WO2025117439A1

WO2025117439A1 - Macrocycle compounds as inhibitors of nlrp3 activity and therapeutic uses thereof

Info

Publication number: WO2025117439A1
Application number: PCT/US2024/057272
Authority: WO
Inventors: Hongjian Zhang; Dongming Shen; Hui Wang; Fei Jiang; Peihua Sun
Original assignee: Viva Star Biosciences Suzhou Co Ltd; Viva Star Biosciences Us Inc
Current assignee: Viva Star Biosciences Suzhou Co Ltd; Viva Star Biosciences Us Inc
Priority date: 2023-11-30
Filing date: 2024-11-25
Publication date: 2025-06-05
Anticipated expiration: 2026-05-30

Abstract

This application discloses novel macrocycle compounds of formula (I) 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

MACROCYCLE 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/CN2023/135591, filed on November 30, 2023, and No. PCT/CN2024/085202, filed on April 1, 2024, the disclosures of both of which are incorporated herein by reference in their entireties.

FIELD OF THE DISCLOSURE

This application relates to macrocyclic pyridazine compounds and analogues as modulators of cytokines such as IL-iβ 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 evidence indicates 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 pro-caspase-1. The formation of NLRP3 inflammasome activates caspase-1, which in turn catalyzes proteolytic reactions, releasing pro-inflammatory cytokines such as interleukin-iβ (IL-iβ) and IL- 18 [Nat. Rev. Immunol. 2013, 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 NLRP3 cause hereditary diseases such as Cryopyrin-associated periodic syndrome (CAPS). In addition, aberrant activation of NLRP3 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, 22(5):550-559]. 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 or X-ray crystal structures [Nature 2022; 604:184-189; J. Mol. Biol. 2021, 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 No.6,166,064; 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], 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. 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, 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. NLRP3 inhibitors may have a role in the treatment of inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis [Front Immunol. 2019, 10:276]. A gut- restricted NLPR3 inhibitor may have advantages over systemic NLRP3 inhibitor in this application. Therefore, gut-restricted NLRP3 inhibitors may have practical utility in treating 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, CN115417856, 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, WO2024/121184, WO2024/137319, WO2024/138045, WO2024/140704, WO2024/140824, WO2024/141534, WO2024/141535, WO2024/145623, WO2024/148029, WO2024/157205, WO2024/157953, WO2024/158941, WO2024/160690, WO2024/160691, WO2024/160692, WO2024/160693, WO2024/160694, WO2024/169858, WO2024/169895, WO2024/188994, WO2024/193541, WO2024/193699, WO2024/193703, WO2024/213552, WO2024/217442, WO2024/218100, and WO2024/218188. This comprehensive compilation of NLRP3 inhibitors based on pyridazines and related structures suggested that most of those compounds show properties suitable as peripherally restricted NLRP3 inhibitors. A few applications showing CNS penetrant NLRP3 inhibitors appear to have various shortcomings. To date, none of the NLRP3 inhibitors currently in human trials with publicly disclosed structures claimed to be CNS penetrants can be reproduced to provide good brain penetration in preclinical species. Thus, the development of CNS penetrating NLRP3 inhibitors is in high demand. None of the applications showed NLRP3 inhibitors having demonstrated to be gut-restricted. Therefore, there is still a need to develop new compounds with robust CNS penetration or gut-restricted distribution which have suitable pharmacokinetic, safety, and chemical/physical properties as NLRP3 inhibitors useful for treatment of various diseases and conditions. SUMMARY OF THE DISCLOSURE The present disclosure aims to meet the foregoing need by providing macrocyclic pyridazine compounds and their derivatives as NLRP3 inhibitors, in particular gut-restricted or CNS penetrant NLRP3 inhibitors. In one aspect, the present disclosure provides a compound having the structure of Formula I:

or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X is NR⁴, S, O, or CR⁵R⁶; Y is CR⁵R⁶ or a bond; Z is N or CR⁷; Ring A is 4-7 membered heterocyclyl, C_6-10 aryl, 5-6 membered heteroaryl, or 4-7 membered carbocyclyl, each optionally substituted with one to three groups independently selected from R¹, except that R¹ is not oxo (=O) when A is C_6-10 aryl or 5-6 membered heteroaryl; W¹, W³, and W⁵ are each independently selected from CR⁵R⁶, O, S, and NR⁴; and W², W⁴, and W⁶ are each independently selected from a bond, CR⁵R⁶, O, S, and NR⁴, with the proviso that no two non-carbon atoms are connected directly nor to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; alternatively, wherein R⁵ and R⁶, R⁴ and R⁵, or R⁴ and R⁶ can form additional 3-4 membered spiro or 5-7 membered bridged rings; m is 0, 1, 2, 3; and n is 0, 1, 2 R¹ at each occurrence is independently selected from -H, C_1-8alkyl, C_3-7 cycloalkyl, C_1-8alkyl-CO-, 4-7 membered heterocyclyl, OR⁸, CO₂R⁸, C(O)NR⁸R⁹, halo, CN, NR⁸R⁹, and oxo (=O), wherein each of C_1-8alkyl, C_3-7cycloalkyl, C_1-8alkyl-CO-, and 4-7 membered heterocyclyl is optionally substituted with 1-3 groups independently selected from R¹⁰; R² is -OH, -OCHF₂, -OCF₃, -CHF₂, -CF₃, -CH₂CF₃, -OMe, -F, or -H; R³ at each occurrence is independently selected from -H, C_3-6cycloalkyl, C_1-6alkyl,C_1- ₆haloalkyl, -O-C_1-6haloalkyl, halo, -CN, -SF₅, -NR⁸R⁹, -OR⁸, -SR⁸, aryl, and heteroaryl, wherein C_3-6cycloalkyl and C_1-6alkyl are each optionally substituted with 1-3 groups independently selected from halo, oxo, and C_1-4alkyl; and wherein aryl and heteroaryl are each optionally substituted with 1-3 groups independently selected from halo and C_1-4alkyl; R⁴ at each occurrence is independently selected from -H, C_1-4 alkyl, -C(O)-C_1-4 alkyl, and C_3-7 cycloalkyl, wherein each of C_1-4 alkyl and C_3-7 cycloalkyl is optionally substituted with 1-3 groups independently selected from R¹⁰; R⁵ and R⁶ at each occurrence are independently selected from -H, halo, -OR⁸, -NR⁸R⁹, C_1-4 alkyl, C_3-7 cycloalkyl, and 4-7 membered heterocyclyl, wherein each of C_1-4 alkyl, C_3-7 cycloalkyl, and 4-7 membered heterocyclyl is optionally substituted with 1-3 groups independently selected from R¹⁰; or alternatively, R⁵ and R⁶ connected to the same atom taken together form =O; or alternatively, R⁵ and R⁶ connected to the same or different atoms can form a 3-6 membered carbocyclic or heterocyclyl ring optionally substituted with 1-3 groups of R¹⁰; R⁷ is independently selected from H, C_1-8 alkyl, C_3-7 cycloalkyl, aryl, heteroaryl, halo, -CN, -OR⁸, -NR⁸R⁹, -CO₂R¹¹, and -C(O)N(R¹¹R¹²), wherein each of C_1-4 alkyl, C_3-7 cycloalkyl, aryl, and heteroaryl is optionally substituted with 1-3 groups independently selected from R¹³; or alternatively, R⁷ and R⁴ or R⁵ or R⁶ can form a 5-7 membered carbocyclic or heterocyclyl ring optionally substituted with 1-3 groups of R¹⁰; R⁸ and R⁹ are independently selected from -H, -C(O)R¹², -C(O)N(R¹¹R¹²), - C(=NR¹²)N(R¹¹R¹²), C_1-6 alkyl, C_3-7 cycloalkyl, and aryl, wherein each of C_1-6 alkyl, C_3-7 cycloalkyl, and aryl is optionally substituted with 1-3 groups independently selected from R¹⁰, except that R¹⁰ is not =O when R⁸ or R⁹ is aryl; R¹⁰ at each occurrence is independently selected from -H, -CO₂R¹¹, -C(O)N(R¹¹)₂, - CN, -OR¹¹, halo, C_1-6 alkyl, cyclopropyl, aryl, =O, -SR¹¹, and -N(R¹¹R¹²); R¹¹ at each occurrence is independently selected from -H, -CO₂R¹², -C(O)R¹², - C(O)NR¹²C(=NR¹²)N(R¹²)₂, -C(=NR¹²)N(R¹²)₂, -C(O)N(R¹²)₂, aryl, and C_1-6 alkyl, wherein each of the aryl and C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂; R¹² at each occurrence is independently selected from -H, aryl, and C_1-4 alkyl, wherein each of the aryl or C_1-4 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂; and R¹³ at each occurrence is independently selected from -H, halo, -OH, -N(R¹²)₂, - NR¹²C(=NR¹²)N(R¹²)₂, -NR¹²C(O)N(R¹²)₂, -NR¹²C(O)R¹², -NR¹²C(O)OR¹², -OC(O)N(R¹²)₂, -CO₂R¹², -COR¹², -C(O)NR¹²C(=NR¹²)N(R¹²)₂, -C(=NR¹²)N(R¹²)₂, -C(O)N(R¹²)₂, aryl, and C_1-6 alkyl, wherein each of the aryl and C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂. In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) according to any embodiment disclosed herein, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt 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 of formula (I) according to any embodiment disclosed herein, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt 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 of formula (I) according to any embodiment disclosed herein, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides use of a compound of formula (I) according to any embodiment disclosed herein, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a disease or condition selected from neurodegenerative disorders, metabolic ailments, inflammatory syndromes, autoinflammatory diseases, cancers, and hereditary diseases. In some embodiments, the disease or condition treatable by the compounds disclosed is a neurodegenerative disorder, a metabolic ailment, an inflammatory syndrome, an autoinflammatory disease, cancer, or a hereditary disease. Other aspects and advantages will be better understood in view of the detailed description, examples, and claims that follow. DETAILED DESCRIPTION OF THE DISCLOSURE The present disclosure provides novel macrocycle compounds and analogues as therapeutic agents 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. In one aspect, the present disclosure provides a compound having the structure of Formula I:

or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X is NR⁴, S, O, or CR⁵R⁶; Y is CR⁵R⁶ or a bond; Z is N or CR⁷; Ring A is 4-7 membered heterocyclyl, C_6-10 aryl, 5-6 membered heteroaryl, or 4-7 membered carbocyclyl, each optionally substituted with one to three groups independently selected from R¹, except that R¹ is not oxo (=O) when A is C_6-10 aryl or 5-6 membered heteroaryl; W¹, W³, and W⁵ are each independently selected from CR⁵R⁶, O, S, and NR⁴; and W², W⁴, and W⁶ are each independently selected from a bond, CR⁵R⁶, O, S, and NR⁴, with the proviso that no two non-carbon atoms are connected directly nor to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; alternatively, wherein R⁵ and R⁶, R⁴ and R⁵, or R⁴ and R⁶ can form additional 3-4 membered spiro or 5-7 membered bridged rings; m is 0, 1, 2, 3; and n is 0, 1, 2 R¹ at each occurrence is independently selected from -H, C_1-8alkyl, C_3-7 cycloalkyl, C_1-8alkyl-CO-, 4-7 membered heterocyclyl, OR⁸, CO₂R⁸, C(O)NR⁸R⁹, halo, CN, NR⁸R⁹, and oxo (=O), wherein each of C_1-8alkyl, C_3-7cycloalkyl, C_1-8alkyl-CO-, and 4-7 membered heterocyclyl is optionally substituted with 1-3 groups independently selected from R¹⁰; R² is -OH, -OCHF₂, -OCF₃, -CHF₂, -CF₃, -CH₂CF₃, -OMe, -F, or -H; R³ at each occurrence is independently selected from -H, C_3-6cycloalkyl, C_1-6alkyl, C_1- ₆haloalkyl, -O-C_1-6haloalkyl, halo, -CN, -SF₅, -NR⁸R⁹, -OR⁸, -SR⁸, aryl, and heteroaryl, wherein C_3-6cycloalkyl and C_1-6alkyl are each optionally substituted with 1-3 groups independently selected from halo, oxo, and C_1-4alkyl; and wherein aryl and heteroaryl are each optionally substituted with 1-3 groups independently selected from halo and C_1-4alkyl; R⁴ at each occurrence is independently selected from -H, C_1-4 alkyl, -C(O)-C_1-4 alkyl, and C_3-7 cycloalkyl, wherein each of C_1-4 alkyl and C_3-7 cycloalkyl is optionally substituted with 1-3 groups independently selected from R¹⁰; R⁵ and R⁶ at each occurrence are independently selected from -H, halo, -OR⁸, -NR⁸R⁹, C_1-4 alkyl, C_3-7 cycloalkyl, and 4-7 membered heterocyclyl, wherein each of C_1-4 alkyl, C_3-7 cycloalkyl, and 4-7 membered heterocyclyl is optionally substituted with 1-3 groups independently selected from R¹⁰; or alternatively, R⁵ and R⁶ connected to the same atom taken together form =O; or alternatively, R⁵ and R⁶ connected to the same or different atoms can form a 3-6 membered carbocyclic or heterocyclyl ring optionally substituted with 1-3 groups of R¹⁰; R⁷ is independently selected from H, C_1-8 alkyl, C_3-7 cycloalkyl, aryl, heteroaryl, halo, -CN, -OR⁸, -NR⁸R⁹, -CO₂R¹¹, and -C(O)N(R¹¹R¹²), wherein each of C_1-4 alkyl, C_3-7 cycloalkyl, aryl, and heteroaryl is optionally substituted with 1-3 groups independently selected from R¹³; or alternatively, R⁷ and R⁴ or R⁵ or R⁶ can form a 5-7 membered carbocyclic or heterocyclyl ring optionally substituted with 1-3 groups of R¹⁰; R⁸ and R⁹ are independently selected from -H, -C(O)R¹², -C(O)N(R¹¹R¹²), - C(=NR¹²)N(R¹¹R¹²), C_1-6 alkyl, C_3-7 cycloalkyl, and aryl, wherein each of C_1-6 alkyl, C_3-7 cycloalkyl, and aryl is optionally substituted with 1-3 groups independently selected from R¹⁰, except that R¹⁰ is not =O when R⁸ or R⁹ is aryl; R¹⁰ at each occurrence is independently selected from -H, -CO₂R¹¹, -C(O)N(R¹¹)₂, - CN, -OR¹¹, halo, C_1-6 alkyl, cyclopropyl, aryl, =O, -SR¹¹, and -N(R¹¹R¹²); R¹¹ at each occurrence is independently selected from -H, -CO₂R¹², -C(O)R¹², - C(O)NR¹²C(=NR¹²)N(R¹²)₂, -C(=NR¹²)N(R¹²)₂, -C(O)N(R¹²)₂, aryl, and C_1-6 alkyl, wherein each of the aryl and C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂; R¹² at each occurrence is independently selected from -H, aryl, and C_1-4 alkyl, wherein each of the aryl or C_1-4 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂; and R¹³ at each occurrence is independently selected from -H, halo, -OH, -N(R¹²)₂, - NR¹²C(=NR¹²)N(R¹²)₂, -NR¹²C(O)N(R¹²)₂, -NR¹²C(O)R¹², -NR¹²C(O)OR¹², -OC(O)N(R¹²)₂, -CO₂R¹², -COR¹², -C(O)NR¹²C(=NR¹²)N(R¹²)₂, -C(=NR¹²)N(R¹²)₂, -C(O)N(R¹²)₂, aryl, and C_1-6 alkyl, wherein each of the aryl and C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X is NR⁴, S, O, or CR⁵R⁶; Y is CR⁵R⁶ or a bond; Z is N or CR⁷; Ring A is 5-6 membered heterocyclyl, 5-6 membered carbocyclyl, or phenyl, each optionally substituted with one to three groups independently selected from R¹; W¹, W³, and W⁵ are each independently CR⁵R⁶, O, or S; and W², W⁴, and W⁶ are each independently a bond, CR⁵R⁶, O, or S, with the proviso that no two non-carbon atoms are connected directly with each other or to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; m is 0, 1, 2, or 3; n is 0, 1, or 2; i at each occurrence is independently 1 or 2; R¹ at each occurrence is independently selected from H, C_1-6alkyl, C_3-6cycloalkyl, C_1- ₆alkyl-CO-, 4-6 membered heterocyclyl, -OR⁸, -CO₂R⁸, -C(O)NR⁸R⁹, halo, -CN, -NR⁸R⁹, oxo (=O), -C_1-6alkylene-(R¹⁰)_i, -C_3-6cycloalkylene-(R¹⁰)_i, -C(O)-C_1-6alkyl-(R¹⁰)_i, and -(4-6 membered heterocyclylene)-(R¹⁰)_i; R² is -OH, -OCHF₂, -OCF₃, -CHF₂, -CF₃, -CH₂CF₃, -OMe, -F, or -H; R³ at each occurrence is independently selected from -H, C_3-6cycloalkyl, C_1-6alkyl, C_1- 6haloalkyl, -O-C_1-6haloalkyl, halo, -CN, -NR⁸R⁹, -OR⁸, -SR⁸, phenyl, and 5-6 membered heteroaryl, wherein the C_3-6cycloalkyl, C_1-6alkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted with 1-3 groups independently selected from halo and C_1-4alkyl; R⁴ at each occurrence is independently selected from -H, C_1-6 alkyl, -C(O)-C_1-6alkyl, C_3-6cycloalkyl, -C_1-6alkylene-(R¹⁰)_i, and -C_3-6cycloalkylene-(R¹⁰)_i; R⁵ and R⁶ at each occurrence are independently selected from -H, halo, -OR⁸, -NR⁸R⁹, C_1-4 alkyl, C_3-6cycloalkyl, 4-6 membered heterocyclyl, -C_1-6alkylene-(R¹⁰)_i, -C_3- ₆cycloalkylene-(R¹⁰)_i, -C(O)-C_1-6alkyl-(R¹⁰)_i, and -(4-6 membered heterocyclylene)-(R¹⁰)_i; or alternatively, R⁵ and R⁶ taken together form oxo (=O); R⁷ is selected from -H, C_1-6 alkyl, C_3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, - halo, -CN, -OR⁸, -NR⁸R⁹, -CO₂R¹¹, -C(O)N(R¹¹R¹²), -C_1-6alkylene-(R¹³)_i, and -C_3- ₆cycloalkylene-(R¹³)_i; R⁸ at each occurrence is independently selected from -H, -C(O)R¹², -C(O)N(R¹¹R¹²), C_1-6 alkyl, C_3-6 cycloalkyl, phenyl, -C_1-6alkylene-(R¹⁰)_i, -C_3-6cycloalkylene-(R¹⁰)_i and - phenylene-(R¹⁰)_i; R⁹ at each occurrence is independently selected from -H, C_1-4 alkyl, and C_3-6 cycloalkyl; R¹⁰ at each occurrence is independently selected from -H, -CN, halo, C_1-4 alkyl, cyclopropyl, phenyl, =O, -OR¹¹, -SR¹¹, -CO₂R¹¹, -C(O)N(R¹¹)₂, and -N(R¹¹R¹²); R¹¹ at each occurrence is independently selected from -H, -CO₂R¹², -C(O)R¹², - C(O)NR¹²C(=NR¹²)N(R¹²)₂, -C(=NR¹²)N(R¹²)₂, -C(O)N(R¹²)₂, phenyl, and C_1-6 alkyl, wherein each of phenyl and C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂; R¹² at each occurrence is independently selected from -H, aryl, and C_1-4 alkyl, wherein each of the aryl or C_1-4 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂; and R¹³ at each occurrence is independently selected from -H, halo, -OH, -N(R¹²)₂, - NR¹²C(=NR¹²)N(R¹²)₂, -NR¹²C(O)N(R¹²)₂, -NR¹²C(O)R¹², -NR¹²C(O)OR¹², -OC(O)N(R¹²)₂, -CO₂R¹², -C(O)R¹², -C(O)NR¹²C(=NR¹²)N(R¹²)₂, -C(=NR¹²)N(R¹²)₂, -C(O)N(R¹²)₂, aryl, and C_1-6 alkyl, wherein each of the aryl and C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, OH, and NH₂. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X is NR⁴, S, O, or CR⁵R⁶; Y is CR⁵R⁶ or a bond; Z is CR⁷; m is 0, 1, 2, or 3; n is 0, 1, or 2; A is 5-6 membered heterocyclyl; W¹ is CR⁵R⁶ or O; W² is O, S, CR⁵R⁶, or bond; W³ is CR⁵R⁶ or O; W⁴ is CR⁵R⁶ or bond; W⁵ is CR⁵R⁶, O, or S; W⁶ is CR⁵R⁶ or bond; with the proviso that no two non-carbon atoms are connected directly with each other or to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; R¹ at each occurrence is independently selected from H, C_1-6 alkyl, C_3-6cycloalkyl, C_1- ₆alkyl-CO-, 4-6 membered heterocyclyl, -OR⁸, -CO₂R⁸, -CONR⁸R⁹, halo, -CN, -NR⁸R⁹, oxo (=O), -C_1-6alkylene-CN, -C_1-6alkylene-halo, -C_1-6alkylene-cyclopropyl, -C_1-6alkylene-phenyl, -C_1-6alkylene-OR¹¹, -C_1-6alkylene-SR¹¹, -C_1-6alkylene-CO₂R¹¹, -C_1-6alkylene-C(O)N(R¹¹)₂, - C_1-6alkylene-N(R¹¹R¹²), -OC(O)R¹², -OC(O)N(R¹¹R¹²), -O-C(=NR¹²)N(R¹¹R¹²), -O-C_3- ₆cycloalkyl, -O-phenyl, -O-C_1-6alkylene-CN, -O-C_1-6alkylene-halo, -O-C_1-6alkylene- cyclopropyl, -O-C_1-6alkylene-phenyl, -O-C_1-6alkylene-OR¹¹, -O-C_1-6alkylene-SR¹¹, -O-C_1- ₆alkylene-CO₂R¹¹, -O-C_1-6alkylene-C(O)N(R¹¹)₂, -O-C_1-6alkylene-N(R¹¹R¹²), -C(O)O-C_1- ₆alkylene-CN, -C(O)O-C_1-6alkylene-halo, -C(O)O-C_1-6alkylene-cyclopropyl, -C(O)O-C_1- ₆alkylene-phenyl, -C(O)O-C_1-6alkylene-OR¹¹, -C(O)O-C_1-6alkylene-SR¹¹, -C(O)O-C_1- ₆alkylene-CO₂R¹¹, -C(O)O-C_1-6alkylene-C(O)N(R¹¹)₂, -C(O)O-C_1-6alkylene-N(R¹¹R¹²); R² is -OH, -OCHF₂, -OCF₃, -CHF₂, -CF₃, -CH₂CF₃, -OMe, -F, or -H; R³ at each occurrence is independently selected from H, C_3-6cycloalkyl, C_1-4alkyl, C_1- ₄haloalkyl, -O-C_1-4haloalkyl, CN, and halo; R⁴ at each occurrence is independently selected from H, C_1-4 alkyl, and -C(O)-C_1-4 alkyl; R⁵ at each occurrence is independently selected from H, halo, -OR⁸, -NR⁸R⁹, and C_1-4 alkyl; R⁶ at each occurrence is independently selected from H and C_1-4 alkyl; R⁷ is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, - halo, -CN, -OR⁸, -NR⁸R⁹, -CO₂R¹¹, -CON(R¹¹R¹²), -C_1-6alkylene-halo, -C_1-6alkylene-OH, - C_1-6alkylene-N(R¹²)₂, -C_1-6alkylene-NR¹²C(=NR¹²)N(R¹²)₂, -C_1-6alkylene-NR¹²C(O)N(R¹²)₂, -C_1-6alkylene-NR¹²C(O)R¹², -C_1-6alkylene-NR¹²C(O)OR¹², -C_1-6alkylene-OC(O)N(R¹²)₂, -C_1- ₆alkylene-CO₂R¹², -C_1-6alkylene-C(O)R¹², -C_1-6alkylene-C(O)N(R¹²)₂, -C_1-6alkylene-CO₂R¹², -C_1-6alkylene-C(O)R¹², -C_1-6alkylene-C(O)NR¹²C(=NR¹²)N(R¹²)₂, -C_1-6alkylene- C(=NR¹²)N(R¹²)₂, -C_1-6alkylene-C(O)N(R¹²)₂, -C_1-6alkylene-phenyl, -OC(O)R¹², - OC(O)N(R¹¹R¹²), -O-C(=NR¹²)N(R¹¹R¹²), -O-C_3-6cycloalkyl, -O-phenyl, -O-C_1-6alkylene- OH, -O-C_1-6alkylene-CO₂R¹¹, -O-C_1-6alkylene-C(O)N(R¹¹)₂, -O-C_1-6alkylene-CN, -O-C_1- ₆alkylene-SR¹¹, -O-C_1-6alkylene-C(O)N(R¹¹R¹²), and -O-C_1-6alkylene-C(O)N(R¹¹)₂; R⁸ at each occurrence is independently H or C_1-4 alkyl; R⁹ at each occurrence is independently H or C_1-4 alkyl; R¹⁰ at each occurrence is independently selected from H, -CN, halo, C_1-4 alkyl, cyclopropyl, phenyl, =O, -OR¹¹, -SR¹¹, -CO₂R¹¹, -CON(R¹¹)₂, and -N(R¹¹R¹²); R¹¹ at each occurrence is independently selected from -H, -CO₂R¹², -COR¹², - C(O)N(R¹²)₂, and C_1-6 alkyl, wherein C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, OH, and NH₂; and R¹² at each occurrence is independently selected from H, aryl, and C_1-4 alkyl, wherein each of the aryl or C_1-4 alkyl is optionally substituted with 1-3 groups independently selected from halo, OH, and NH₂. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X is NR⁴, S, or O; Y is CR⁵R⁶ or a bond; Z is CR⁷; m is 0, 1, or 2; n is 0 or 1; A is 6 membered heterocyclyl; W¹ is CR⁵R⁶ or O; W² is O, S, or CR⁵R⁶; W³ is CR⁵R⁶ or O; W⁴ is CR⁵R⁶ or bond; W⁵ is CR⁵R⁶, O, or S; W⁶ is CR⁵R⁶ or bond; with the proviso that no two non-carbon atoms are connected directly with each other or to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; R¹ at each occurrence is independently selected from -H, C_1-6 alkyl, C_3-6cycloalkyl, C_1-6alkyl-CO-, 4-6 membered heterocyclyl, -OR⁸, -CO₂R⁸, -CONR⁸R⁹, halo, -CN, -NR⁸R⁹, oxo (=O), -C_1-6alkylene-OR¹⁰, -C_1-6alkylene-OC(O)NH₂, -C_1-6alkylene-C(O)OR¹¹, - C(O)OR¹¹, and -C(O)O-C_1-6alkylene-OR¹⁰; R² is -OH, -OCHF₂, -OCF₃, -OMe, -F, or -H; R³ at each occurrence is independently selected from H, C_3-6cycloalkyl, C_1-4alkyl, C_1- ₄haloalkyl, -O-C_1-4haloalkyl, -CN, and halo; R⁴ at each occurrence is independently selected from H, C_1-4 alkyl, and -C(O)-C_1-4 alkyl; R⁵ at each occurrence is independently H or C_1-4 alkyl; R⁶ at each occurrence is independently H or C_1-4 alkyl; R⁷ is selected from -H, -CN, C_1-6 alkyl, -OR⁸, -NR⁸R⁹, -O-CO₂R¹¹, -CON(R¹¹R¹²), - C_1-6alkylene-OH, -C_1-6alkylene-N(R¹²)₂, -C_1-6alkylene-NR¹²C(=NR¹²)N(R¹²)₂, -C_1-6alkylene- NR¹²C(O)N(R¹²)₂, -C_1-6alkylene-NR¹²C(O)R¹², -C_1-6alkylene-NR¹²C(O)OR¹², -C_1-6alkylene- OC(O)N(R¹²)₂, -C_1-6alkylene-CO₂R¹², -C_1-6alkylene-C(O)R¹², -C_1-6alkylene-C(O)N(R¹²)₂, - OC(O)R¹², -OC(O)N(R¹¹R¹²), -O-C_1-6alkylene-OH, -O-C_1-6alkylene-CO₂R¹¹, -O-C_1- ₆alkylene-C(O)N(R¹¹)₂, -O-C_1-6alkylene-CN, -O-C_1-6alkylene-SR¹¹, -O-C_1-6alkylene- C(O)N(R¹¹R¹²), and -O-C_1-6alkylene-C(O)N(R¹¹)₂; R⁸ at each occurrence is independently H or C_1-4 alkyl; R⁹ at each occurrence is independently H or C_1-4 alkyl; R¹⁰ at each occurrence is independently selected from H, -CN, halo, C_1-4 alkyl, cyclopropyl, phenyl, =O, -OR¹¹, -SR¹¹, -CO₂R¹¹, -CON(R¹¹)₂, and -N(R¹¹R¹²); R¹¹ at each occurrence is independently selected from -H, -CO₂R¹², -C(O)R¹², - C(O)N(R¹²)₂, and C_1-6 alkyl, wherein C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂; and R¹² at each occurrence is independently selected from -H, aryl, and C_1-4 alkyl, wherein each of the aryl or C_1-4 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X is NR⁴; Y is CR⁵R⁶ or a bond; Z is CR⁷; m is 0, 1, or 2; n is 0 or 1; A is piperidinyl; W¹ is CR⁵R⁶ or O; W² is O, CR⁵R⁶, or bond; W³ is CR⁵R⁶ or O; W⁴ is CR⁵R⁶ or bond; W⁵ is CR⁵R⁶ or O; W⁶ is CR⁵R⁶ or bond; with the proviso that no two non-carbon atoms are connected directly with each other or to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; R¹ at each occurrence is independently selected from H, C_1-4 alkyl, -OR⁸, -CO₂R⁸, - CONR⁸R⁹, halo, -CN, -NR⁸R⁹, -C_1-4alkylene-OH, -C_1-4alkylene-O-C_1-4alkyl, -C_1-4alkylene- OC(O)NH₂, -C_1-6alkylene-C(O)OH, -C_1-6alkylene-C(O)O-C_1-6alkyl, -C(O)OH, -C(O)O-C_1- ₆alkyl, and -C(O)O-C_1-6alkylene-OH; R² is -OH, -OCHF₂, -OCF₃, -OMe, or -F; R³ at each occurrence is independently selected from H, C_3-6cycloalkyl, C_1-2alkyl, C_1- ₂haloalkyl, and -O-C_1-2haloalkyl; R⁴ at each occurrence is independently selected from H and -C(O)-C_1-2 alkyl; R⁵ at each occurrence is independently H or C_1-2 alkyl; R⁶ at each occurrence is independently H or C_1-2 alkyl; R⁷ is selected from -H, -CN, C_1-6 alkyl, -CON(R¹¹R¹²), -C_1-4alkylene-OH, -C_1- ₄alkylene-N(R¹²)₂, -C_1-4alkylene-NR¹²C(O)N(R¹²)₂, -C_1-4alkylene-NR¹²C(O)R¹², -C_1- ₄alkylene-NR¹²C(O)OR¹², -C_1-4alkylene-OC(O)N(R¹²)₂, -C_1-6alkylene-CO₂R¹², -C_1-6alkylene- C(O)R¹², and -C_1-4alkylene-C(O)N(R¹²)₂; R⁸ at each occurrence is independently H or C_1-4 alkyl; R⁹ at each occurrence is independently H or C_1-4 alkyl; R¹¹ at each occurrence is independently H or C_1-4 alkyl; and R¹² at each occurrence is independently H or C_1-4 alkyl. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X = NH; Y = a bond; Z = CR⁷;

