the metabolic ailment type 2 diabetes or atherosclerosis; the inflammatory disease is gout flares or osteoarthritis; the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis; the cancer is lung cancer, the hereditary disease is Cryopyrin-associated periodic syndrome. In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers. 42 160112428.1 Docket No.: 358117.00008 In another aspect, the present disclosure provides a method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof. In another aspect, the present disclosure provides a method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof. In another aspect, the present disclosure provides use of a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, for treatment of a disease or disorder associated with NLRP3 activities in a subject in need of treatment. In another aspect, the present disclosure provides use of a pharmaceutical composition comprising a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, for treatment of a disease or disorder associated with NLRP3 activities in a subject in need of treatment. In another aspect, the present disclosure provides use of a compound as defined according to any foregoing embodiments of this aspect, or a stereoisomer, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for treatment of a disease or disorder associated with NLRP3 activities in a subject in need of treatment. In some embodiments, the disease or condition is a neurodegenerative disorder, a metabolic ailment, an inflammatory syndrome, an autoinflammatory disease, cancer, or a hereditary disease treatable by an NLRP3 inhibitor. In some embodiments, the neurodegenerative disorder is Parkinson’s disease or Alzheimer’s disease; the metabolic ailment is type 2 diabetes or atherosclerosis; the inflammatory disease is gout flares or osteoarthritis; the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis; the cancer is lung cancer; and the hereditary disease is Cryopyrin-associated periodic syndrome. 43 160112428.1 Docket No.: 358117.00008 Unless defined otherwise, 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 belongs. The term “alkyl" refers to a branched or unbranched monovalent aliphatic hydrocarbon radical derived from an alkane containing 1 to 12 carbon atoms by removal of one hydrogen atom. In certain embodiments, an alkyl group contains 1 to 10 carbons. In certain embodiments, an alkyl group contains 1 to 8 carbons. In certain embodiments, sometimes preferably, an alkyl group contains 1 to 6 carbons, and in certain embodiments, sometimes more preferably, an alkyl group contains 1 to 4 carbons. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl, or the like, and their isomeric counterparts. The alkyl group can be substituted or unsubstituted. The term “alkenyl” refers to any univalent aliphatic hydrocarbon radical derived from an alkene containing 2 to 12 carbons by removal of one hydrogen atom. In certain embodiments, an alkenyl group contains 2 to 12 carbons. In certain embodiments, an alkenyl group contains 2 to 8 carbons. In certain embodiments, sometimes preferably, an alkenyl group contains 2 to 6 carbons, and in certain embodiments, sometimes more preferably, an alkenyl group contains 2 to 4 carbons. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, or the like, and their isomeric counterparts. The alkenyl group can be substituted or unsubstituted. The term “alkynyl" refers to a univalent aliphatic hydrocarbon radical derived from an alkyne containing 2 to 12 carbon atoms by removal of one hydrogen atom. In certain embodiments, an alkynyl group contains 2 to 10 carbons. In certain embodiments, an alkynyl group contains 2 to 8 carbons. In certain embodiments, sometimes preferably, an alkynyl group contains 2 to 6 carbons, and in certain embodiments, sometimes more preferably, an alkynyl group contains 2 to 4 carbons. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, or the like, and their isomeric counterparts. The alkynyl group can be substituted or unsubstituted. The term "cycloalkyl" refers to any univalent radical formed by removal of one hydrogen atom from a cycloalkane. In certain embodiments, cycloalkyl group contains 3 to 10 44 160112428.1 Docket No.: 358117.00008 carbons. In certain embodiments, cycloalkyl group contains 3 to 8 carbons. In certain embodiments, sometimes preferably, cycloalkyl group contains 3 to 6 carbons. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. The cycloalkyl can be substituted or unsubstituted. The term "heterocyclyl" refers to a monocyclic or polycyclic non-aromatic carbocycle radical containing at least one heteroatom (N, O, and / or S) in the ring. At least one ring in the heterocyclyl ring system is non-aromatic, and it can have any degree of saturation. The heteroatom can be located on the non-aromatic or aromatic ring of a heterocyclyl group. The heterocyclyl can have 3 to 14, 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 a heterocyclyl group may preferably be a 3-, 4-, 5-, 6-, or 7-membered monocyclic group, and sometimes a heterocyclyl preferably may preferably be a 8-, 9, or 10-membered bicyclic group. Examples of heterocyclyl include, but not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thietanyl, piperidinyl, piperazinyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3- dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathianyl, 1,4-oxathianyl , 2H-1,3- dioxolanyl, 1,3-dithiolanyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinone, oxazolidinone, thiazolidinyl, 1,3-oxathiolyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl and tetrahydroquinolinyl. The term “alkylene” refers to a saturated linear or branched divalent aliphatic hydrocarbon group, derived by removing two hydrogen atoms the parent alkane containing 1 to 12 carbon atoms (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon atom(s)), sometimes preferably 1 to 8 carbon atom(s), sometimes more preferably 1 to 6 carbon atom(s), and sometimes more preferably 1 to 4 carbon atom(s). Non-limiting examples of alkylene groups 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-butylidene (-CH2CH2CH2CH2-), etc. The alkylene group can be substituted or unsubstituted. The term “alkenylene” refers to an alkylene containing 2 to 12 carbon atoms defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, preferably 45 160112428.1 Docket No.: 358117.00008 C2-10alkenylene, more preferably C2-8alkenylene, sometimes more preferably C2-6alkenylene, and sometimes even more prefereably C2-4alkenylene. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, - CH2CH=CHCH2- etc. The alkenylene group can be substituted or unsubstituted. In the present disclosure, “alkyl” and “alkylene,” “alkenyl” and “alkenylene,” “aryl” and “arylene,” “cycloalkyl” and “cycloalkylene,” or the like, may sometimes be used interchangeably. Thus, interpretation of these terms should be based on the context as would be understood by a person of ordinary skill in the art. The term “aryl” refers to a 6 to 14 membered all-carbon monocyclic ring or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group, and has a completely conjugated pi- electron system. Preferably aryl is 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. The aryl group can be substituted or unsubstituted. The term “heteroaryl” refers to a 5 to 14 membered aryl system having 1 to 4 heteroatom(s) selected from O, S and N as ring atoms. Preferably a heteroaryl is 5- to 10- membered (such as 5, 6, 7, 8, 9 and 10 membered), more preferably 5- or 6- membered, for example, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, benzothienyl, and the like. The heteroaryl can be fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl. The heteroaryl group can be substituted or unsubstituted. The term “alkoxy” refers to both an -O-(alkyl), for example, methoxy, ethoxy, propoxy, butoxy, and the like. The term “cycloalkoxy” refers to -O-(cycloalkyl), for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The term “bond” refers to a covalent bond using a sign of “-”. The term “hydroxyl” refers to an -OH group. The term “halogen” or “halo” refers to fluoro, chloro, bromo or iodo atoms. The term “amino” refers to a -NH2group. The term "alkylthio" refers to alkyl-S-. 46 160112428.1 Docket No.: 358117.00008 The term “alkylamino” refers to “alkyl-NH-”, or sometimes dialkyl amino (-NRaRb), where the two alkyl groups (Raand Rb) can be the same or different. Sometimes preferably, the alkyl group is a C1-C6alkyl, and sometimes more preferably, the alkyl is a C1-C4alkyl. Examples of alkylamino include, but are not limited to, CH3-NH-, -N(CH3)2, -N(CH2CH3)2, - NHCH2CH3, -N(CH3)(CH2CH3), -NH-But, -N(CH3)(But), or the like. The term “cyano” refers to a -CN group. The term "haloalkyl" means an alkyl group substituted by one or more halogen atoms, wherein the halogen atoms can be the same or different. The term “nitro” refers to a -NO2group. The term “oxo group” refers to a =O group. The term “carboxyl” refers to a -C(O)OH group. The term “alkoxycarbonyl” refers to a -C(O)O(alkyl) group. The term “alkylcarbonyl” refers to a -C(O)-alkyl group. The term “optional” or “optionally” means that the event or circumstance described subsequently can, but need not, occur, and the description includes the instances in which the event or circumstance may or may not occur. For example, “the heterocyclyl group optionally substituted by an alkyl” means that an alkyl group can be, but need not be, present, and the description includes the case of the heterocyclyl group being substituted with an alkyl and the heterocyclyl group being not substituted with an alkyl. The term “substituted” refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atom(s), independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable. The term “covalent bonding principle”, as used herein, refers to those basic rules and principles in formation of covalent bonds in an organic compound, as generally understood by a person of ordinary skill in the art. For example, a carbon atom is tetravalent and can form only four covalent bonds (e.g., four single bonds, or a double bonds plus two single bonds, etc.), an oxygen is divalent and can only form two covalent bonds (two single bond in -O-, or a double bond in =O). 47 160112428.1 Docket No.: 358117.00008 In some embodiments, when an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group, or the like, or a moiety thereof, is substituted, the substituent group(s) can be substituted at any available connection point(s), and the substituents can be one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from C1-C6alkyl, halogen, C1-C6alkoxy, C1-C6alkenyl, C1-C6alkynyl, C1-C6alkylthio, C1-C6alkylamino, di-(C1-C6alkyl)amino, thiol, hydroxyl, nitro, cyano, amino, C3- C6 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3- C6cycloalkoxy, C1-C6cycloalkylthio, 5- to 10-membered heterocyclylthio and oxo group. In some embodiments, sometimes preferably, the substituents are independently selected from C1-C6alkyl, halogen, C1-C6alkoxy, C1-C6alkylthio, C1-C6alkylamino, di-(C1-C6alkyl)amino, thiol, hydroxyl, nitro, cyano, amino, and oxo group. In some embodiments, sometimes more preferably, the substituents are independently selected from C1-C4alkyl, halogen, C1-C4alkoxy, C1-C4alkylthio, C1-C4alkylamino, di-(C1-C4alkyl)amino, thiol, hydroxyl, nitro, cyano, and amino. As a person of ordinary skill in the art would understand, an oxo (=O) group cannot be a substituent of an aryl or heteroaryl group, or at an unsaturated carbon in any other group. Denotation of carbon atoms or ring atoms in a substituent group, such as alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, or the like, may take different forms but they should be understood to mean a same thing as would be understood by those skilled in the art. For example, an alkyl group containing 1 to 6 carbon atoms may be denoted as “C1-C6alkyl,” “C1-6alkyl,” “C1-6alkyl,” or the like, which may occur for other substituent groups as well. The term “isomer,” as used herein, refers to all possible types of isomerism a compound may have, as suitable in the context. They may include stereoisomers, configurational isomers, geometrical isomers, conformational isomers, or the like. The term “stereoisomer” refers to isomers that are structurally identical but differ in the arrangement of the atoms in space, which may or may not by caused by asymmetric (chiral) centers in the structure. It includes enantiomers, diastereomers, atropisomers, or the like, and their respective mixtures. The term “atropisomers” refers to a special type of stereoisomer, i.e., conformational stereoisomers, which result from steric hindrance in a molecule such that rotation about a single bond is hindered or greatly slowed. Some atropisomers could be separated and isolated in a stable form. For example, certain compounds of the present disclosure may exist in the form of a mixture of atropisomers (e.g., an equal ratio mixture, a mixture enriched in one atropisomer) or a purified atropisomer under different conditions. All such stereoisomers and mixtures thereof are encompassed within the scope of the present 48 160112428.1 Docket No.: 358117.00008 disclosure, whether a compound is presented as a chiral form or not, whether only one single isomer or multiple isomers are presented. The present disclosure also encompasses cis- / trans- (or Z- / E-) isomers caused by the different configurations of substituents on a double bond, especially C=C, which are sometimes called geometrical isomers. The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term “tautomer” or “tautomeric form” refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form into another. Non-limiting examples include keto-enol tautomerism, imine-enamine tautomerism, or the like. As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, 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, unrecited elements or method steps. The terms “a” and “an” and “the” and similar references in the present disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like. The term “and / or” as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items. When used in a list of two or more items, the term “and / or” means that any one of the listed items can be employed by itself, or any combination of two or more of the listed items can be employed. A “pharmaceutical composition” refers to a mixture of one or more of the compounds described in the present disclosure or physiologically / pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biological activity. The term “pharmaceutically acceptable,” as used herein, refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical 49 160112428.1 Docket No.: 358117.00008 judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and are effective for their intended use. “Pharmaceutically acceptable salts” refer to salts of the compounds of the disclosure, such salts being safe and effective when used in a mammal and have corresponding biological activity. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable nitrogen atom with a suitable acid. Pharmaceutically acceptable salts are well known in the art. See, e.g., S. M. Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids. Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen bisulfide as well as organic acids, such as para-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, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid acid, and related inorganic and organic acids. Preferred pharmaceutically acceptable salts include the hydrochloride or hydrobromide salts. Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, and N-methylmorpholine. The term “prodrug,” as used herein, refers to a derivative of a compound that can be transformed in vivo to yield the parent compound, for example, by hydrolysis under physiological conditions. Common examples of prodrugs in the present disclosure include, but are not limited to, esters or amides, for example, the compound of formula (IIa), (IIb), or (IIc): 50 160112428.1 Docket No.: 358117.00008 wherein R11and / or R12is an acyl group (e.g., acetyl, propionyl, formyl, benzoyl, or the like). When it is possible that, for use in therapy, therapeutically effective amounts of a compound of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the disclosure further provides pharmaceutical compositions, which include any compounds of the present disclosure, or pharmaceutically acceptable salts thereof, and one or more, preferably one to three, pharmaceutically acceptable carriers, diluents, or other excipients. The carrier(s), diluent(s), or other excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the subject being treated. In the compounds disclosed herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. For example, substitution with heavier isotopes, such as replacing hydrogen (H) with deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half- life or reduced dosage requirements) and hence may be preferred in some circumstances. In addition, certain isotopically-labeled compounds (e.g., with3H and14C) are useful in compound and / or substrate tissue distribution assays. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent. The present disclosure also encompasses all suitable isotopic derivatives of the compounds disclosed. The term “isotopic derivative” refers to a compound in which at least one atom is replaced with an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into the compounds of the present disclosure 51 160112428.1 Docket No.: 358117.00008 include stable and radioactive isotopes of hydrogen, carbon, boron, nitrogen, oxygen, phosphorus, or the like, such as2H (deuterium, D),3H (deuterium, T),11C,13C,14C,15N,17O,18O, etc. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Typically, the pharmaceutical compositions of this disclosure will be administered from once every 1 to 5 days to about 1-5 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials 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 employed, the duration of treatment, and the age, gender, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compound is most desirably administered at a concentration level that will generally afford effective results without causing substantial harmful or deleterious side effects. When the compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more, preferably one or two, additional therapeutic or prophylactic agent, both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen. Pharmaceutical formulations may be adapted for administration by any appropriate route, for example, by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Oral administration or administration by injection are preferred. 52 160112428.1 Docket No.: 358117.00008 Pharmaceutical formulations adapted for oral administration may be presented 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 liquid emulsions or water-in-oil emulsions. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present. Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and / or and absorption agent such as betonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by 53 160112428.1 Docket No.: 358117.00008 means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages. Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form so that a given quantity 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 through the use of a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added. Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release, for example, by coating or embedding particulate material in polymers, wax, or the like. It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. The term “subject,” "patient,” or the like, includes both humans and other mammalian animals, including but not limited to cats, dogs, bigs, horses, sheep, goats, monkeys, chimpanzees, and so on, preferably humans. The term “therapeutically effective amount" refers to an amount of a compound or composition that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. A "therapeutically effective amount" can vary depending on, inter alia, the compound, the disease and its severity, and the age, weight, or other factors of the subject to be treated. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously. 54 160112428.1 Docket No.: 358117.00008 The term “treat”, “treating”, “treatment”, or the like, refers to: (i) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (ii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and / or condition. In addition, the compounds of present disclosure may be used for their prophylactic effects in preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder, and / or condition but has not yet been diagnosed as having it. When the term “about” is applied to a parameter, such as pH, concentration, temperature, or the like, it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%, and sometimes more preferably with ±2%. As would be understood by a person skilled in the art, when a parameter is not critical, a number is often given only for illustration purpose, instead of being limiting. The following non-limiting synthetic schemes, preparation methods and processes, and examples further illustrate certain aspects of the present disclosure. Compound Preparation and Biological Assays As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. 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 thereof. Abbreviations The following abbreviations have the indicated meanings: AcOH = acetic acid Boc = t-butyloxy carbonyl BOP = Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate CyJohn Phos = (2-biphenyl)dicyclohexylphosphine DBU = 1,8-Diazabicyclo[5,4,0]undec-7-ene DCM = dichloromethane DIAD = Diisopropyl azodicarboxylate 55 160112428.1 Docket No.: 358117.00008 DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide EtOH = ethanol EtOAc = ethyl acetate FA = formic acid HCHO = formaldehyde HPLC = high performance liquid chromatography Hr or h= hour LC-MS = liquid chromatography - mass spectrometry LiBHEt3= Lithium Triethylborohydride M= mol / L. m-CPBA = M-Chloroperoxybenzoic Me = methyl MeCN = acetonitrile MeOH = methanol MOMCl = chloromethyl methyl ether MsCl = Methane sulfonyl chloride NaBH3CN = Sodium cyanoborohydride NaH = sodium hydride NMP = 1-Methyl-2-pyrrolidinone NMR = nuclear magnetic resonance NOE = nuclear Overhauser effect Pd(dppf)Cl2= dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium Pd(dtbpf)Cl2= [1,1'-Bis(di-tert-butylphosphino)ferrocene]palladium(II)Dichloride PE = petroleum ether Pd(OAc)2= Palladium (II) Acetate POCl3= Phosphorus oxychloride Py = pyridine RT = room temperature Rt = Retention time Sat. = saturated SFC = Supercritical Fluid Chromatography SPhos Pd G2 = Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2- (2'-amino-1,1'-biphenyl)]palladium(II) 56 160112428.1 Docket No.: 358117.00008 TBSCl = tert-Butyldimethylsilyl chloride t-Bu-TMG = 2-tert-butyl-1,1,3,3-tetramethyl-guanidine TEA = triethylamine TFA = Trifluoracetic acid TFAA = Trifluoroacetic anhydride Tf2O = Trifluoromethanesulfonic anhydride THF = Tetrahydrofuran TLC = Thin layer chromatography. General Conditions and Procedures In the following examples, the chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company and the like) and used without further purification. THF was continuously refluxed and freshly distilled from sodium and benzophenone under nitrogen, dichloromethane was continuously refluxed and freshly distilled from CaH2under nitrogen. Flash chromatography was performed on Biotage Isolera One via column with silica gel particles of 200-300 mesh. Analytical and preparative TLC plates were HSGF 254 (0.15- 0.2 mm thickness, Shanghai Anbang Company, China). NMR spectra were recorded using Brucker AVANCE NEO 400 (Brucker, Switzerland) at around 20 - 30 °C unless otherwise specified. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiple; dd, doublet of doublets; bs, broad signal. Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were run with electrospray ionization (ESI) from a Shimadzu LCMS2020 Mass Spectrometer (Shimadzu, Japan). Compound purification was carried out as needed using a variety of methods including, but not limited to, preparative chromatography under acidic, neutral, or basic conditions using either normal phase or reverse phase HPLC or flash columns or Prep-TLC plates. Preparative HPLC: unless otherwise described, the compounds were purified using a SHIMADZU LH-40 or FRC-40 equipped with a YMC-Triart C18 Column (5 μm, 120A, 250 x 20 mm) and the following solvent system: H2O, MeCN, and 0.1% FA in H2O or H2O, MeOH, and 0.1% FA in H2O or H2O, MeCN, and 0.1% NH4OH / NH4HCO3in H2O or H2O, MeCN, and 0.1% NH4OH / NH4HCO3in H2O. Specific elution gradients were based on the retention times obtained with an analytical LC-MS, however, in general all elution gradients of H2O and MeCN or MeOH were run over a 20 minutes run time with a flow rate of 20 mL / min. An auto- blend method was used to ensure a concentration of 0.1% FA throughout each run. For 57 160112428.1 Docket No.: 358117.00008 purifications using eluents containing FA, the final products after lyophilization or drying are full or partial salt of FA as evident from NMR. The qualitative nature of these salts is listed in the descriptions in the Examples. Analytical LC-MS: analytical LC-MS was performed on a SHIMADZU LCMS2020 instrument equipped with a Shim-pack Scepter C18Column (3.0 x 33 mm, 3 μm), a column temperature of 40 °C and using the following solvent system: Solvent A: 0.05% HCOOH in H2O; and Solvent B: MeCN. All compounds were run using the same elution gradient, i.e., 20% to 95% Solvent B over a 3 min run time with a flow rate of 1.2 mL / min. Preparative Chiral SFC Separation: stereoisomer mixtures were separated using a Waters SFC 80 (Waters, USA) or Nexera UC Prep (Shimadzu, Japan) system instrument on one of the following columns: ChiralPak AS-H (21.2 x 250 mm,5μm), ChiralPak IA (21.2 x 250 mm,5μm), ChiralPak AD-H (21.2 x 250 mm, 5μm), or ChiralPak IC (21.2 x 250 mm, 5μm); eluting with either 0.05% diethylamine in MeOH / CO2, or 0.05% diethylamine in EtOH / CO2or 0.05% diethylamine in isopropanol / CO2with a flow rate of 40 mL / min and a column temperature of 40 °C. Analytical Chiral SFC Separation: stereoisomer mixtures or single enantiomers were analyzed using a Waters UPCC (Waters, USA) or UC (Shimadzu, Japan) on one of the following columns: ChiralPak AS-H (4.6 x 100 mm, 3.5μm), ChiralPak IA (4.6 x 100 mm, 3.5μm), ChiralPak AD-H (4.6 x 100 mm, 3.5μm), or ChiralPak IC (4.6 x 100 mm, 3.5μm); eluting with either 0.05% diethylamine in MeOH / CO2, or 0.05% diethylamine in EtOH / CO2or 0.05% diethylamine in isopropanol / CO2, with a flow rate of 1.8 mL / min and a column temperature of 40 °C. Schemes for the preparation of final targets: General Scheme 1: 160112428.1 Docket No.: 358117.00008 In general scheme 1, treatment of formulae I and II with appropriate base and solvent (e.g., NaH, DMF) gave formulae III. The protecting group of formulae III was removed under appropriate conditions (e.g., TFA or HCl to remove Boc group) to give formulae IV. Treatment of formulae IV under reductive amination conditions (such as NaBH3CN, formaldehyde in formic acid, etc.) or alkylation conditions afforded the final product formulae V. General scheme 2 PRG2O PRG1ROPRG1N R6In under SNArconditions (e.g., NaH, DMF) gave formulae VII. Formulae III were prepared from formulae VII with appropriate phenyl-borates under Suzuki coupling conditions (such as Pd(dtbpf)Cl2with base in appropriate solvents, etc.). The protecting group of formulae III was removed under appropriate conditions (e.g., TFA or HCl to remove Boc group) to give formulae IV. Treatment of formulae IV under reductive amination conditions (such as NaBH3CN, formaldehyde in formic acid, etc.) or alkylation conditions afforded the final product formulae V. Examples of Preparative Intermediates Intermediate 1 Tert-butyl (R)-3-mercaptopiperidine-1-carboxylate Step 1: Tert-butyl (S)-3-((methylsulfonyl)oxy)piperidine-1-carboxylate 59 160112428.1 Docket No.: 358117.00008 To a solution of tert-butyl (S)-3-hydroxypiperidine-1-carboxylate (4 g, 20 mmol) in DCM (50 mL) was added TEA (8.3 mL, 60 mmol) followed by drop-wise addition of MsCl (4.6 g, 40 mmol) at 0 ℃ and the mixture was stirred at RT for 2 hrs. The mixture was quenched with ice- water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness to give the title compound (5.5 g) as a solid.1H 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)+. Step 2: Tert-butyl (R)-3-(acetylthio)piperidine-1-carboxylate To a solution of tert-butyl (S)-3-((methylsulfonyl)oxy)piperidine-1-carboxylate (4.5 g, 16 mmol) in DMF (50 mL) was added potassium thioacetate (4.6 g, 40 mmol) at RT and the mixture was stirred under N2at 100 ℃ for 1 hour. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to give the title compound (1.6 g) as an oil.1H 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)+. Step 3: Tert-butyl (R)-3-mercaptopiperidine-1-carboxylate To a solution of tert-butyl (R)-3-(acetylthio)piperidine-1-carboxylate (1.0 g, 3.9 mmol) in MeOH (10 mL) was added K2CO3(1.1 g, 7.7 mmol) at 0 ℃ and the mixture was stirred at 0 ℃ for 15 mins. 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)+. Intermediate 2a & Intermediate 2b Tert-butyl (R)-3-((6-chloro-5-methylpyridazin-3-yl)thio)piperidine-1-carboxylate (Intermediate 2a) & tert-butyl (R)-3-((6-chloro-4-methylpyridazin-3-yl)thio)piperidine- 1-carboxylate (Intermediate 2b) 60 160112428.1 Docket No.: 358117.00008 To a solution of tert-butyl (R)-3-mercaptopiperidine-1-carboxylate (6.67 g, 30.7 mmol) in DMF (100 mL) was added NaH (1.47 g, 61.3 mmol, 60% dispersion in mineral oil) in portions at 0 ℃ and the mixture was stirred under N2at 40 ℃ for 30 mins.3,6-Dichloro-4-methyl-1,2- diazine (10 g, 61.35 mmol) was added to the above mixture and the resulting mixture was stirred at RT overnight. The mixture was quenched with sat. aq. NH4Cl solution at 0oC and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compound (4.4 g, a mixture of regio-isomers) as a solid.1H 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)+. Intermediates 3 and 4 6-Chloro-3-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4-methylpyridazine (Intermediate 3) & 3-chloro-6-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4- methylpyridazine (Intermediate 4) To a solution of 5-bromo-2-chlorophenol (26.5 g, 128 mmol) in THF (300 mL) was added NaH (5.12 g, 128 mmol, 60% dispersion in mineral oil) in portions at 0 °C under N2and the mixture was stirred at RT for 1 hr. MOMCl (12 mL, 153 mmol) was added at 0 °C and the mixture was stirred at RT overnight. The mixture was quenched with water at 0 °C and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5% EtOAc in PE) to afford the title compound (30 g) as an oil. 61 160112428.1 Docket No.: 358117.000081H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.23 (s, 2H), 3.52 (s, 3H). Step 2: 1-Chloro-4-cyclopropyl-2-(methoxymethoxy)benzene 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) was added Cs2CO3(38.9 g, 119 mmol), tricyclohexyl phosphine (4.2 g, 14.9 mmol) and Pd(OAc)2(1.3 g, 5.96 mmol) under N2at RT, the mixture was degassed with N2three times and stirred at 85 °C for 16 hrs. The mixture was diluted with EtOAc, and layers separated. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10% EtOAc in PE) to afford the title compound (7.5 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.2 Hz, 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). Step 3: (4-Cyclopropyl-2-(methoxymethoxy)phenyl)boronic acid 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) were added TEA (5.9 mL, 42.3 mmol), CyJohn Phos (990 mg, 2.82 mmol) and Ni(NO3)2(260 mg, 1.41 mmol) under N2at 0 °C and the mixture was stirred under N2at 0 °C for 1 hr. The mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to afford the title compound (670 mg) as an oil. Step 4: 6-Chloro-3-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4-methylpyridazine and 3-chloro-6-(4-cyclopropyl-2-(methoxymethoxy)phenyl)-4-methylpyridazine 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) was added K2CO3 (934 mg, 6.76 mmol) and Pd(dppf)Cl2 (198 mg, 0.270 mmol) under N2 at RT. The mixture was degassed with N2three times and stirred under N2at 90 °C for 3 hrs. The mixture was diluted with water upon cooling to RT and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to Intermediate 3 (160 mg) followed by Intermediate 4 (650 mg) as oils. 62 160112428.1 Docket No.: 358117.00008 The structure of Intermediate 4 was confirmed by NOE. Intermediate 3: LC / MS (ESI) m / z: 305 (M+H)+. Intermediate 4:1H NMR (400 MHz, 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)+. Intermediates 5 3-Chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine To a mixture of (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (1.1 g, 5.19 mmol) and 6- chloro-4-methylpyridazin-3-ol (500 mg, 3.46 mmol) in 1,4-dioxane (10 mL) and water (4 mL) was added K2CO3(1.4 g, 10.38 mmol) and 1,1'-bis(di-t-butylphosphino)ferrocene palladium dichloride (223 mg, 0.35 mmol) under N2. The mixture was degassed with N2three times and stirred under N2at 90 °C for 3 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% of EtOAc in PE) to give the title compound (650 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 11.46 (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)+. Step 2: 3-Chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine 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) was added POCl3(351 mg, 2.29 mmol) under N2and the mixture was stirred at 60 ℃ for 3 hrs. The mixture was concentrated under reduced pressure to dryness. The residue diluted with ice-water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% of EtOAc in PE) to give the title compound (370 mg) as a solid. LC / MS (ESI) (m / z): 303 / 305 (M+H)+. The intermediates in Table 1 below were prepared using similar procedures described for the preparation of Intermediate 3 and Intermediate 4 from appropriate starting materials. 63 160112428.1 Docket No.: 358117.00008 Table 1. Intermediates Prepared using Procedures for Intermediates 5 Intermediate Structure H NMR, LCMS 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.8 ), S , 8 ), S 9 = 6 Intermediate 11 6-Chloro-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4-methylpyridazine Step 1: 2-(6-Chloro-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol 64 160112428.1 Docket No.: 358117.00008 To a solution of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (7.90 g, 26.2 mmol) in DCM (50 mL) was added BBr3(104.8 mL, 104.8 mmol, 1 M in DCM) drop- wisely at -78 ℃ and the mixture was stirred at -78 ℃ to RT for 2 hrs. The mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 2: 6-Chloro-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4-methylpyridazine To a solution of 2-(6-chloro-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (5.00 g, 17.4 mmol) in DCM (50 mL) was added DIPEA (4.50 g, 34.9 mmol) followed by drop-wise addition of MOMCl (2.11 g, 26.1 mmol) at 0oC and the mixture was stirred at RT for 3 hrs. The mixture was quenched with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compound (2.52 g) as a solid.1H 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)+. Intermediate 12 2-(2-Fluoro-6-methoxy-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane To a solution of 1-fluoro-3-methoxy-5-(trifluoromethyl)benzene (2.00 g, 10.3 mmol) in THF (20 mL) was added n-BuLi (6.5 mL, 10.3 mmol, 2.5 M in Hexanes) drop-wisely at -78 °C and the mixture was stirred at -78 °C for 1 hr. To the reaction mixture was added 2-isopropoxy- 4,4,5,5-tetramethyl-l,3,2- dioxaborolane (2.3 mL, 11.0 mmol) at -78 °C and the resulting mixture was stirred at -78 °C for 2 hrs. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried 65 160112428.1 Docket No.: 358117.00008 over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% EtOAc in PE) to give the title compound (1.8 g) as a solid.1H 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). Intermediate 13 Tert-butyl (R)-3-((6-chloropyridazin-3-yl)thio)piperidine-1-carboxylate To a solution of mL) were added Cs2CO3(3.30 g, 10.1 mmol) and tert-butyl (R)-3-mercaptopiperidine-1-carboxylate (1.10 g, 5.07 mmol) at 0oC and the mixture was stirred at 80oC for 5 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. EXAMPLES Example 1 (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5- (trifluoromethyl)phenol, formic salt (partial) - - 66 160112428.1 Docket No.: 358117.00008 3-yl)thio)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-mercaptopiperidine-1-carboxylate (718 mg, 3.3 mmol) in DMF (10 mL) was added NaH (198 mg, 4.95 mmol, 60% dispersion in mineral oil) under N2at 0 ℃ and the mixture was stirred at 40 ℃ for 30 mins. 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 stirred under N2at 30 ℃ overnight. 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 under reduced pressure to dryness. The residue was purified by flash 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)+. Step 2: (R)-2-(4-methyl-6-(piperidin-3-ylthio)pyridazin-3-yl)-5-(trifluoromethyl)phenol To a solution of tert-butyl (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)thio)piperidine-1-carboxylate (100 mg, 0.21 mmol) in DCM (3 mL) was added BBr3(155 mg, 0.62 mmol) at -78 ℃ and the mixture was stirred at -78 ℃ for 10 mins and RT for 2 hrs. The mixture was quenched with sat. aq. NaHCO3 solution and extracted with DCM three times. 