W¹ = CH₂ or O; W² = O, CH₂, or bond; W³ = CH₂ or O; W⁴ = CH₂ or bond; W⁵ = CH₂ or O; W⁶ = CH₂ or bond; with the proviso that no two non-carbon atoms are connected directly with each other or to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; m = 0, 1, or 2; n = 0 or 1; R¹ = H, CH₃, -CH₂OH, -CH₂CH₂OH, -CH₂OC(O)NH₂, -CH₂CH₂C(O)OH, - CH₂CH₂C(O)OCH₃, -CH₂CH₂C(O)OCH₂CH₃, -CH₂CH₂C(O)O-iPr, -CH₂CH₂C(O)OBu^t, - CH₂CH₂CH₂C(O)OH, -CH₂CH₂CH₂C(O)OCH₃, -C(O)OH, -C(O)OCH₃, -C(O)OCH₂CH₃, - C(O)O-iPr, -C(O)OCH₂CH₂OH, or -C(O)OCH₂CH₂CH₂OH; R² = OH or F; R³ = -CF₃, -OCH₃, -OCHF₂, -OCF₃, or cyclopropyl; and R⁷ = H, -CN, -CH₂OH, -CH₂NH₂, -CH₂OC(O)NH₂, -CH₂NHC(O)NH₂, - CH₂NHC(O)CH₃, -CH₂NHC(O)OCH₃, -CH₂CH₂C(O)OH, -CH₂CH₂C(O)OCH₃, - CH₂CH₂C(O)NH₂, or -C(O)NH₂. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, having a structure selected from formula (Ia):