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)+. Step 3: (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5- (trifluoromethyl)phenol, formic salt (partial) 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) was added 37% aq. HCHO (0.035 mL, 0.95 mmol), AcOH (0.011 mL, 0.19 mmol) and NaBH3CN (36 mg, 0.57 mmol) at RT and the mixture was stirred under N2at RT for 0.5 hr. The mixture was quenched with sat. aq. NH4Cl solution and extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*21 mm, 10 ~ 90% MeCN in H2O with 0.1% FA) to give the title compound (20 mg) as a solid.1H NMR (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 67 160112428.1 Docket No.: 358117.00008 (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)+. The examples listed in Table 2 were prepared following the methods and protocols similar to those described for the synthesis of Example 1 from appropriate starting materials. Table 2. Examples Prepared Using Procedure for Example 1 Example Structure & Name H-NMR, LC / MS 9 0 - 4 6 9 , 1 4 9 9 , 68 160112428.1 Docket No.: 358117.00008 methylpiperidin-3-yl)thio)pyridazin- 2H). LC / MS (ESI) m / z: 384 (M+H)+. 3-yl)-5-(trifluoromethyl)phenol 8 6 - I) 52 z, S 69 160112428.1 Docket No.: 358117.00008 1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.57 (s, - 17 6 xa p e 2-(4-methyl-6-(((R)-1-methylpiperidin-3-yl)sulfinyl)pyridazin-3-yl)-5- (trifluoromethyl)phenol 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) was added Oxone (72 mg, 0.12 mmol) at 0 ℃ and the mixture was stirred at 0 ℃ for 0.5 hr. 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 prep-HPLC (YMC-Actus Triart C18, 10 ~ 90% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (2 mg) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.28 (s, 1H), 3.20 - 3.16 (m, 2H), 2.67 - 2.58 (m, 1H), 2.46 - 2.41 (m, 1H), 2.31 (s, 3H), 2.28 - 2.21 (m, 1H), 2.18 (s, 3H), 1.88 - 1.73 (m, 2H), 1.64 - 1.50 (m, 2H). LC / MS (ESI) (m / z): 400 (M+H)+. Example 12 (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)sulfonyl)pyridazin-3-yl)-5- (trifluoromethyl)phenol, trifluoroacetic acid salt 70 160112428.1 Docket No.: 358117.00008 Step 1: 3- yl)sulfonyl)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)thio)piperidine-1-carboxylate (250 mg, 0.52 mmol) in DCM (5 mL) was added m-CPBA (210 mg, 1.0 mmol) and the mixture was stirred at RT for 3 hrs. The mixture was quenched with sat. aq. Na2SO3 solution and extracted with DCM twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 2: (R)-2-(4-methyl-6-(piperidin-3-ylsulfonyl)pyridazin-3-yl)-5- (trifluoromethyl)phenol 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) was added BBr3 (143 mg, 0.59 mmol) drop-wisely at -78 ℃ and the mixture was stirred under N2at -78 ℃ for 10 mins and RT for 2 hrs. The mixture was quenched with sat. aq. NaHCO3solution at 0 ℃ and extracted with DCM three times. 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)+. Step 3: (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)sulfonyl)pyridazin-3-yl)-5- (trifluoromethyl)phenol, trifluoroacetic acid salt To 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 37% aq. HCHO (0.05 mL), a drop of AcOH and NaBH3CN (25 mg, 0.39 mmol) at 0oC. and the mixture was stirred at RT for 0.5 hr. The mixture was quenched with ice-water and extracted with EtOAc twice. 71 160112428.1 Docket No.: 358117.00008 The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (YMC-ActusTriart C18, 30 ~ 60% MeCN in water with 0.1% TFA) to give the title compound (12 mg) as a white solid.1H 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)+. Example 13 (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol 6-(piperidin-3- ylthio)pyridazine hydrochloride To a solution of tert-butyl (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)thio)piperidine-1-carboxylate (450 mg, 0.9 mmol) in DCM (5 mL) was added HCl / 1,4-dioxane (5 mL, 4 M) and the mixture was stirred at RT for 2 hrs. The mixture was concentrated under reduced pressure to dryness 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)+. Step 2: (R)-2-(3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)thio)piperidin-1-yl)ethan-1-ol 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) was added 2-((tert- butyldimethylsilyl)oxy)acetaldehyde (477 mg, 2.7 mmol), AcOH (0.05 mL, 0.9mmol) and NaBH3CN (169 mg, 2.7 mmol) at 0oC and the mixture was stirred at RT for 0.5 hr. The mixture was quenched with ice-water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure 72 160112428.1 Docket No.: 358117.00008 to dryness to give the title compound (350 mg) as an oil. LC / MS (ESI) (m / z): 428 (M+H)+. Step 3: (R)-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol To a solution of (R)-2-(3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)thio)piperidin-1-yl)ethan-1-ol (300 mg, 0.7 mmol) in DCM (3 mL) was added BBr3(250 mg, 0.7 mmol) at -78 ℃ and the mixture was stirred at 0 ℃ for 1 hr. The mixture was quenched with MeOH at 0oC and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-ActusTriart C18, 40 ~ 95% MeCN in water with 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)+. Example 14 (R)-5-methyl-2-(4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)phenol 3- yl)thio)piperidine-1-carboxylate and tert-butyl (R)-3-((6-(2-methoxy-4-methylphenyl)-4- methylpyridazin-3-yl)thio)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((6-chloro-5-methylpyridazin-3-yl)thio)piperidine-1- carboxylate and tert-butyl (R)-3-((6-chloro-4-methylpyridazin-3-yl)thio)piperidine-1- carboxylate (500 mg, 1.46 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added (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) at RT. The mixture was degassed with N2three times and stirred under N2atmosphere at 90oC for 4 hrs. The mixture was cooled to RT, diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. 73 160112428.1 Docket No.: 358117.00008 The residue was purified by flash column chromatography (silica gel, 0 - 40% EtOAc in PE) to give compound 2 (110 mg) and compound 2a (60 mg) as solids. Compound 2:1H 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)+. Step 2: (R)-5-methyl-2-(4-methyl-6-(piperidin-3-ylthio)pyridazin-3-yl)phenol To a solution of tert-butyl (R)-3-((6-(2-methoxy-4-methylphenyl)-5-methylpyridazin-3- yl)thio)piperidine-1-carboxylate (100 mg, 0.233 mmol) in DCM (3 mL) was added BBr3(2.3 mL, 2.3 mmol, 1 M in DCM) drop-wisely at -78 ℃ and the mixture was stirred at -78 ℃ to RT for 2 hrs. The mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with DCM three times. 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)+. Step 3: (R)-5-methyl-2-(4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)phenol 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% aq. HCHO (0.1 mL) in MeOH (2 mL) was added AcOH (19.2 mg, 0.32 mmol) and NaBH3CN (30.2 mg, 0.48 mmol) at 0 ℃ and the mixture was stirred at RT for 20 mins. The mixture was quenched with water and extracted with DCM twice. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-ActusTriart C18250*20 mm, 0-95% acetonitrile in H2O with 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)+. Example 15 (R)-5-chloro-2-(4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)phenol 74 160112428.1 Docket No.: 358117.00008 for the synthesis of Example 14.1H NMR (400 MHz, DMSO-d6) δ 7.44 (s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 6.84 (s, 1H), 6.78 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)+. Example 16 & Example 17 3-Fluoro-2-(4-methyl-6-(((R)-1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5- (trifluoromethyl)phenol (Example 16) & (R)-3-fluoro-2-(5-methyl-6-((1-methylpiperidin- 3-yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol (Example 17) for the synthesis of Example 14 except the regio-isomers were separated in the final step by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5 ~ 95% MeCN in H2O with 0.1% FA) to give Example 16 followed by Example 17 as solids. Example 16:1H 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), 75 160112428.1 Docket No.: 358117.00008 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 17:1H 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 (m, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 2.19 - 2.15 (m, 1H), 1.99 - 1.92 (m, 1H), 1.89 - 1.79 (m, 1H), 1.70 - 1.62 (m, 1H). LC-MS (ESI) (m / z): 402.4 (M+H)+. Example 18 2-(6-((2,2-Dimethyltetrahydro-2H-pyran-4-yl)thio)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol Step 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) was added MsCl (1.76 g, 15.4 mmol) at 0 ℃ under N2. The reaction mixture was stirred at RT for 3 hrs. The reaction mixture was diluted with water and extracted with DCM twice. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness to give the title compound (1.5 g) as an oil.1H 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). Step 2: S-(2,2-Dimethyltetrahydro-2H-pyran-4-yl) ethanethioate To a solution of 2,2-dimethyltetrahydro-2H-pyran-4-yl methanesulfonate (1.5 g, 7.28 mmol) in DMF (10 mL) was added potassium thioacetate (2.1 g, 18.2 mmol), and the reaction mixture was stirred under N2at 100 ℃ for 3 hrs. The mixture was diluted with sat. aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 3: 2,2-Dimethyltetrahydro-2H-pyran-4-thiol 76 160112428.1 Docket No.: 358117.00008 To the solution of S-(2,2-dimethyltetrahydropyran-4-yl) ethanethioate (508 mg, 2.70 mmol) in MeOH (10 mL) was added K2CO3(1.1 g, 8.09 mmol) at RT and the mixture was stirred at RT for 4 hrs. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness to give the title compound (298 mg) as an oil. LC / MS (ESI) m / z: 147 (M+H)+. Step 4: 6-((2,2-Dimethyltetrahydro-2H-pyran-4-yl)thio)-3-(2-methoxy-4- (trifluoromethyl)phenyl)-4-methylpyridazine To a solution of 2,2-dimethyltetrahydro-2H-pyran-4-thiol (298 mg, 2.04 mmol) in DMF (10 mL) was added NaH (204 mg, 5.10 mmol, 60% dispersion in mineral oil) at 0 ℃ and the reaction mixture was stirred at 40 ℃ for 30 mins. To the mixture was added 6-chloro-3-(2- methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (514 mg, 1.70 mmol) and the resulting mixture was stirred at 30 ℃ overnight. The mixture was quenched with sat. aq. NH4Cl solution at 0oC and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 5: 2-(6-((2,2-Dimethyltetrahydro-2H-pyran-4-yl)thio)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol 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) was added BBr3(577 mg, 2.3 mmol) under N2at -78 ℃ and the mixture was stirred at RT for 3 hrs. The mixture was poured into ice-cooled sat. aq. NaHCO3solution and extracted with DCM twice. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Triart C18, 40 ~ 50% MeCN in water with 0.1% FA) to give the title compound (10.3 mg) as a solid.1H 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)+. Example 19 (Rac)-2-(4-methyl-6-(((1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)thio)pyridazin- 3-yl)-5-(trifluoromethyl)phenol, formic acid salt 77 160112428.1 Docket No.: 358117.00008 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) was added NaBH4 (336 mg, 8.9 mmol) and the mixture was stirred under N2 atmosphere at 0 °C for 1 hr. The mixture was quenched with ice-water and extracted with EtOAc three times. 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)+. Step 2: Tert-butyl 2-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 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) was added DIPEA (853 mg, 6.6 mmol) followed by drop-wise addition of MsCl (570 mg, 5.0 mmol) at 0 °C and the mixture was stirred at 0 °C for 1 hr. The mixture was diluted with sat. aq. NaHCO3solution and extracted with EtOAc three times. 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)+. Step 3: Tert-butyl 2-(acetylthio)-8-azabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 2-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (800 mg, 2.62 mmol) DMF (15 mL) was added potassium ethanethioate (450 mg, 3.93 mmol) and the mixture was stirred under N2atmosphere at 60 °C for 2 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% of EtOAc in PE) to give the title compound (700 mg) as a solid. LC-MS (ESI) (m / z): 286.1 (M+H)+. Step 4: Tert-butyl 2-mercapto-8-azabicyclo[3.2.1]octane-8-carboxylate 78 160112428.1 Docket No.: 358117.00008 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) was added K2CO3(1.02 g, 7.35 mmol) and the mixture was stirred under N2atmosphere at 40 °C for 4 hrs. The mixture was quenched with aq. HCl (30 mL, 0.5 M) at 0oC and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (550 mg) as a solid. LC-MS (ESI) (m / z): 244.1 (M+H)+. Step 5: (Rac)-tert-butyl (1R,2R,5S)-2-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)thio)-8-azabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 2-mercapto-8-azabicyclo[3.2.1]octane-8-carboxylate (400 mg, 1.64 mmol) in MeCN (20 mL) was added Cs2CO3(1.07 g, 3.28 mmol) and 6-chloro-3-(2-methoxy- 4-(trifluoromethyl)phenyl)-4-methylpyridazine (595 mg, 1.97 mmol) and the mixture was stirred under N2atmosphere at 80 °C for 3 hrs. The mixture was cooled to RT and filtered. The filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% of EtOAc in PE) to give the title compound (400 mg) as a solid. LC-MS (ESI) (m / z): 510.2 (M+H)+. Step 6: (Rac)-2-(6-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)thio)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol To a solution of (rac)-tert-butyl (1R,2R,5S)-2-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)thio)-8-azabicyclo[3.2.1]octane-8-carboxylate (400 mg, 0.78 mmol) in DCM (20 mL) was added BBr3(3 mL, 3 mmol, 1M in DCM) drop-wisely at -78oC and the mixture was stirred at RT for 1 hour. The mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash 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)+. Step 7: (Rac)-2-(4-methyl-6-(((1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol To a solution of (rac)-2-(6-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)thio)-4- methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (250 mg, 0.63 mmol) in MeOH (10 mL) was added formaldehyde (40 mg, 1.33 mmol), acetic acid (0.1 mL) and NaBH3CN (200 mg, 3.18 mmol) at 0oC and the mixture was stirred at RT for 30 mins. The mixture was quenched with sat. aq. NH4Cl solution and extracted EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*21mm, 5 ~ 95% MeCN in H2O with 0.1% FA) to 79 160112428.1 Docket No.: 358117.00008 give the title compound (150 mg) as a solid.1H NMR (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)+. Example 20 & Example 21 2-(4-Methyl-6-(((1S,2S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)thio)pyridazin-3-yl)- 5-(trifluoromethyl)phenol (Example 20) & 2-(4-Methyl-6-(((1R,2R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)thio)pyridazin-3-yl)- 5-(trifluoromethyl)phenol (Example 21) Example 19 were resolved by chiral SFC to give Example 20 (peak 1, Rt= 3.403 min) and Example 21 (peak 2, Rt= 4.225 min) as solids, the configuration assignments were based on bioactivity in comparison with similar analogs made from chiral starting materials. Chiral SFC condition: Column: ChiralPak C-IG, 250×30mm I.D., 5µm; Mobile phase: A= CO2 and B= MeOH (0.1% DEA in MeOH); Isocractic: 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 21:1H 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)+. Example 22 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol 80 160112428.1 Docket No.: 358117.00008 To a solution of (2S,4S)-4-hydroxytetrahydropyrrole-2-carboxylic acid (20 g, 152.5 mmol) in EtOH (180 mL) was added SOCl2(19.05 g, 160 mmol) drop-wisely at 0 °C and the mixture stirred at 80oC for 6 hrs. The mixture was concentrated under reduced pressure to dryness to give the title compound (22 g) as a solid. LC-MS (ESI) (m / z):160 (M+H)+. Step 2: Ethyl (2S,4S)-1-benzyl-4-hydroxypyrrolidine-2-carboxylate To a solution of ethyl (2S,4S)-4-hydroxytetrahydropyrrole-2-carboxylate hydrochloride (22 g, 112 mmol) in DCM (500 mL) was added TEA (34.93 mL, 251.3 mmol) followed by drop-wise addition of benzyl bromide (15.69 mL, 131.9 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 hrs. The mixture was quenched with ice-water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0~40% of EtOAc in PE) to give the title compound (25 g) as a solid. LC-MS (ESI) (m / z): 250 (M+H)+. Step 3: Ethyl (2S,4S)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylate To a mixture of ethyl (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) was added TBSCl (13.0 g, 86.3 mmol) in portions at 0 °C and the mixture was stirred at RT for 16 hrs. The mixture was 81 160112428.1 Docket No.: 358117.00008 diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash 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)+. Step 4: ((2S,4S)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methanol To a solution of ethyl (2S,4S)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2- carboxylate (20 g, 55.0 mmol) in THF (300 mL) was added LiBHEt3 (110.5 mL, 110.5 mmol, 1 M in THF) drop-wisely at 0 ℃ and the mixture was stirred under N2atmosphere at 25 ℃ for 24 hrs. The mixture was quenched with sat. aq. NH4Cl solution at 0 ℃ and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash 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)+. Step 5: (3R,5S)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol To a solution of ((2S,4S)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-yl)methanol (10.0 g, 31.1 mmol) in anhydrous THF (120 mL) was added TFAA (6.53 mL, 46.7 mmol) drop-wisely at -78oC and the mixture was stirred at -78oC for 1 hr. Then TEA (4.32 mL, 31.1 mmol) was added drop-wisely to the above mixture at -78oC and the resulting mixture was stirred at 70oC for 16 hrs. The mixture was cooled to RT and quenched with aq. NaOH solution (100 mL, 2.5 M). The resulting mixture was stirred at RT for 1 hour. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compound (7.0 g) as an oil.1H NMR (400 MHz, CDCl3) δ 7.32 - 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), 2.68 - 2.47 (m, 2H), 2.45 - 2.38 (m, 1H), 2.33 - 2.22 (m, 1H), 1.79 - 1.67 (m, 2H), 0.86 (s, 9H), 0.00 (s, 3H), -0.06 (s, 3H). LC-MS (ESI) m / z: 322.5 (M+H)+. Step 6: (3S,5S)-1-benzyl-3-((tert-butyldimethylsilyl)oxy)-5-fluoropiperidine To a solution of (3R,5S)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol (5.0 g, 15.6 mmol) in DCM (60 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (2.46 mL, 18.7 mmol) drop-wisely at -78oC and the mixture was stirred at -78oC for 5 hours. The mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with DCM twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica 82 160112428.1 Docket No.: 358117.00008 gel, 0 - 20% EtOAc in PE) to give the title compound (3.23 g) as an oil.1H 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, 1H), 3.09 - 3.00 (m, 1H), 2.91 - 2.78 (m, 1H), 2.41 - 2.29 (m, 1H), 1.96 - 1.77 (m, 2H), 1.45 - 1.31 (m, 1H), 0.82 (s, 9H), 0.00 (s, 3H), -0.02 (s, 3H). LC-MS (ESI) m / z: 324.4 (M+H)+. Step 7: (3S,5S)-3-((tert-butyldimethylsilyl)oxy)-5-fluoropiperidine To a solution of (3S,5S)-1-benzyl-3-((tert-butyldimethylsilyl)oxy)-5-fluoropiperidine (1.8 g, 5.58 mmol) in THF (20 mL) was added Pd / C (200 mg, 10% wt.), Pd(OH)2(100 mg, 10% wt.) and AcOH (0.042 mL, 0.730 mmol) at 0oC. The mixture was degassed with N2 three times and stirred under a H2balloon at 40oC for 16 hrs. 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)+. Step 8: Tert-butyl (3S,5S)-3-((tert-butyldimethylsilyl)oxy)-5-fluoropiperidine-1- carboxylate To a solution of (3S,5S)-3-((tert-butyldimethylsilyl)oxy)-5-fluoropiperidine (940 mg, 4.02 mmol) in DCM (15 mL) was added Boc2O (1.46 g, 6.74 mmol) and TEA (1.56 mL, 11.23 mmol) at 0oC and the mixture was stirred at 25oC for 4 hrs. The mixture was diluted with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 28% EtOAc in PE) to give the title compound (1.16 g) as a solid. LC-MS (ESI) m / z: 278.4 (M+H-56)+. Step 9: Tert-butyl (3S,5S)-3-fluoro-5-hydroxypiperidine-1-carboxylate To a solution of tert-butyl (3S,5S)-3-((tert-butyldimethylsilyl)oxy)-5-fluoropiperidine-1- carboxylate (900 mg, 2.70 mmol) in DMF (2 mL) was added TBAF (3.24 mL, 3.24 mmol, 1M in THF) at 0oC and the mixture was stirred at 25oC for 2 hrs. The mixture was diluted with EtOAc, washed with sat. aq. NH4Cl solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash 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)+. Step 10: Tert-butyl (3S,5S)-3-fluoro-5-((methylsulfonyl)oxy)piperidine-1-carboxylate To a solution of tert-butyl (3S,5S)-3-fluoro-5-hydroxypiperidine-1-carboxylate (350 mg, 1.60 mmol) in DCM (5 mL) was added TEA (0.44 mL, 3.22 mmol) followed by drop-wise addition of MsCl (274 mg, 2.40 mmol) at 0 ℃ and the mixture was stirred under N2atmosphere at 25 ℃ for 2 hrs. The mixture was diluted with DCM, washed with water and 83 160112428.1 Docket No.: 358117.00008 brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 11: Tert-butyl (3R,5S)-3-(acetylthio)-5-fluoropiperidine-1-carboxylate To a solution of tert-butyl (3S,5S)-3-fluoro-5-((methylsulfonyl)oxy)piperidine-1-carboxylate (200 mg, 0.67 mmol) in DMA (2 mL) was added potassium thioacetate (192 mg, 1.68 mmol) at 25 ℃ and the mixture was stirred under N2 atmosphere at 100 ℃ for 1 hr. The reaction was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 12: Tert-butyl (3S,5R)-3-fluoro-5-mercaptopiperidine-1-carboxylate To a solution of tert-butyl (3R,5S)-3-(acetylthio)-5-fluoropiperidine-1-carboxylate (160 mg, 0.58 mmol) in MeOH (3 mL) was added K2CO3(159 mg, 1.15 mmol) at 0 ℃ and the mixture was stirred under N2atmosphere at 0 ℃ for 15 mins. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (110 mg) as an oil, which was directly used in the next reaction without purification. Step 13: Tert-butyl (3S,5R)-3-fluoro-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)thio)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-mercaptopiperidine-1-carboxylate (80 mg, 0.26 mmol) in MeCN (3 mL) was added Cs2CO3(214 mg, 0.66 mmol) and 6-chloro-3-(2-methoxy-4- (trifluoromethyl)phenyl)-4-methylpyridazine (75 mg, 0.31 mmol) and the mixture was stirred under N2atmosphere at 90oC for 3 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 14: 2-(6-(((3R,5S)-5-fluoropiperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol To a solution of tert-butyl (3S,5R)-3-fluoro-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)thio)piperidine-1-carboxylate (40 mg, 0.08 mmol) in DCM (3 mL) was added BBr3(49.9 mg, 0.20 mmol) drop wisely at -78 ℃ and the mixture was stirred at 25 ℃ for 2 hrs. The reaction was quenched with sat. aq. NaHCO3solution at 0oC and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, 84 160112428.1 Docket No.: 358117.00008 filtered, and concentrated under reduced pressure to give the title compound (15 mg) as a solid. LC-MS (ESI) m / z: 388.4 (M+H)+. Step 15: 2-(6-(((3R,5S)-5-fluoro-1-methylpiperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol 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) was added paraformaldehyde (10.8 mg, 0.36 mmol), AcOH (0.01 mL, 0.04 mmol) followed by sodium cyanoborohydride (7.9 mg, 0.12 mmol) at 0oC and the mixture was stirred under N2atmosphere at RT for 0.5 hour. The mixture was quenched with sat. aq. NaHCO3 solution at 0oC and extracted with DCM twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep- HPLC (YMC-Actus Triart C18250*20 mm, 20 ~ 95% MeCN in H2O with 0.1% NH4OH) to give the title compound (1.13 mg,) as a solid.1H 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)+. Example 23 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)thio)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol - 85 160112428.1 Docket No.: 358117.00008 To a solution of (3R,5S)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol (3 g, 9.33 mmol) in THF (30 mL) was added PPh3(4.9 g, 18.7 mmol) and 4-nitrobenzoic acid (1.7 g, 10.3 mmol) under N2atmosphere at 0 ℃ and the mixture was stirred at this temperature for 30 mins. To the above mixture was added DIAD (3.8 g, 18.7 mmol) and the resulting mixture was stirred at 0 ℃ for 30 mins and 50 ℃ for 16 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 2: (3S,5S)-1-benzyl-5-((tert-butyldimethylsilyl)oxy)piperidin-3-ol 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) was added LiOH·H2O (536 mg, 12.8 mmol) and the mixture was stirred at RT overnight. 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 directly used in the next reaction without purification. LC-MS (ESI) (m / z): 322.3 (M+H)+. Step 3-12: 2-(6-(((3R,5R)-5-fluoro-1-methylpiperidin-3-yl)thio)-4-methylpyridazin-3-yl)- 5-(trifluoromethyl)phenol The title compound was prepared following methods and protocols as those described in Example 22 step 6-15 as a solid.1H NMR (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)+. Example 24 (R)-3-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-4-methyl-6-((1-methylpiperidin- 3-yl)thio)pyridazine To a - 3-yl)-5- (trifluoromethyl)phenol (20 mg, 0.052 mmol) in DMF (4 mL) and water (1 mL) was added 86 160112428.1 Docket No.: 358117.00008 sodium chlorodifluoroacetate (40 mg, 0.26 mmol) and Cs2CO3(60 mg, 0.18 mmol) and the mixture was stirred under N2atmosphere at 100 ℃ for 16 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (Column: YMC-Actus Triart C18, 10 ~ 60% MeCN in water with 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)+. Example 25 & Example 26 (R)-2-(4-((1-methylpiperidin-3-yl)thio)pyrido[3,4-d]pyridazin-1-yl)-5- (trifluoromethyl)phenol (Example 25) & (R)-2-(1-((1-methylpiperidin-3- yl)thio)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (Example 26) Step 1: 4- and 1- 87 160112428.1 Docket No.: 358117.00008 chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine 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) was added Pd(dtbpf)Cl2(237 mg, 0.36 mmol) and K2CO3(1.50 g, 10.9 mmol), the mixture was degassed with N2three times and stirred under N2at 50 ℃ for 3 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 30% EtOAc in PE) to give the title compounds as a mixture of regio-isomers (800 mg) as a solid. LC / MS (ESI) (m / z): 340 (M+H)+. Step 2: 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 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) was added t-BuOK (374 mg, 3.06 mmol) at 0 ℃ and the mixture was stirred at RT for 2 hrs. The mixture was poured into ice-water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness to give title compounds as a mixture of regio-isomers (490 mg) as a solid. LC / MS (ESI) (m / z): 322 (M+H)+. Step 3: Tert-butyl (R)-3-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido[3,4- d]pyridazin-4-yl)thio)piperidine-1-carboxylate and tert-butyl (R)-3-((4-(2-methoxy-4- (trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)thio)piperidine-1-carboxylate 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) was added tert-butyl (R)-3-mercaptopiperidine-1-carboxylate (497 mg, 2.29 mmol) followed by DBU (464 mg, 3.05 mmol) and BOP (1.35 g, 3.05 mmol) at 0oC and the mixture was stirred at 80 ℃ for 3 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to give the title compounds as a mixture of regio-isomers (300 mg) as a solid. LC / MS (ESI) (m / z): 521 (M+H)+. 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 To a solution of tert-butyl (R)-3-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrido-[3,4- 88 160112428.1 Docket No.: 358117.00008 d]pyridazin-4-yl)thio)piperidine-1-carboxylate and tert-butyl (R)-3-((4-(2-methoxy-4- (trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-1-yl)thio)piperidine-1-carboxylate (300 mg, 0.57 mmol) in DCM (5 mL) was added BBr3(286 mg, 1.14 mmol) drop-wisely at -60 ℃ and the mixture was stirred at RT for 1 hr. The mixture was quenched with MeOH (2 mL) at -60 ℃, poured into ice-cooled sat. aq. NaHCO3solution and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compounds as a mixture of regio-isomers (210 mg) as a solid. LC / MS (ESI) (m / z): 407 (M+H)+. Step 5: (R)-2-(4-((1-methylpiperidin-3-yl)thio)pyrido[3,4-d]pyridazin-1-yl)-5- (trifluoromethyl)phenol (Example 25) & (R)-2-(1-((1-methylpiperidin-3- yl)thio)pyrido[3,4-d]pyridazin-4-yl)-5-(trifluoromethyl)phenol (Example 26) To 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 AcOH (0.1 mL) and 37% aq. HCHO (0.18 mL, 2.45 mmol) followed by NaBH3CN (93 mg, 1.48 mmol) at 0 ℃ and the mixture was stirred at RT for 30 mins. The mixture was quenched with sat. aq. NaHCO3solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 10 ~ 90% MeCN in H2O with 0.1% NH4OH) to give Example 25 (second eluant, 25 mg) and Example 26 (first eluant, 28 mg) as solids. The regio-chemistry was confirmed by NOE. Example 25:1H 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)+. Example 27 and Example 28 (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) 89 160112428.1 Docket No.: 358117.00008 To a mixture of (2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)boronic acid (prepared following the procedure in Intermediate B8 from WO2020163541, 600 mg, 2.74 mmol) and 1,4- dichloropyrido[3,4-d]pyridazine (1.10g, 5.48 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added Pd(dtbpf)Cl2(177 mg, 0.27 mmol) and K2CO3(1.14 g, 8.22 mmol) under N2atmosphere. The reaction mixture was degassed with N2three times and stirred at 90oC for 3 hrs. After cooling to RT, 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 under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 60% EtOAc in PE) to give the title compounds as a mixture of regio-isomers (500 mg) as a solid. LC-MS (ESI) (m / z): 339.0 (M+H)+. Step 2: Tert-butyl (R)-3-((1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)pyrido[3,4- d]pyridazin-4-yl)thio)piperidine-1-carboxylate & tert-butyl (R)-3-((4-(2-methoxy-4-(2H- 1,2,3-triazol-2-yl)phenyl)pyrido[3,4-d]pyridazin-1-yl)thio)piperidine-1-carboxylate 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) was added tert-butyl (R)-3- mercaptopiperidine-1-carboxylate (289 mg, 1.33 mmol) and Cs2CO3(866 mg, 2.66 mmol) at RT and the mixture was stirred under N2atmosphere at 90 ℃ for 2 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 2% MeOH in DCM) to give the title compounds (300 mg) as a solid. LC-MS (ESI) (m / z): 520.3 (M+H)+. Step 3: (R)-2-(4-(piperidin-3-ylthio)pyrido[3,4-d]pyridazin-1-yl)-5-(2H-1,2,3-triazol-2- yl)phenol & (R)-2-(1-(piperidin-3-ylthio)pyrido[3,4-d]pyridazin-4-yl)-5-(2H-1,2,3- triazol-2-yl)phenol 90 160112428.1 Docket No.: 358117.00008 To a solution of tert-butyl (R)-3-((1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)pyrido[3,4- d]pyridazin-4-yl)thio)piperidine-1-carboxylate (250 mg, 0.48 mmol) in DCM (3 mL) was added BBr3(0.96 mL, 0.96 mmol, 1 M in DCM) drop wisely at -78 ℃ and the mixture was stirred at -78 ℃ to RT for 2 hrs. The mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compounds (200 mg,) as a solid. LC-MS (ESI) (m / z): 406.1 (M+H)+. 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 To 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 added 37% aq. HCHO (0.2 mL), AcOH (0.05 mL) followed by NaBH3CN (90 mg, 1.43 mmol) at RT and the mixture was stirred under N2 atmosphere at RT for 0.5 hour. The mixture was quenched with sat. aq. NH4Cl solution at 0oC and extracted with DCM twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*21 mm, 10 ~ 90% MeCN in H2O with 0.1% FA) to give the title compounds (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, the configuration assignments were confirmed by NOE. Chiral SFC condition: Column: ChiralPak IB, 250×20 mm I.D., 5µm; Mobile phase: A= CO2and B= MeOH (0.1% 2 M NH3in MeOH); Isocratic: B 40%; Flow rate: 60 mL / min. Example 27:1H 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)+. 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)+. Example 29 91 160112428.1 Docket No.: 358117.00008 (R)-2-(4-((1-methylpiperidin-3-yl)thio)phthalazin-1-yl)-5-(trifluoromethyl)phenol To a mixture of (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (500 mg, 2.27 mmol) and 4-chlorophthalazin-1-ol (411 mg, 2.27 mmol) in 1,4-dioxane (5 mL) and water (2 mL) were added K2CO3(942 mg, 6.82 mmol) and Pd(dtbpf)Cl2(147 mg, 0.23 mmol) under N2atmosphere. The mixture was degassed with N2three times and stirred under N2atmosphere at 90 °C for 3 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 50% of 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)+. Step 2: 1-Chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazine To a solution of 4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazin-1-ol (350 mg, 1.09 mmol) in 1,4-dioxane (4 mL) was added POCl3(670 mg, 4.37 mmol) and the mixture was stirred at 60 ℃ for 3 hrs. The mixture was concentrated under reduced pressure to dryness. The residue was neutralized with sat. aq. NaHCO3solution at 0oC and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% of EtOAc in PE) to give the title compound (150 mg) as a solid. LC-MS (ESI) (m / z): 339.1 / 341.1 (M+H)+. Step 3: Tert-butyl (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazin-1- yl)thio)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-mercaptopiperidine-1-carboxylate (192 mg, 0.89 mmol) in DMF (2 mL) was added NaH (53 mg, 1.33 mmol, 60% dispersion in mineral oil) at 0 °C under N2atmosphere and the mixture was stirred at 40 ℃ for 30 mins. A solution of 1-chloro-4-(2- 92 160112428.1 Docket No.: 358117.00008 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 under N2atmosphere at 30 ℃ for 3 hrs. The mixture was quenched with ice water and extracted with EtOAc twice. The combined organic layers were washed with sat. aq. NH4Cl solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% of EtOAc in PE) to give the title compound (120 mg) as yellow solid. LC / MS (ESI) (m / z): 520.3 (M+H)+. Step 4: (R)-2-(4-(piperidin-3-ylthio)phthalazin-1-yl)-5-(trifluoromethyl)phenol To a solution of tert-butyl (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazin-1- yl)thio)piperidine-1-carboxylate (120 mg, 0.23 mmol) in DCM (2 mL) was added BBr3(116 mg, 0.46 mmol) drop-wisely at -78 °C under N2atmosphere and the mixture was stirred at RT for 30 minutes. The mixture was quenched with sat. aq. NaHCO3solution at 0 °C and extracted with EtOAc three times. 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)+. Step 5: (R)-2-(4-((1-methylpiperidin-3-yl)thio)phthalazin-1-yl)-5-(trifluoromethyl)phenol To 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 and 37% aq. HCHO (0.27 mL) followed by sodium cyanoborohydride (33 mg, 0.52 mmol) at 0 ℃ and the mixture was stirred at RT for 20 mins. The mixture was quenched with ice water and filtered. The filtrate was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10 ~ 95% MeCN in H2O with 0.1% NH4OH) to give the title compound (2 mg) as a solid.1H 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)+. Example 30 (R)-2-(4-((1-methylpiperidin-3-yl)thio)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1- yl)-5-(trifluoromethyl)phenol 93 160112428.1 Docket No.: 358117.00008 Step 5H- To a mixture of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[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) was added Pd(dtbpf)Cl2(37 mg, 0.06 mmol) and K2CO3(2.2 g, 15.87 mmol)) under N2atmosphere. The reaction mixture was degassed with N2three times and stirred at 90 ℃ for 3 hrs. After cooling to RT, 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 under reduced pressure to dryness. The residue was purified by flash 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)+. Step 2: Tert-butyl (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-1-yl)thio)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-mercaptopiperidine-1-carboxylate (397 mg, 1.83 mmol) in DMF (2 mL) was added NaH (110 mg, 2.74 mmol, 60% dispersion in mineral oil) under N2atmosphere at 0 ℃ and the mixture was stirred under N2atmosphere at RT for 30 mins. A solution of 1-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyridazine (300 mg, 0.91 mmol) in DMF (3 mL) was added to the above mixture at 0 ℃ and the resulting mixture was stirred under N2atmosphere at 30 ℃ for 16 hrs. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 3: (R)-2-(4-(piperidin-3-ylthio)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5- (trifluoromethyl)phenol 94 160112428.1 Docket No.: 358117.00008 To a solution of tert-butyl (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyridazin-1-yl)thio)piperidine-1-carboxylate (350 mg, 0.69 mmol) in DCM (3 mL) was added BBr3(0.2 mL, 2.06 mmol) drop-wisely at -78 ℃ and the mixture was stirred at -78 ℃ for 10 mins and RT for 2 hrs. The mixture was quenched with sat. aq. NaHCO3solution at 0 ℃ and extracted with DCM twice. 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)+. Step 4: (R)-2-(4-((1-methylpiperidin-3-yl)thio)-6,7-dihydro-5H-cyclopenta[d]pyridazin- 1-yl)-5-(trifluoromethyl)phenol 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 aq. HCHO (0.13 mL, 1.26 mmol, 37% wt.) in MeOH (1.5 mL) was added NaBH3CN (48 mg, 0.76 mmol) and the mixture was stirred at RT for 30 mins. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep- HPLC (YMC-Actus Triart C18250*21 mm, 20 ~ 95% MeCN in H2O with 0.1% FA) to give the title compound (27.9 mg) as a solid.