, wherein A, X, Z, m, n, R¹, R², R³, R⁵, R⁶, and W¹ to W⁶ are as defined in any foregoing embodiments of formula I. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, having a structure selected from formula (Ib):

, wherein A, X, m, n, R¹, R², R³, R⁵, R⁶, R⁷, and W¹ to W⁶ are as defined in any foregoing embodiments of formula I. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, having a structure selected from formula (Ic):

, wherein X, m, n, R¹, R², R³, R⁵, R⁶, R⁷, and W¹ to W⁶ are as defined in any foregoing embodiments of formula I. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, having a structure selected from formula (Id):

. wherein X, m, n, R¹, R², R³, R⁵, R⁶, R⁷, and W¹ to W⁶ are as defined in any foregoing embodiments of formula I. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, having a formula (Ie):

, wherein A, X, Z, m, n, R¹, R², R³, and W¹ to W⁶ are as defined in any foregoing embodiments of formula I. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, having a structure selected from formula (If):

, wherein A, X, m, n, R¹, R², R³, R⁷, and W¹ to W⁶ are as defined in any foregoing embodiments of formula I. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, having a structure selected from formula (Ig):

, wherein A, X, m, n, R¹, R³, R⁷, and W¹ to W⁶ are as defined in any foregoing embodiments of formula I. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, having a structure selected from formula (Ih):

. wherein X, m, n, R¹, R³, R⁷, and W¹ to W⁶ are as defined in any foregoing embodiments of formula I. In some embodiments, the present disclosure provides a compound of formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any foregoing embodiment disclosed, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹, W³, and W⁵ are each CH₂; and W², W⁴, and W⁶ are each independently CH₂ or a bond. In some embodiments, the present disclosure provides a compound of formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any foregoing embodiment disclosed, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹, W², W³, and W⁵ are each CH₂; and W⁴ and W⁶ are each a bond. In some embodiments, the present disclosure provides a compound of formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any foregoing embodiment disclosed, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹, W², W³, W⁴, and W⁵ are each CH₂; and W⁶ is a bond. In some embodiments, the present disclosure provides a compound of formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any foregoing embodiment disclosed, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹, W², W³, W⁴, W⁵, and W⁶ are each CH₂. In some embodiments, the present disclosure provides a compound of formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any foregoing embodiment disclosed, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹, W³, W⁵, and W⁶ are each CH_2; W² is O; and W⁴ is CH₂ or a bond. In some embodiments, the present disclosure provides a compound of formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any foregoing embodiment disclosed, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹, W², W⁵, and W⁶ are each CH_2; W³ is O; and W⁴ is CH₂ or a bond. In some embodiments, the present disclosure provides a compound of formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any foregoing embodiment disclosed, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹ is O; W², W³, and W⁵ are each CH₂; W⁴ is O; and W⁶ is CH₂ or a bond. In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds of List 1. List 1