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)+. The examples listed in Table 3 were prepared following the methods and protocols similar to those described for the synthesis of Example 30 from appropriate starting materials. Table 3. Examples Prepared Using Procedure for Example 30 Example Structure & Name H-NMR, LC / MS J ), 160112428.1 Docket No.: 358117.00008 p (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)thio)-1,2,4-triazin-6-yl)-5- (trifluoromethyl)phenol 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) were added (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) under N2atmosphere at RT. The mixture was degassed with N2three times and stirred under N2atmosphere at 80oC for 6 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (4.5 g) as a solid.1H 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)+. Step 2: 3,5-Dichloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine 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) was added DIEA (4 mL) and the mixture was stirred at 96 160112428.1 Docket No.: 358117.00008 100oC overnight. The mixture was concentrated under reduced pressure to dryness. The residue was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE, with 5% DCM) to give the title compound (2.1 g) as a solid.1H 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)+. Step 3: 3-Chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4-triazine To a solution of 3,5-dichloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-1,2,4-triazine (2 g, 6.19 mmol) in THF (10 mL) was added MeMgBr (3.1 mL, 9.3 mmol, 3 M in 2-methyl-THF) drop-wisely at -60oC and the mixture was stirred under N2atmosphere at -60oC for 30 mins and at -20oC for 1 hr. The reaction mixture was quenched with sat. aq. NH4Cl solution at -20oC and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 4: Tert-butyl (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4- triazin-3-yl)thio)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-mercaptopiperidine-1-carboxylate (143 mg, 0.66 mmol) in MeCN (5 mL) was added 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) and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 5: (R)-2-(5-methyl-3-(piperidin-3-ylthio)-1,2,4-triazin-6-yl)-5- (trifluoromethyl)phenol To a solution of tert-butyl (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-1,2,4- triazin-3-yl)thio)piperidine-1-carboxylate (140 mg, 0.289 mmol) in DCM (5 mL) was added BBr3(1.45 mL, 1.45 mmol, 1 M in DCM) drop-wisely at -78oC and the mixture was stirred at RT for 2 hrs. The reaction mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% MeOH in DCM) to give the 97 160112428.1 Docket No.: 358117.00008 title compound (52 mg) as a solid. LC / MS (ESI) (m / z): 371.1 (M+H)+. Step 6: (R)-2-(5-methyl-3-((1-methylpiperidin-3-yl)thio)-1,2,4-triazin-6-yl)-5- (trifluoromethyl)phenol 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% aq. HCHO (0.08 mL) in MeOH (2 mL) was added AcOH (2 drops) and NaBH3CN (17 mg, 0.270 mmol) at 0 ℃ and the mixture was stirred at RT for 20 mins. The mixture was quenched with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Triart C18, 250*20 mm, 5 um, 5 ~ 95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (5 mg) as a solid.1H 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)+. Example 34 (R)-2-(4-((1-methylpiperidin-3-yl)thio)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5- (trifluoromethyl)phenol Step 1: 1-(2-Methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazine-4(3H)- thione To a stirred solution of 1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin- 4(3H)-one (prepared following the procedure of WO2024013395 Example 11, 150 mg, 0.48 mmol) in pyridine (3 mL) was added phosphorus pentasulfide (431 mg, 0.92 mmol) at 25oC and the mixture was stirred in a sealed tube at 150oC for 6 hrs. The reaction mixture was poured into ice-water and stirred at 0oC for 10 mins. The solid which precipitated 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). 98 160112428.1 Docket No.: 358117.00008 Step 2: Ethyl 2-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4- yl)thio)acetate 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) was added ethyl 2-bromoacetate (105 mg, 0.614 mmol) and K2CO3(212 mg, 1.537 mmol) at 25oC and the mixture was stirred at 25oC for 3 hrs. The mixture was diluted with water and extracted with EtOAc twice. 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). Step 3: Tert-butyl (R)-3-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2- d][1,2,4]triazin-4-yl)thio)piperidine-1-carboxylate To a solution of ethyl 2-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2- d][1,2,4]triazin-4-yl)thio)acetate (70 mg, 0.17 mmol) in DMF (2 mL) was added DIPEA (66 mg, 0.51 mmol) and tert-butyl (R)-3-mercaptopiperidine-1-carboxylate (184 mg, 0.85 mmol) and the mixture was stirred at 100oC for 16 hrs. 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 flash 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)+. Step 4: (R)-2-(4-(piperidin-3-ylthio)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5- (trifluoromethyl)phenol To a solution of tert-butyl (R)-3-((1-(2-methoxy-4-(trifluoromethyl)phenyl)pyrrolo[1,2- d][1,2,4]triazin-4-yl)thio)piperidine-1-carboxylate (39 mg, 0.076 mmol) in DCM (3 mL) was added BBr3(0.2 mL, 0.20 mmol, 1M in DCM) drop-wisely at -78 ℃ and the mixture was stirred at -78 ℃ for 10 mins and RT for 2 hrs. The mixture was quenched with sat. aq. NaHCO3 solution at 0oC and extracted with DCM twice. 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 directly used in the next reaction without purification. LC / MS (ESI) m / z: 395.1 (M+H)+Step 5: (R)-2-(4-((1-methylpiperidin-3-yl)thio)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5- (trifluoromethyl)phenol To a solution of (R)-2-(4-(piperidin-3-ylthio)pyrrolo[1,2-d][1,2,4]triazin-1-yl)-5- 99 160112428.1 Docket No.: 358117.00008 (trifluoromethyl)phenol (20 mg, 0.05 mmol) in MeOH (1 mL) was added aq. HCHO solution (0.1 mL, 37% wt.), AcOH (0.05 mL) followed by NaBH3CN (15.8 mg, 0.24 mmol) at RT and the mixture was stirred under N2atmosphere at RT for 0.5 hr. The mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with DCM twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (Welch xbidge xb- C18250*21.2 mm, 20 ~ 95% MeCN in H2O with 0.1% FA) to give the title compound (3.5 mg) as a solid.1H 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)+. Example 35 (R)-2-(2-methyl-7-((1-methylpiperidin-3-yl)thio)pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5- (trifluoromethyl)phenol Step1: 3- To a solution of methyl 3-methyl-1H-pyrazole-5-carboxylate (10 g, 19.21 mmol) in EtOH (30 mL) was added N2H4.H2O (3 mL) at 25 ℃ and the reaction mixture was stirred at 80 ℃ for 16 hrs. The reaction mixture was concentrated under reduced pressure to dryness. The residue was 100 160112428.1 Docket No.: 358117.00008 triturated with 1 / 1 mixture of water / MeOH and filtered. The filter cake was washed with water, dried under vacuum to give the title compound (6.4 g) as a solid. LC-MS (ESI) (m / z): 141.1 (M+H)+. Step 2: 2-Methylpyrazolo[1,5-d][1,2,4]triazin-4(5H)-one To a solution of 3-methyl-1H-pyrazole-5-carbohydrazide (6.4 g, 45.67 mmol) in DMF (20 mL) was added triethoxymethane (6.1 mL, 54.8 mmol) at 25 ℃ and the mixture was stirred in a CEM microwave reactor at 165 ℃ for 1 hr. The mixture was cooled to RT 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)+. Step 3: 7-Bromo-2-methylpyrazolo[1,5-d][1,2,4]triazin-4(5H)-one To a mixture of 2-methylpyrazolo[1,5-d][1,2,4]triazin-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) was added benzyltrimethylammonium tribromide (4.58 g, 11.72 mmol) at 0 ℃ and the mixture was stirred at 25 ℃ for 16 hrs. Then the mixture was quenched with a mixture of sat. aq. Na2S2O3solution and sat. aq. NaHCO3solution and extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 4: Tert-butyl (R)-3-((2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-d][1,2,4]triazin-7- yl)thio)piperidine-1-carboxylate To a mixture of 7-bromo-2-methylpyrazolo[1,5-d][1,2,4]triazin-4(5H)-one (1.5 g, 10.09 mmol) and K2CO3(5.4 g, 10.52 mmol) in NMP (10 mL) was added tert-butyl (R)-3- mercaptopiperidine-1-carboxylate (2.13 g, 6.13 mmol) at 0 ℃ and the mixture was stirred at 120 ℃ for 16 hrs. The reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 5: Tert-butyl (R)-3-((2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5- d][1,2,4]triazin-7-yl)thio)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((2-methyl-4-oxo-4,5-dihydropyrazolo[1,5-d][1,2,4]triazin-7- yl)thio)piperidine-1-carboxylate (800 mg, 0.21 mmol) in DCM (5 mL) was added pyridine (346 mg, 0.11 mmol) followed by drop-wise addition of Tf2O (925 mg, 0.28 mmol) at 0 ℃ and 101 160112428.1 Docket No.: 358117.00008 the mixture was stirred at 0 ℃ for 2 hrs. The mixture was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 6: Tert-butyl (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)-2- methylpyrazolo[1,5-d][1,2,4]triazin-7-yl)thio)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((2-methyl-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 (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) under N2atmosphere at 25 ℃. The mixture was degassed with N2three times and stirred at 50 ℃ overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20% EtOAc in PE) to give the title compound (112 mg) as a solid. LC-MS (ESI) (m / z): 524.2 (M+H)+. Step 7: (R)-2-(2-methyl-7-(piperidin-3-ylthio)pyrazolo[1,5-d][1,2,4]triazin-4-yl)-5- (trifluoromethyl)phenol To a solution of tert-butyl (R)-3-((4-(2-methoxy-4-(trifluoromethyl)phenyl)-2- methylpyrazolo[1,5-d][1,2,4]triazin-7-yl)thio)piperidine-1-carboxylate (112 mg, 0.21 mmol) in DCM (3 mL) was added a solution of BBr3(1 mL, 1 mmol, 1M in DCM) drop-wisely at - 78oC and the mixture was stirred at RT for 50 mins. The reaction mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness to give the title compound (80 mg) as a solid, which was directly used in the next reaction without purification. LC-MS (ESI) m / z: 410.1 (M+H)+. 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 To 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 aq. HCHO (30 mg, 0.38 mmol, 37% wt.), a drop of AcOH and NaBH3CN (18 mg, 0.29 mmol) at 0 ℃ and the mixture was stirred at 25 ℃ for 30 minutes. The mixture was quenched with ice-water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over 102 160112428.1 Docket No.: 358117.00008 anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by pre-HPLC (YMC-Actus Triart C18250*21 mm, 10 ~ 95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (20 mg) as a solid.1H NMR (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)+. Example 36 (R)-2-(5-(hydroxymethyl)-4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5- (trifluoromethyl)phenol (trifluoromethyl)phenyl)-5-methylpyridazine 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) were added 2- (benzyloxy)acetic acid (200 mg, 1.20 mmol), AgNO3(20 mg, 0.12 mmol) and K2S2O8(244 mg, 0.902 mmol) under N2atmosphere and the mixture was stirred under N2atmosphere at 70 ℃ overnight. The mixture was quenched with sat. aq. NaHCO3solution and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 2: Tert-butyl (R)-3-((4-cyano-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)thio)piperidine-1-carboxylate 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) were added tert-butyl (R)-3-mercaptopiperidine-1-carboxylate (176 mg, 0.81 mmol) and Cs2CO3103 160112428.1 Docket No.: 358117.00008 (397 mg, 1.22 mmol) and the mixture was stirred under N2atmosphere at 90 ℃ for 3 hrs. The reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 3: (R)-2-(5-(hydroxymethyl)-4-methyl-6-(piperidin-3-ylthio)pyridazin-3-yl)-5- (trifluoromethyl)phenol hydrochloride To a solution of tert-butyl (R)-3-((4-((benzyloxy)methyl)-6-(2-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidine-1-carboxylate (194 mg, 0.306 mmol) in DCM (3 mL) was added BCl3(1 mL, 1 M in hexane) at 0 ℃ under N2atmosphere and the mixture was stirred at RT for 3 hrs. Thes mixture was quenched with MeOH at 0 ℃ and concentrated under reduced pressure to dryness to give the title compound (150 mg) as a solid, which was directly used in the next reaction without purification. LC-MS (ESI) (m / z): 400.2 (M+H)+. Step 4: (R)-2-(5-(hydroxymethyl)-4-methyl-6-((1-methylpiperidin-3-yl)thio)pyridazin-3- yl)-5-(trifluoromethyl)phenol 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) were added aq. HCHO (0.2 mL, 37% wt.), NaBH3CN (87 mg, 1.382 mmol) and AcOH (0.05 mL, 0.873 mmol) and the mixture was stirred under N2atmosphere at RT for 1 hr. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 20 ~ 60% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (22.6 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.42 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.9 Hz, 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)+. Example 37 (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3- yl)thio)pyridazine-4-carbonitrile 104 160112428.1 Docket No.: 358117.00008 1- carboxylate To a solution of 3,6-dichloro-5-methyl-1,2-diazine-4-carbonitrile (100 mg, 0.53 mmol) in MeCN (3 mL) were added tert-butyl (R)-3-mercaptopiperidine-1-carboxylate (173 mg, 0.80 mmol) and DIPEA (206 mg, 1.60 mmol) and the mixture was stirred under N2atmosphere at RT overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 2: Tert-butyl (R)-3-((4-cyano-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)thio)piperidine-1-carboxylate To a mixture of tert-butyl (R)-3-((6-chloro-4-cyano-5-methylpyridazin-3-yl)thio)piperidine-1- carboxylate (116 mg, 0.31 mmol) in 1,4-dioxane (6 mL) and water (0.6 mL) were added (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) under N2 atmosphere at RT and the mixture was stirred under N2atmosphere at 100 ℃ overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 3: (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3- ylthio)pyridazine-4-carbonitrile hydrochloride To a solution of tert-butyl (R)-3-((4-cyano-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)thio)piperidine-1-carboxylate (88 mg, 0.16 mmol) in 1,4-dioxane (2 mL) 105 160112428.1 Docket No.: 358117.00008 was added HCl / 1,4-dioxane (2 mL, 4 M) and the mixture was stirred at RT for 2 hrs. The mixture was concentrated under reduced pressure to dryness to give the title compound (80 mg) as a solid, which was directly used in the next reaction without purification. LC / MS (ESI) (m / z): 395.2 (M+H)+. Step 4: (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3- yl)thio)pyridazine-4-carbonitrile To a solution of (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3- ylthio)pyridazine-4-carbonitrile hydrochloride (80 mg, 0.16 mmol) in MeOH (2 mL) were added aq. HCHO (0.2 mL, 37% wt.), NaBH3CN (40 mg, 0.63 mmol) and AcOH (0.05 mL) successively and the mixture was stirred under N2atmosphere at RT for 1 hour. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 20 ~ 60% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (12.6 mg) as a solid.1H NMR (400 MHz, 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)+. Example 38 (R)-2-(4-methyl-5-((methylamino)methyl)-6-((1-methylpiperidin-3-yl)thio)pyridazin-3- yl)-5-(trifluoromethyl)phenol -5- methylpyridazin-3-yl)thio)piperidine-1-carboxylate To a solution of 6-chloro-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4- methylpyridazine (600 mg, 1.80 mmol) in MeCN (15 mL) was added tert-butyl (R)-3- mercaptopiperidine-1-carboxylate (588 mg, 2.71 mmol) and Cs2CO3(1.76 g, 5.41 mmol) at 106 160112428.1 Docket No.: 358117.00008 RT and the mixture was stirred under N2atmosphere at 90oC for 16 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash 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)+. Step 2: Tert-butyl (R)-3-((4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-6-(2- (methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidine- 1-carboxylate To a mixture of tert-butyl (R)-3-((6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)thio)piperidine-1-carboxylate (350 mg, 0.58 mmol) in MeCN (5 mL) and water (5 mL) was added K2S2O8(212 mg, 1.17 mmol) and AgNO3(20 mg, 0.12 mmol) under N2atmosphere at RT, the mixture was degassed with N2three times and stirred at 60 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 40% EtOAc in PE) to afford the title compound (280 mg) as a solid. LC-MS (ESI) m / z: 690.7 (M+H)+. Step 3: Benzyl (R)-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3- ylthio)pyridazin-4-yl)methyl)(methyl)carbamate To a solution of tert-butyl (R)-3-((4-((((benzyloxy)carbonyl)(methyl)amino)methyl)-6-(2- (methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)thio)piperidine-1- carboxylate (280 mg, 0.41 mmol) in 1,4-dioxane (3 mL) was added HCl / 1,4-dioxane (1 mL, 4 M) and the mixture was stirred at RT for 1 hr. The mixture was basified with sat. aq. NaHCO3solution and extracted with EtOAc twice. 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)+. Step 4: Benzyl (R)-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin-3-yl)thio)pyridazin-4-yl)methyl)(methyl)carbamate To a mixture of benzyl (R)-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin- 3-ylthio)pyridazin-4-yl)methyl)(methyl)carbamate (210 mg, 0.38 mmol), aq. HCHO (0.2 mL, 37% wt.) and AcOH (46 mg, 0.77 mmol) in MeOH (2 mL) was added NaBH3CN (72 mg, 1.15 mmol) at 0oC and the mixture was stirred at RT for 30 mins. The mixture was quenched with sat. aq. NaHCO3solution and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness to give the title 107 160112428.1 Docket No.: 358117.00008 compound (160 mg) as a solid. LC-MS (ESI) m / z: 560.9 (M+H)+. Step 5: (R)-2-(4-methyl-5-((methylamino)methyl)-6-((1-methylpiperidin-3- yl)thio)pyridazin-3-yl)-5-(trifluoromethyl)phenol To a solution of benzyl (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) was added BBr3(1.25 mL, 1.25 mmol, 1M in DCM) drop-wisely at -78oC and the mixture was stirred at -78oC to RT for 3 hrs. The mixture was quenched with EtOH at -78oC and concentrated under reduced pressure to dryness. The residue was purified by pre-HPLC (YMC-Actus Triart C18250*21 mm, 10 ~ 95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (29 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 7.9 Hz, 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)+. Example 39 (R)-3-chloro-2-(6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5- (trifluoromethyl)phenol (VS-6959) Cl CF Cl CF Cl CF Cl CF Cl CF NaH, I MOMCl, DIPEA + uene I I D + Tol CM I I Cl CF 108 160112428.1 Docket No.: 358117.00008 (trifluoromethyl)phenol To a solution of 3-chloro-5-(trifluoromethyl)phenol (10 g, 51.0 mmol) in toluene (100 mL) was added NaH (4.08 g, 102 mmol, 60% dispersion in mineral oil) portion-wise at 0oC and the mixture was stirred at 0oC for 30 mins. Then iodine (12.9 g, 51.0 mmol) was added to the above mixture in portions at 0oC and the mixture was stirred at RT for 3 hrs. The mixture was quenched with sat. aq. NH4Cl solution at 0oC, acidified with 2 M HCl to pH = 5 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 10 % EtOAc in PE) to give a mixture of the title compounds (13 g) as a solid. LC-MS (ESI) m / z: 321 (M-H)-. Step 2: 1-Chloro-2-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzene and 5-chloro- 2-iodo-1-(methoxymethoxy)-3-(trifluoromethyl)benzene 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) was added DIEA (15.6 g, 121 mmol) followed by drop-wise addition of MOMCl (4.87 g, 60.5 mmol) at 0oC and the mixture was stirred under N2atmosphere at RT for 2 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 5 % EtOAc in PE) to give the title compounds (14 g) as an oil in about 3:1 ratio.1H NMR (400 MHz, 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). Step 3: 2-(2-Chloro-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane and 2-(4-chloro-2-(methoxymethoxy)-6- (trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 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-dioxaborolane (24.5 g, 192 mmol) in 1,4-dioxane (150 mL) were added TEA (26.9 mL, 192 mmol), CyJohn Phos (1.34 g, 3.83 mmol) and Pd(OAc)2(0.86 g, 3.83 mmol) successively under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 95 °C overnight. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to 109 160112428.1 Docket No.: 358117.00008 dryness. The residue was purified by flash chromatography (silica gel, 0 - 8% EtOAc in PE) to give the title compounds (4.6 g) as an oil in about 5:2 ratio.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). Step 4: 3-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)phenol and 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- (trifluoromethyl)phenol To a mixture of 2-(2-chloro-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane and 2-(4-chloro-2-(methoxymethoxy)-6- (trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.5 g, 9.56 mmol) in DCM (50 mL) was added TFA (30 mL) at 0 ℃ and the mixture was stirred at RT for 16 hrs. The mixture was concentrated under reduced pressure to dryness and the residue was dissolved in EtOAc. The mixture was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 25% EtOAc in PE) to give the title compounds (0.8 g) as an oil. LC-MS (ESI) m / z: 321 (M-H)-. Step 5: Tert-butyl (R)-3-((6-(2-chloro-6-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3- yl)thio)piperidine-1-carboxylate and Tert-butyl (R)-3-((6-(4-chloro-2-hydroxy-6- (trifluoromethyl)phenyl)pyridazin-3-yl)thio)piperidine-1-carboxylate To a mixture of 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)phenol and 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3- (trifluoromethyl)phenol (614 mg, 1.91 mmol) in 1,4-dioxane (10 mL) and water (1 mL) were added tert-butyl (R)-3-((6-chloropyridazin-3-yl)thio)piperidine-1-carboxylate (350 mg, 1.06 mmol), Na2CO3(337 mg, 3.18 mmol), and Pd(PPh3)4(119 mg, 0.106 mmol) under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 120oC for 2 hrs. Another portion of 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 5-(trifluoromethyl)phenol and 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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 120oC for 16 hrs. The mixture was cooled to RT, diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 20 % 110 160112428.1 Docket No.: 358117.00008 EtOAc in PE) to give Compound 6 (50 mg) followed by Compound 6-1 (200 mg) as solids. Compound 6:1H NMR (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 = 8.9 Hz, 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 were assigned based on their1H observed19F HOSEY spectra where NOE effects were observed for both compounds between relevant aromatic protons and the CF3group. LC-MS (ESI) m / z: 490.1 (M+H)+. Step 6: (R)-3-Chloro-2-(6-(piperidin-3-ylthio)pyridazin-3-yl)-5-(trifluoromethyl)phenol To a solution of tert-butyl (R)-3-((6-(2-chloro-6-hydroxy-4-(trifluoromethyl)phenyl)pyridazin- 3-yl)thio)piperidine-1-carboxylate (50 mg, 0.10 mmol) in DCM (1 mL) was added HCl / 1,4- dioxane (1 mL, 4 M) and the mixture was stirred at RT for 20 mins. The mixture was neutralized with sat. aq. NaHCO3solution and extracted with DCM twice. 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)+. Step 7: (R)-3-chloro-2-(6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-5- (trifluoromethyl)phenol To a mixture of (R)-3-chloro-2-(6-(piperidin-3-ylthio)pyridazin-3-yl)-5- (trifluoromethyl)phenol (35 mg, 0.090 mmol) and aq. HCHO (0.1 mL, 37% wt.) in MeOH (1 mL) were added AcOH (10.8 mg, 0.18 mmol) and NaBH3CN (17.0 mg, 0.27 mmol) at 0 ℃ and the mixture was stirred at RT for 20 mins. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10 ~ 95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (8 mg) as a white solid.1H 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 spectrum. 111 160112428.1 Docket No.: 358117.00008 Example 40 (R)-5-chloro-2-(6-((1-methylpiperidin-3-yl)thio)pyridazin-3-yl)-3- (trifluoromethyl)phenol (VS-6960) for the synthesis of Example 39.1H NMR (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 spectrum. Reference Examples Reference Example 1 (R)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5- (trifluoromethyl)phenol The title compound was US20200361898. LC / MS (ESI) m / z: 367 (M+H)+. Reference Example 2 (R)-2-(4-(3-hydroxybutyl)-5,6,7,8-tetrahydrophthalazin-1-yl)-5-(trifluoromethyl)phenol The title compound was WO2023003002. LC / MS (ESI) 112 160112428.1 Docket No.: 358117.00008 m / z: 367 (M+H)+. Reference Examples 3 to 5 in Table 4 below were prepared following the procedures in WO2022216971. Reference examples 6 and 7 were prepared following procedures from WO2023028534 (Compound I-97) and US Patent 11,618,751 (Example 4), respectively. Table 4. Reference Examples 3-7 Reference LC / MS (ESI) Example #Structure Namem / z (M+H)+ The compounds of this invention were evaluated in a variety of assays to assess their suitability for potential development. It is appreciated that a successful development candidate needs to possess a combination of potency, pharmacokinetic, and safety characteristics. Because we are 113 160112428.1 Docket No.: 358117.00008 interested in CNS indications, compounds intended for those applications should also have adequate exposure in the brain tissue. While an exceptional property in one aspect, for example potency, may be able to compensate to some degree a poor reading in another aspect, for example, pharmacokinetics, most of the time that one exceptional property does not guarantee a compound’s success. The key to success is the balance of properties among all the relevant parameters. We believe that we have achieved a good balance of properties from some of the compounds disclosed herein. Biology assay Example 1: IL-1β inhibition assay in THP-1 cells The ability of test compounds to inhibit the formation of IL-1β in human THP-1 cells were assessed using the following protocol: 1. THP-1 cells (ATCC #TIB-202) were maintained 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) 2. On the day of experiment, THP-1 cells (~5.5 X 105cells / mL) were seeded into 384- well plate in 45 μL RPMI-1640 medium per well (without FBS). 1.0 μg / ml LPS (SIGMA, L6529) was added to prime the cells 3. 5 μL Compounds in serial dilution (10 doses starting from 5 μM, 1:3 dilution) or vehicle (0.05% DMSO in medium) were added to the appropriate wells 4. Cells were incubated for 3 hrs at 37℃, 5% CO2. 5 μL Nigericin (MEC, HY-100381) (final conc.5 μM) was added to sample wells and positive control wells to stimulate the cells; 5 μL RPMI-1640 medium (without FBS) was added to the negative wells 5. After 1 hr incubation at 37℃, 5% CO2, 8 μL supernatant was transferred into 384-well assay plates, 8 μL RPMI-1640 medium (without FBS) was added into each well; standard solutions were prepared in parallel 6. IL-1β levels were measured using Human IL-1β kits (PerkinElmer, 62HIL1BPEH) according to manufacturer’s instruction; plates were read on an HTRF®compatible reader (PE Nivo) 7. Data analysis: the concentrations of IL-1β for treated wells were calculated by the standard curve. The IC50data is fitted to a non-liner regression equation (log inhibitor vs. response - Variable slope four parameters 114 160112428.1 Docket No.: 358117.00008 8. The resulting IC50 or geomean of IC50’s from THP-1 cells were shown in Error! Reference source not found.Table 5. Data which is >300 nM is listed as +, data which is 100~300 nM is listed as ++, data which is 30~100 nM is listed as +++, data which is 10~30 nM is listed as ++++, data which is 3~10 nM is listed as +++++, data which is 1~3 nM is listed as ++++++, and data which is <1 nM is listed as +++++++. These results showed that the compounds of this disclosure showed potent inhibition of IL-1β formation in THP-1 Table 5. Inhibition of IL-1β in THP-1 cells Example # IL-1β IC501 +++++++ 160112428.1 Docket No.: 358117.00008 24 + 25 ++++ Biology assay Exam The following protocol is used to assess the inhibiting potential of compounds on hERG (the human Ether-à-go-go-Related gene) channel with QPatch automated patch-clamp system in CHO-hERG cells. Method: CHO cells stably expressing the transcript of hERG were investigated by the automated whole-cell patch clamp technique, using the QPatch system (Sophion). Cells were grown in 175 cm2flasks in serum supplemented F12 medium in 37oC 5% CO2incubator. Two days after plating (at 70-80% confluence), culture medium was removed and cells were washed 116 160112428.1 Docket No.: 358117.00008 with 7 mL PBS (Phosphate Buffered Saline), then cells were treated with 3 mL Detachin for 2 min at 37oC, followed by the addition of 7 mL serum-free medium, cells were resuspended in the growth medium at a density of 2-5*106cells / mL. The cell suspension was then transferred to the QPatch system, where it was centrifuged; the cells were washed and resuspended in extracellular solution (in mM): 140 NaCl, 5 KCl, 1 CaCl2, 1.25 MgCl2, 10 HEPES and 10 glucose, pH 7.4 with NaOH. The composition of the intracellular solution was (in mM): 140 KCl, 1 MgCl2, 1 CaCl2, 10 EGTA and 10 HEPES, pH 7.2 with KOH. The cells were held at - 80 mV and activated by a +40 mV pre-pulse of 5 s duration followed by a step to -50 mV for 5 s. The voltage protocol is to be repeated every 15 s, the peak of the tail current evoked by the −50 mV step was recorded and measured as test parameter. The solutions containing the compounds were applied to the cells for 2.5 min following a 5 min baseline recording in extracellular solution. Each cell was received from six escalating concentrations. Each concentration was tested on at least 3 cells (n≥3). The reference compound cisapride was applied at the end of the test compound addition. Data Analysis: Data were retrieved and analyzed using Assay Software v5.6.4 provided by Sophion, GraphPad Prism 8 and Excel. The concentrations of compounds to yield 50 % block of the hERG currents (IC50) were obtained by fitting normalized concentration-inhibition relationships to the equation in Prism 8 software as below: Y=Bottom + (Top-Bottom) / (1 + 10^((LogIC50– X)*HillSlope)) where Y is the inhibition% corresponding to X, [X] is the Log value of concentration of compound in the external solution and HillSlope is the Hill coefficient. The ratio of inhibition was calculated by using the equation: Inhibition = (1-I / Io)*100 %, where Io and I are the hERG current amplitude measured at -50 mV in the presence and absence of the test compound. The results from hERG assay are shown in Table 6. They showed that the compounds from this disclosure displayed more favorable hERG profile compared to compound from prior art. Table 6. Inhibition Potential of Compounds at hERG Channel Example # hERG IC50, µM # Data fro Biology assay Example 3: Brain penetration of compounds in mice (Kp and 117 160112428.1 Docket No.: 358117.00008 Kp,uu) The in vivo total brain to plasma ratio was assessed in C57 BL / 6 mice after oral of the compound at 30 mg / kg. For each time point, a group of 3 male C57 BL / 6 mice (6~9 weeks of age, ~30 g from Vital River, Shanghai, China) were dosed via oral gavage following overnight fasting. Food was provided 4 h post dosing if the terminal time point was beyond 4 h. The test compound was formulated in 1:1 PEG400 and saline at 3.0 mg / mL at a dosing volume of 10 mL / kg. At designed timepoints approximately 40.0 µL whole blood was collected into EDTA-K2tube via facial vein and placed on ice. Blood samples were centrifuged at 12,000 rpm for 10 minutes at 4 °C to obtain plasma, then immediately frozen and stored at -75±15°C prior to analysis. The animals are euthanized with CO2after the final collection of whole blood and the animals are perfused with saline via the left ventricle. The whole brain is then collected and rinsed with cold saline, dried on filtrate paper, weighed, and snap frozen by placing on dry ice. The brain tissue samples are then transferred to the freezer at -75±15°C prior to analysis. At the time of analysis, brain samples were homogenized with buffer (methanol: 15 mM PBS= 1:2) by tissue weight (g) to buffer volume (mL) ratio of 1:4. Plasma and brain drug levels were quantified by LC-MS / MS on an AB Sciex Triple QuadTM4500 instrument using a ZORBAX Eclipse XDB-C18, 3.5 µm (or 5 µm) 2.l*50 mm column. Quantitation was performed using a calibration curve prepared in blank plasma or blank brain homogenate. Brain to plasma ratio (Kp) was usually calculated as total brain drug concentration divided by total plasma drug concentration, both in terms of area under the curve (AUC). In this instance, we are also referring to Kpas the ratio of total brain drug concentration to total plasma drug concentration at individual time points as measure of brain penetration. Plasma protein binding and brain homogenate protein binding were measured by equilibrium dialysis using a 96-well equilibrium dialysis plate (HTDialysis) fitted with a dialysis membrane with 12-14 KDa molecular weight cut off. The dialysis membranes were soaked in ultra-pure water for 60 minutes to separate strips, then in 20% ethanol for 20 minutes, finally in ultra-pure water for 20 minutes. The dialysis set up was assembled according to the manufacturer's instruction. Each cell received 150 µL of plasma or brain homogenate (1 g brain tissue + 4 mL dialysis buffer) spiked with 1 µM of test compound and dialyzed against 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 in an incubator at 37°C with 5% CO2at 100 rpm for 4 hours. At the end of incubation, compound 118 160112428.1 Docket No.: 358117.00008 concentration was measured in both chambers by LC-MS / MS on a Triple QuadTM4500 from ABSciex after separation on a ZORBAX Eclipse XDB-C18, 3.5 µm (or 5 µm) 2.l*50 mm column. Peak area ratio between testing compound and internal standard were calculated for buffer (receiver) chamber (F) or in plasma or brain homogenate chamber (T). Free fraction in plasma (fu,pl) or brain (fu,br) were calculated using the following equations where D was the dilution factor used for preparing brain homogenate which was 5 in this case. fu,pl =ி் f^ / ^u,br =் / ிି^ା^ / ^Kp,uu, the free brain to free plasma was often defined as the ratio of unbound (free) AUC between brain and plasma: AUCbr* fu,br / AUCpl* fu,pl. In this instance, we are also referring to Kp,uuas the ratio of free brain drug concentration to free plasma drug concentration at individual time points as measure of brain penetration. The results of select compounds in mouse brain penetration assays were shown in Error! Reference source not found.Error! Reference source not found.. These data demonstrated that some compounds of this invention showed surprisingly higher free brain exposure and much higher free brain vs free plasma concentration ratios compared with most compounds from prior arts. The higher free brain exposures from compounds of this invention are even more favorable when the potency of the compounds was considered. Some of the SAR was also very surprising and unexpected. For example, the significant changes in relative protein binding between plasma and brain among Examples 1 and 6, which resulted in Example 6 having significantly higher Kp,uuratios than Example 1 even though the total brain to plasma ratios were in opposite direction. Table 7. CNS Penetration of Compounds in C57 BL / 6 Mice Following Oral Dosing Total conc.brng / g Kpratio Free conc.br, ng / g Kp,uuratio 119 160112428.1 Docket No.: 358117.00008 Reference Example 14450 4813 1.83 2.15 116 125 0.26 0.43 The iv and po pharmacokinetic profiles of the compound were evaluated in male SD rats (6-9 weeks of age, 200~250 g body weight from Vital River, Shanghai, China). Six rats were randomly assigned to 2 groups (N=3 / group), including IV (1 mg / kg) and PO (2 mg / kg) dosing groups. Weigh appropriate amount of compound, add 1:1 PEG400 and saline, stir thoroughly to prepare the drug solution with a concentration of 0.5 mg / mL for IV dosing or 0.2 mg / mL for PO dosing. Animals in PO group were fasted overnight before dosing but given ad libitum access to water and provided with food 4 hrs after dosing. Animals in IV group were given ad libitum access to food and water. Blood was collected at several time points up to 24 hr. Approximately 150 µL whole blood was collected into EDTA-K2tube via jugular vein or tail vein and placed on ice. The whole blood samples were then centrifuged for 10 min at 4°C, 12000 rpm within 30 min after collection. Approximately 50 µL plasma was taken and placed in a labeled 1.5 mL tube and then stored in the freezer at -75±15°C before analysis. Plasma concentrations of test compound will be determined by using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) on a Triple QuadTM4500 from ABSciex after separation on a ZORBAX Eclipse XDB-C18, 3.5 µm 2.l*50 mm or 5 µm 4.6*50 mm column. Quantitation was performed using a calibration curve prepared in blank plasma. The WinNonlin software (Phoenix) was used for pharmacokinetic analysis from the concentrations versus time data by statistical moment method of non-compartment model (t1 / 2, AUClast, Cmax, Tmax and MRTlast, etc.). Alternatively, brain samples were taken at the terminal time point and analyzed for drug concentration using method similar to those described above for the mouse experiment. Free fractions for rat plasma and brain were also similarly determined to provide both Kpand Kp,uu120 160112428.1 Docket No.: 358117.00008 from rats. In another screening mode, multiple compounds were dosed as a mixture to the same group of rats to obtain pharmacokinetic profile for a group of compounds to be compared in the same animals. The results of pharmacokinetic profiles of select compounds in rats from this invention were shown in Table 8Error! Reference source not found.. These data showed that some compounds from this invention showed appealing pharmacokinetic profile in rats. Some of the results were unexpected. For example, one would expect Example 6 will have higher clearance than Example 1 due to higher lipophilicity and the addition of three metabolically labile benzylic type hydrogens. However, a significant reduction in clearance and an increase in half-life and exposure were observed instead. Table 8. Pharmacokinetic Profiles of Select Compounds in SD Rats Example Clp, AUCNiv, Kp,uu 24 t1 / 2, h Vd, L / kg %F MRTpo, h#mL / min / k h*n / mL / m kh showed superior combination of properties with respect to potency, safety, brain penetration, and preclinical pharmacokinetics. Therefore, they demonstrated potential for further development. Although the present disclosure includes references to various embodiments or examples, it should be understood that these embodiments and examples are merely illustrative of the principles and applications of certain aspects of the invention. Numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the invention, which are intended to be encompassed by the present disclosure. All patents or non-patent references cited in this application are incorporated herein by reference in their entireties without admission of any of them as prior art. 121 160112428.1

Claims

Docket No.: 358117.00008 CLAIMS What is claimed is:

1. A compound having the structure of Formula I: , or a stereoisomer, a acceptable salt orprodrug thereof, wherein: represents a single or double bond; X is NR1, CH2, O, S or a bond; R1is H, alkyl, cycloalkyl, alkyl-CO-, or heterocyclyl, wherein the alkyl, cycloalkyl, alkyl-CO, heterocyclyl are each optionally substituted with one to five groups independently selected from R7; R2at each occurrence is independently selected from R7, or two R2groups and the intervening connecting atoms form a 3- to 6-membered ring optionally comprising one or two heteroatoms independently selected from O, N, and S, wherein said ring is optionally substituted with one to five groups independently selected from R7; or two nonadjacent R2 groups taken together form a 1- to 3-membered bridge optionally comprising one heteroatom selected from O, N, and S, wherein the bridge is optionally substituted by one to three substituents independently selected from R7; or alternatively, R1and an adjacent R2and the intervening connecting atoms form a 5- or 6- membered heterocyclyl optionally comprising one additional heteroatom independently selected from O, N, and S, wherein the heterocyclyl is optionally substituted with one to three groups independently selected from R7; W1 and W2 are together selected from: (i) both nothing, (ii) both O, (iii) nothing and O, and (iv) NR3and O, wherein R3is H, alkyl, cycloalkyl, alkyl-CO-, CN, NO2, aryl, or heteroaryl, wherein alkyl, cycloalkyl, alkyl-CO-, aryl, and heteroaryl are each optionally substituted with 122 160112428.1Docket No.: 358117.00008 one to five groups independently selected from R8; or alternatively, R3and an R2together with their intervening connecting atoms form a 5- to 8- membered heterocyclic ring optionally comprising one additional heteroatom independently selected from O, N, and S and optionally substituted with 1 to 3 groups independently selected from R7; Y is CR4a, N, or C=O; Z is CR4b, N, or N-R9, with the provisos that Y and Z are not both N; and if Y is C=O, then Z is N-R9; or alternatively, Y and Z taken together is S; or alternatively, Y and Z taken together is part of a 5- to 7-membered carbocylic, 5- to 7-membered heterocyclic, six-membered aromatic or heteroaromatic, or 5-membered heteroaromatic ring fused to the existing ring containing N-N, each optionally substituted by one to three substituents independently selected from R4a, R4b, R9, R10, and R11; R4a and R4b are independently selected from H, alkyl, cycloalkyl, CN, haloalkyl, phenyl, -C1-6alkyl-OR9, -C1-6alkyl-NHR9, and -C1-6alkyl-N(R9)2; R5is OH, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or C1-6haloalkoxy; R6at each occurrence is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6haloalkoxyl, C3-6cycloalkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, halo, CN, SF5, NHR9, N(R9)2, OR9, and SR9; or alternatively, two adjacent R6groups together with their intervening connecting atoms form a 5- or 6-membered carbocyclic, heterocyclic, aromatic, or heteroaromatic ring fused to the existing phenyl ring; R7at each occurrence is independently selected from H, C1-6alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9; R8at each occurrence is independently selected from H, C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl CN, phenyl, and halo; R9at each occurrence is independently H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; R10at each occurrence is independently H, C1-6alkyl, C3-6cycloalkyl, halo, or CF3; R11 at each occurrence is independently H, C1-6 alkyl, C3-6 cycloalkyl, or =O; 123 160112428.1Docket No.: 358117.00008 m is 0, 1, or 2; n is 0, 1, 2, 3, or 4, with the proviso that m+n≥2; i is 0, 1, 2, 3, 4; and j is 0, 1, 2, 3, 4.

2. The compound of claim 1, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is NR1, CH2, O, S or a bond; R1is H, C1-6alkyl, C3-6cycloalkyl, C1-6alkyl-CO-, 4-6 membered heterocyclyl, wherein the C1-5alkyl, C3-6cycloalkyl, C1-4alkyl-CO-, and 4-6 membered heterocyclyl are each optionally substituted with one to three groups independently selected from R7; R2 at each occurrence is independently selected from R7, or two R2 groups and the intervening connecting atom(s) form a 3- to 6-membered ring optionally comprising a heteroatom selected from O, N, and S, and the ring is optionally substituted with one or two groups independently selected from R7; or two nonadjacent R2groups taken together form a 1- to 3-membered bridge optionally comprising one heteroatom selected from O, N, and S, wherein the bridge is optionally substituted by one to three substituents independently selected from R7; or alternatively, R1and an adjacent R2and the intervening connecting atoms form a 5- or 6- membered heterocyclyl optionally comprising one additional heteroatom selected from O, N, and S, wherein the heterocyclyl is optionally substituted with one to three groups independently selected from R7; W1and W2are together selected from: (i) both nothing, (ii) both O, (iii) nothing and O, and (iv) NR3and O, wherein R3is H, C1-5alkyl, C3-6cycloalkyl, C1-4alkyl-CO, CN, NO2, C6aryl, or 5- or 6-membered heteroaryl optionally substituted with one to three groups independently selected from R8; or alternatively, R3and R2taken together with the intervening connecting atoms form a 5- to 8- membered heterocyclic ring optionally comprising one additional heteroatom selected from O, N, and S as part of this ring and optionally substituted with one or two groups independently selected from R7Y is CR4a, N, or C=O; 124 160112428.1Docket No.: 358117.00008 Z is CR4b, N, or N-R9; with the provisos that Y and Z are not both N, and if Y is C=O, then Z is N-R9; or alternatively, Y and Z taken together is S; or alternatively, Y and Z taken together is part of a 5- to 7-membered carbocyclic, 5- to 7-membered heterocyclic, six-membered aromatic or heteroaromatic, or 5-membered heteroaromatic ring optionally substituted by one or two substituents independently selected from R4a, R4b, R9, R10, and R11; R4aand R4bare independently selected from H, C1-4alkyl, C3-6cycloalkyl, CN, CF3, or phenyl; R5is OH, OCHF2, OCF3, CHF2, CF3, CF3CH2, or OMe; R6 at each occurrence is independently selected from H, CF3, CF2CF3, OCF3, C3-6cycloalkyl, C1-4alkyl, CHF2, OCHF2, halo, CN, SF5, NHR9, N(R9)2, OR9, and SR9; or alternatively, two R6groups together with intervening connecting atoms form a 5- or 6-membered carbocyclic, heterocyclic, aromatic, or heteroaromatic ring fused to the existing phenyl ring; R7at each occurrence is independently selected from H, C1-4alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9; R8at each occurrence is independently selected from H, C1-4alkyl, cyclopropyl, CF3, CHF2, CN, phenyl, and halo; R9at each occurrence is independently H, C1-4alkyl, or cyclopropyl; R10at each occurrence is independently H, C1-4alkyl, cyclopropyl, halo, or CF3; R11at each occurrence is independently H, C1-4alkyl, cyclopropyl or =O; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4, with the proviso that m+n≥2; i is 0, 1, 2, or 3; and j is 0, 1, or 2.