,

O O

O O O

_HO N N _{HN HO} HN CF₃ N N HN OCF₃ HN O HO O O O 124, 125, H_O O _{N HO}

N N N N HN OCF₃ ^O HN _OMe O NC O O O 126, 127, O O O O N_{HO N HO} N N N N HN OMe HN OCF₃ O 128, ^OH O , O O HO HO N_{HO N HO} N N N N HN OCF₃ HN OCF₃ OH O , ^OH O , O HO N_HO O _{N HO} N N N N HN OCF₃ O HN OCF₃ O^H O , ^OH O , N_HO O _{N HO} N N N N HN _OCHF2 ^O HN _OMe _OH O _{, OH} O _,

In some embodiments, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds listed in Table 5 having an IC₅₀ value smaller than 1000 nM in inhibition of IL-1β formation in THP-1 cells (List 2). In some embodiments, sometimes preferably, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds listed in Table 5 having an IC₅₀ value smaller than 300 nM in inhibition of IL-1β formation in THP-1 cells (List 3). In some embodiments, sometimes more preferably, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds listed in Table 5 having an IC₅₀ value smaller than 50 nM in inhibition of IL-1β formation in THP-1 cells (List 4). In some embodiments, sometimes even more preferably, the present disclosure provides a compound of formula I, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds listed in Table 5 having an IC₅₀ value smaller than 15 nM in inhibition of IL-1β formation in THP-1 cells (List 5). In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any embodiment disclosed herein, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt 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 of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any embodiment disclosed herein, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt 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 of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any embodiment disclosed herein, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt 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 to the subject an effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any embodiment disclosed herein, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, 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 present disclosure provides a method for treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any embodiment disclosed herein, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, 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, in the present disclosure, 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, osteoarthritis, ulcerative colitis, or Crohn’s disease; the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis; the cancer is lung cancer, breast cancer, prostate cancer, skin cancer, colorectal cancer, and pancreatic cancer; and the hereditary disease is cryopyrin-associated periodic syndrome. In another aspect, the present disclosure provides use of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any embodiment disclosed herein, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a disease or condition selected from neurodegenerative disorders, metabolic ailments, inflammatory syndromes, autoinflammatory diseases, cancers, and hereditary diseases. In some embodiments, in the present disclosure, the neurodegenerative disorder is Parkinson’s disease or Alzheimer’s disease. In some embodiments, in the present disclosure, the metabolic ailment is type 2 diabetes or atherosclerosis. In some embodiments, in the present disclosure, the inflammatory disease is gout flares, osteoarthritis, ulcerative colitis, or Crohn’s disease. In some embodiments, in the present disclosure, the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis. In some embodiments, in the present disclosure, the cancer is lung cancer, breast cancer, prostate cancer, skin cancer, colorectal cancer, and pancreatic cancer. In some embodiments, in the present disclosure, the hereditary disease is cryopyrin- associated periodic syndrome. In one aspect, the present disclosure provides compounds having the structure of Formula (I):

or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: X is NR⁴, S, O, or CR⁵R⁶; Y is CR⁵R⁶ or a bond; Z is N or CR⁷; Ring A is 4-7 membered heterocyclyl, C_6-10 aryl, 5-6 membered heteroaryl, or 4-7 membered carbocyclyl, each optionally substituted with one to three groups independently selected from R¹, except that R¹ is not oxo (=O) when A is C_6-10 aryl or 5-6 membered heteroaryl; W¹, W³, and W⁵ are each independently selected from CR⁵R⁶, O, S, and NR⁴; and W², W⁴, and W⁶ are each independently selected from a bond, CR⁵R⁶, O, S, and NR⁴, with the proviso that no two non-carbon atoms are connected directly nor to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶ with the exception that S-S bond is allowed; alternatively, wherein R⁵ and R⁶, R⁴ and R⁵, or R⁴ and R⁶ can form additional 3-4 membered spiro or 5-7 membered bridged rings; R¹ at each occurrence is independently selected from H, C_1-5alkyl, C_3-7 cycloalkyl, C_1- ₄alkyl-CO, 4-7 membered heterocyclyl, OR⁸, CO₂R⁸, CONR⁸R⁹, halo, CN, NR⁸R⁹, and oxo (=O), wherein each of C_1-5alkyl, C_3-7cycloalkyl, C_1-4alkyl-CO, and 4-7 membered heterocyclyl is optionally substituted with 1-3 groups independently selected from R¹⁰; R² is OH, OCHF₂, OCF₃, CHF₂, CF₃, CF₃CH₂, OMe, F, or H; R³ at each occurrence is independently selected from H, C_3-6cycloalkyl, C_1-4alkyl, haloC_1-4alkyl, O-haloC_1-4alkyl, halo, CN, SF₅, NR⁸R⁹, OR⁸, SR⁸, aryl, and heteroaryl, wherein C_3-6cycloalkyl and C_1-4alkyl are each optionally substituted with 1-3 groups independently selected from halo, oxo, and C_1-3alkyl; and wherein aryl and heteroaryl are each optionally substituted with 1-3 groups independently selected from halo and C_1-3alkyl; R⁴ at each occurrence is independently selected from H, C_1-4 alkyl, and C_3-7 cycloalkyl, wherein each of C_1-4 alkyl and C_3-7 cycloalkyl is optionally substituted with 1-3 groups independently selected from R¹⁰; R⁵ and R⁶ are independently selected from H, halo, OR⁸, NR⁸R⁹, C_1-4 alkyl, C_3-7 cycloalkyl, and 4-7 membered heterocyclyl, wherein each of C_1-4 alkyl, C_3-7 cycloalkyl, and 4-7 membered heterocyclyl is optionally substituted with 1-3 groups independently selected from R¹⁰; or alternatively, R⁵ and R⁶ connected to the same atom taken together form =O; or alternatively, R⁵ and R⁶ connected to the same or different atoms can form a 3-6 membered carbocyclic or heterocyclyl ring optionally substituted with 1-3 groups of R¹⁰; R⁷ is independently selected from H, C_1-4 alkyl, C_3-7 cycloalkyl, aryl, heteroaryl, halo, CN, OR⁸, NR⁸R⁹, CO₂R¹¹, and CON(R¹¹R¹²), wherein each of C_1-4 alkyl, C_3-7 cycloalkyl, aryl, and heteroaryl is optionally substituted with 1-3 groups independently selected from R¹¹; or alternatively, R⁷ and R⁴ or R⁵ or R⁶ can form a 5-7 membered carbocyclic or heterocyclyl ring optionally substituted with 1-3 groups of R¹⁰; R⁸ and R⁹ are independently selected from H, COR¹², C(O)N(R¹¹R¹²), C(=NR¹²)N(R¹¹R¹²), C_1-4 alkyl, C_3-7 cycloalkyl, and aryl, wherein each of C_1-4 alkyl, C_3-7 cycloalkyl, and aryl is optionally substituted with 1-3 groups independently selected from R¹⁰, except that R¹⁰ is not =O when R⁸ or R⁹ is aryl; R¹⁰ at each occurrence is independently selected from H, CO₂R¹¹, CON(R¹¹)₂, CN, OR¹¹, halo, C_1-4 alkyl, cyclopropyl, aryl, =O, SR¹¹, and N(R¹¹R¹²); R¹¹ at each occurrence is independently selected from H, halo, OH, N(R¹²)₂, NR¹²C(=NR¹²)N(R¹²)₂, NR¹²C(=O)N(R¹²)₂, NR¹²C(=O)R¹², NR¹²C(=O)OR¹², OC(=O)N(R¹²)₂, CO₂R¹², COR¹², C(O)NR¹²C(=NR¹²)N(R¹²)₂, C(=NR¹²)N(R¹²)₂, C(=O)N(R¹²)₂, aryl, and C_1-6 alkyl, wherein each of the aryl and C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, OH, and NH₂; R¹² at each occurrence is independently selected from H, aryl, and C_1-4 alkyl, wherein each of the aryl or C_1-4 alkyl is optionally substituted with 1-3 groups independently selected from halo, OH, and NH₂; m is 0, 1, 2, 3; and n is 0, 1, 2. In some embodiments, the compound of formula (I), or a stereoisomer, or a pharmaceutically acceptable salt thereof, has a formula (Ia):