3. The compound of claim 1, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: 125 160112428.1Docket No.: 358117.00008 X is NR1or O; R1is hydrogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkyl-CO-, -C1-6alkyl-OR9, -C1-6alkyl- C(O)OR9, or 4- to 6-membered heterocyclyl, each, except hydrogen, optionally substituted with one to three groups independently selected from C1-4alkyl, halo, CN, =O, OR9, SR9, NHR9, and N(R9)2; R2at each occurrence is independently selected from C1-6alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9, or two adjacent R2groups and the intervening connecting atoms form a 5- or 6-membered ring optionally comprising one or two heteroatoms independently selected from O, N, and S, wherein said ring is optionally substituted with one to three groups independently selected from C1-4alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9; or two nonadjacent R2groups taken together form a C1-3alkylene bridge optionally substituted by one or two substituents independently selected from C1-4alkyl, halo, CN, =O, OR9, SR9, NHR9, N(R9)2, and CO2R9; W1 and W2 together are selected from: (i) both nothing, (ii) both O, and (iii) nothing and O; Y is CR4aor N; Z is CR4bor N, provided that Y and Z are not both N; or alternatively, Y and Z taken together is part of a 5- or 6-membered carbocyclic, 5- or 6-membered heterocyclic, six-membered aromatic or heteroaromatic, or 5-membered heteroaromatic ring, each fused to the existing ring containing N-N and each optionally substituted by one to three substituents independently selected from halo, CN, =O (excluding aromatic and heteroaromatic), C1-6alkyl, C3-6cycloalkyl, C1-6haloalkyl, phenyl, -C1-6alkyl- OR9, -C1-6alkyl-NHR9, and -C1-6alkyl-N(R9)2; R4aand R4bare independently selected from H, C1-6alkyl, C3-6cycloalkyl, CN, C1-6haloalkyl, phenyl, -C1-6alkyl-OR9, -C1-6alkyl-NHR9, and -C1-6alkyl-N(R9)2; R5is OH, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6at each occurrence is independently selected from hydrogen, C1-4alkyl, C1-4haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, halo, CN, NHR9, N(R9)2, OR9, or SR9; R9at each occurrence is independently H, C1-4alkyl, or C1-4haloalkyl, or C3-6cycloalkyl; 126 160112428.1Docket No.: 358117.00008 m is 1, or 2; n is 1, 2, or 3; i is 0, 1, 2, 3; and j is 1, 2, 3.

4. The compound of any one of claims 1 to 3, having a structure of formula (I-a): , or a stereoisomer, aacceptable salt or prodrug thereof, wherein X, m, n, R2, Y, Z, R5, and R6 are as defined in any one of claims 1 to 3.

5. The compound of any one of claims 1 to 4, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein is selected from:Docket No.: 358117.00008 wherein: Z1, Z2, Z3, and Z4are independently selected from CR10and N, with the proviso that at most one of them is N; Z5is O, NR9, S, SO, or SO2; Y1is a bond, CHR11, or SO2; o and p are selected from the following combinations among the columns: o = 0 0 0 2 3 4 1 1 2 2 3 16. The compound according to claim 4 or 5, having a structure of formula (I-a-1): , or a stereoisomer, aacceptable salt or prodrug thereof, wherein: X is NR1or O; Y and Z are as defined in claim 5; R5is independently selected from OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, and C1-2haloalkoxy; R6ais independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4 haloalkyl; R9 at each occurrence is independently H or C1-4 alkyl. 128 160112428.1Docket No.: 358117.00008 7. The compound according to any one of claims 1 to 5, having a structure of formula (I-b): , or a stereoisomer, a acceptable salt orprodrug thereof, wherein n1=0, 1, or 2; and R1, R2, Y, Z, R5, and R6are as defined in any one of claims 1 to 5.

8. The compound according to claim 7, having a structure of formula (I-b-1): (R2)i,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: Y and Z are as defined in claim 5; n1is 0 or 1; R5is independently selected from OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, and C1-2haloalkoxy; R6ais independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; R9at each occurrence is independently H or C1-4alkyl.

9. The compound according to any one of claims 1 to 5, having a structure of 129 160112428.1Docket No.: 358117.00008 formula (I-c): R R 75R2N N jor a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: r is 0, 1, or 2; and Y, Z, R1, R2, j, R6, and R7are as defined in claim 4 or 5.

10. The compound according to claim 9, having a structure of formula (I-c-1): ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: r is 0 or 1; Y and Z are as defined in claim 5; R5is independently selected from OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, and C1-2haloalkoxy; R6ais independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; and R9at each occurrence is independently H or C1-4alkyl.

11. The compound according to any one of claims 1 to 5, having a structure of formula (I-d): 130 160112428.1Docket No.: 358117.00008 ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein X, R2, m, n, Y, Z, and R6are as defined in any one of claims 1 to 4.

12. The compound according to claim 11, having a structure of formula (I-d-1): ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is NR1or O; Y and Z are as defined in claim 5; R6a is independently selected from halo, CN, OR9, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; and R9at each occurrence is independently H or C1-4alkyl.

13. The compound according to any one of claims 1 to 5, having a structure of formula (I-e): 131 160112428.1Docket No.: 358117.00008 ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; and R1, R2, Y, Z, and R6are as defined in any one of claims 1 to 5.

14. The compound according to claim 13, having a structure of formula (I-e-1): , or a stereoisomer, aacceptable salt or prodrug thereof, wherein: n1=0 or 1; Y and Z are as defined in claim 5; R6ais independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; and R9at each occurrence is independently H or C1-4alkyl.

15. The compound according to any one of claims 1 to 5, having a structure of formula (I-f): 132 160112428.1Docket No.: 358117.00008 ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; and R1, R2, i, j, R4a, R4b, and R6are as defined in any one of claims 1 to 5.

16. The compound according to claim 15, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1is 1; i is 0, 1, or 2; j is 1 or 2; R1is hydrogen, C1-6alkyl, C1-6alkyl-CO-, -C1-6alkyl-OR9, or -C1-6alkyl-C(O)OR9; R2at each occurrence is independently hydrogen, C1-6alkyl, or halo; or two nonadjacent R2groups taken together form a C1-3alkylene bridge optionally substituted by one or two substituents independently selected from R7; R4a and R4b are independently selected from H, C1-6 alkyl, CN, C1-6 haloalkyl, -C1-6alkyl-OR9, -C1-6alkyl-NHR9, and -C1-6alkyl-N(R9)2; R5is OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6at each occurrence is independently selected from hydrogen, halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5- membered heteroaryl; R7is hydrogen, C1-4alkyl, halo, or OR9; and R9at each occurrence is independently H or C1-4alkyl.

17. The compound according to claim 15 or 16, having a structure of formula (I-f- 1): 133 160112428.1Docket No.: 358117.00008 , or a stereoisomer, a acceptable salt or prodrug thereof, wherein:R1is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2OH; R2is H or F; R4ais H, CN, -CH3, -CH2OH, or -CH2NHCH3; R4bis H or -CH3; R5is -OH, -CF3, or -OCHF2; R6is H, F, Cl, -CF3, or -CH3; and R6ais -CF3, -CH3, .

18. The compoundor 16, having a structure of formula (I-f- 2): ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: r is 0, 1, or 2; R1is hydrogen, C1-6alkyl, C1-6alkyl-CO-, -C1-6alkyl-OR9, or -C1-6alkyl-C(O)OR9; R2is hydrogen, C1-6alkyl, or halo; R4aand R4bare independently selected from H, C1-6alkyl, CN, C1-6haloalkyl, -C1-6alkyl-OR9, -C1-6alkyl-NHR9, and -C1-6alkyl-N(R9)2; 134 160112428.1Docket No.: 358117.00008 R5is OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6at each occurrence is independently selected from hydrogen, halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5- membered heteroaryl; R7is C1-4alkyl, halo, and OR9; and R9at each occurrence is independently H or C1-4alkyl.

19. The compound according to claim 18, having a structure of formula (I-f-2-a): ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: R1is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2OH; R4ais H, CN, -CH3, -CH2OH, or -CH2NHCH3; R4bis H or -CH3; R5is -OH, -CF3, or -OCHF2; R6is H, F, Cl, -CF3, or -CH3; and R6ais -CF3, -CH3, cyclopropyl, Cl, or .

20. The compound according to any one of claims 1 to 5, having a structure of formula (I-g): 135 160112428.1Docket No.: 358117.00008 ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; R1, R2, R5, R6and R10are as defined in any one of claims 1 to 5; and Z1, Z2, Z3, and Z4are each independently CR10or N, with the proviso that no more than one of them are N.

21. The compound according to claim 20, having a structure of formula (I-g-1), (I- g-2), or (I-g-3): ,or prodrug thereof, wherein: i is 0, 1, or 2; R1at each occurrence is independently hydrogen, C1-6alkyl, C1-6alkyl-CO-, -C1-6alkyl- OR9, or -C1-6alkyl-C(O)OR9; R2at each occurrence is independently hydrogen, C1-6alkyl, or halo; R5at each occurrence is independently OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6aat each occurrence is independently selected from halo, CN, OR9, C1-4alkyl, C1-4136 160112428.1Docket No.: 358117.00008 haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; R9at each occurrence is independently H or C1-4alkyl; and R10at each occurrence is independently H, C1-4alkyl, cyclopropyl, halo, or CF3.

22. The compound according to claim 20 or 21, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0; R1is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2OH; R5is -OH, -CF3, or -OCHF2; R6is H, F, Cl, -CF3, or -CH3; and R6a is -CF3, -CH3, cyclopropyl, Cl, or ; and R10is H.

23. The compound according to any one of claims 1 to 5, having a structure of formula (I-h), (I-i), or (I-j): ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; and R1, R2, R5, R6, and R10are as defined in any one of claims 1 to 4.

24. The compound according to claim 23, having a structure of formula (I-h-1), (I- i-1), or (I-j-1): 137 160112428.1Docket No.: 358117.00008 ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0, 1, or 2; R1at each occurrence is independently hydrogen, C1-6alkyl, C1-6alkyl-CO-, -C1-6alkyl- OR9, or -C1-6alkyl-C(O)OR9; R2at each occurrence is independently hydrogen, C1-6alkyl, or halo; R5at each occurrence is independently OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6aat each occurrence is independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; R9at each occurrence is independently H or C1-4alkyl; and R10at each occurrence is independently H, C1-4alkyl, cyclopropyl, halo, or CF3.

25. The compound according to claim 24, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0; R1is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2OH; R5is -OH, -CF3, or -OCHF2; R6is H, F, Cl, -CF3, or -CH3; and R6ais -CF3, -CH3, R10is H or -CH3.138 160112428.1Docket No.: 358117.00008 26. The compound according to any one of claims 1 to 5, having a structure of formula (I-k): ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; i is 0, 1, or 2; q is 0 or 1; Y1is -CH2- or -S(O)2-; and R1, R2, R5, R6, and R11are as defined in any one of claims 1 to 5.

27. The compound according to claim 26, having a structure of formula (I-k-1), (I- k-2), (I-k-3): ,salt or prodrug thereof, wherein: i is 0, 1, or 2; R1at each occurrence is independently hydrogen, C1-6alkyl, C1-6alkyl-CO-, -C1-6alkyl- OR9, or -C1-6alkyl-C(O)OR9; 139 160112428.1Docket No.: 358117.00008 R2at each occurrence is independently hydrogen, C1-6alkyl, or halo; R5at each occurrence is independently OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6aat each occurrence is independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; R9at each occurrence is independently H or C1-4alkyl; and R11at each occurrence is independently H, C1-4alkyl, cyclopropyl, halo, or CF3.

28. The compound according to claim 27, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0; R1is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2OH; R5is -OH, -CF3, or -OCHF2; R6is H, F, Cl, -CF3, or -CH3; and R6ais -CF3, -CH3, R11at each occurrence iscyclopropyl, or =O.

29. The compound according to any one of claims 1 to 5, having a structure of formula (I-l): , 160112428.1Docket No.: 358117.00008 or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n1=0 or 1; and R1, R2, R4b, R5, and R6are as defined in any one of claims 1 to 5.

30. The compound according to claim 29, having a structure of formula (I-l-1): ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0, 1, or 2; R1at each occurrence is independently hydrogen, C1-6alkyl, C1-6alkyl-CO-, -C1-6alkyl- OR9, or -C1-6alkyl-C(O)OR9; R2at each occurrence is independently hydrogen, C1-6alkyl, or halo; R4bis H, C1-6alkyl, CN, or C1-6haloalkyl, R5at each occurrence is independently OH, halo, C1-2alkyl, C1-2haloalkyl, C1-2alkoxy, or C1-2haloalkoxy; R6aat each occurrence is independently selected from halo, CN, OR9, C1-4alkyl, C1-4haloalkyl, C1-4haloalkoxy, C3-6cycloalkyl, 5-membered heterocyclyl, and 5-membered heteroaryl; R6at each occurrence is independently selected from hydrogen, halo, OR9, C1-4alkyl, and C1-4haloalkyl; and R9at each occurrence is independently H or C1-4alkyl.

31. The compound according to claim 30, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: i is 0; 141 160112428.1Docket No.: 358117.00008 R1is -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2OH; R4bis H or -CH3; R5is -OH, -CF3, or -OCHF2; R6is H, F, Cl, -CF3, or -CH3; and R6ais -CF3, -CH3, .

32. The compound2, having a structure of formula (I-m): (R2)ij,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein: n=0 or 1; and R1, R2, R6, and R9are as defined in claim 1 or 2.

33. The compound according to any one of claims 1 to 5, having a structure of formula (I-n): ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt or prodrug thereof, wherein Y, Z, R2, m, n, i, and R6are as defined in any one of claims 1 to 5. 142 160112428.1Docket No.: 358117.00008 34. The compound according to claim 33, having a structure of formula (I-n-1): , or a stereoisomer, a tautomer, acceptable salt orprodrug thereof, wherein: i is 0, 1, 2, or 3; R2is H, F, or -CH3; R4ais H, CN, -CH3, -CH2OH, or -CH2NHCH3; R4bis H or -CH3; R5is -OH, -CF3, or -OCHF2; R6is H, F, Cl, -CF3, or -CH3; and R6ais -CF3, -CH3, cyclopropyl, Cl, or .

35. The compound according to claim 1 or 2, or a stereoisomer, tautomer, an isotopic derivative, or a 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 a compound according to any one of claims 1 to 35, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers.

37. A method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering an effective amount of a compound of any one of claims 1 to 35, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 36 to the subject. 143 160112428.1Docket No.: 358117.00008 38. A method for treating or preventing a disease or condition in a subject in need thereof, comprising administering an effective amount of a compound of any one of Claims 1 to 35, or a stereoisomer, tautomer, an isotopic derivative, a pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition of claim 36 to the subject, wherein the disease or condition is a neurodegenerative disorder, a metabolic ailment, an inflammatory syndrome, an autoinflammatory disease, cancer, or a hereditary disease.

39. The method of claim 28, wherein the neurodegenerative disorder is Parkinson’s disease or Alzheimer’s disease; the metabolic ailment is type 2 diabetes or atherosclerosis; the inflammatory disease is gout flares or osteoarthritis; the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis; the cancer is lung cancer; and the hereditary disease is Cryopyrin-associated periodic syndrome. 144 160112428.1

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