, wherein all the m, n, A, X, Z, R¹, R², R³, R⁵, R⁶, and W¹ through W⁶ groups are as defined in formula (I). In some embodiments, the compound of formula (I), or a stereoisomer, or a pharmaceutically acceptable salt thereof, has a formula (Ib):

, wherein all the m, n, A, X, R¹, R², R³, R⁵, R⁶, R⁷, and W¹ through W⁶ groups are as defined in formula (I). In some embodiments, the compound of formula (I), or a stereoisomer, or a pharmaceutically acceptable salt thereof, has a formula (Ic):

, wherein all the m, n, X, R¹, R², R³, R⁵, R⁶, R⁷, and W¹ through W⁶ groups are as defined in formula (I). In some embodiments, the compound of formula (I), or a stereoisomer, or a pharmaceutically acceptable salt thereof, has a formula (Id):

, wherein all the m, n, X, R¹, R³, R⁵, R⁶, R⁷, and W¹ through W⁶ groups are as defined in formula (I). In some embodiments, the compound of formula (I), or a stereoisomer, or a pharmaceutically acceptable salt thereof, has a formula (Ie):

, wherein all the m, n, A, X, Z, R¹, R², R³, and W¹ through W⁶ groups are as defined in formula (I). In some embodiments, the compound of formula (I), or a stereoisomer, or a pharmaceutically acceptable salt thereof, has a formula (If):

, wherein all the m, n, A, X, R¹, R², R³, R⁷, and W¹ through W⁶ groups are as defined in formula (I). In some embodiments, the compound of formula (I), or a stereoisomer, or a pharmaceutically acceptable salt thereof, has a formula (Ig):

, wherein all the m, n, A, X, R¹, R³, R⁷, and W¹ through W⁶ groups are as defined in formula (I). In some embodiments, the compound of formula (I), or a stereoisomer, or a pharmaceutically acceptable salt thereof, has a formula (Ih):

, wherein all the m, n, X, R¹, R³, R⁷, and W¹ through W⁶ groups are as defined in formula (I). In some embodiments, in the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (Ih), or a stereoisomer, or a pharmaceutically acceptable salt thereof, W¹, W³, and W⁵ are each CH₂; and W², W⁴, and W⁶ are each independently CH₂ or a bond. In some embodiments, in the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (Ih), or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein W¹, W², W³, and W⁵ are each CH₂; and W⁴ and W⁶ are each a bond. In some embodiments, in the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (Ih), or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein W¹, W², W³, W⁴, and W⁵ are each CH₂; and W⁶ is a bond. In some embodiments, in the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (Ih), or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein W¹, W², W³, W⁴, W⁵, and W⁶ are each CH₂. In some embodiments, in the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (Ih), or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein W¹, W³, W⁵, and W⁶ are each CH₂; W² is O; and W⁴ is a bond. In some embodiments, in the compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (Ih), or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein W¹, W², W⁵, and W⁶ are each CH_2; W³ is O; and W⁴ is a bond. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih) according to any embodiments disclosed, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In some embodiments, 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 of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih), or a stereoisomer, or a pharmaceutically acceptable salt thereof, according to any embodiments disclosed. In some embodiments, 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 a pharmaceutical composition comprising an effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih), or a stereoisomer, a pharmaceutically acceptable salt thereof, according to any embodiments disclosed. In some embodiments, the present disclosure provides use of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih) according to any one of the embodiments disclosed herein, or a stereoisomer, or a pharmaceutically acceptable salt or thereof, for treatment of a disease or disorder associated with NLRP3 activities in a subject in need of treatment. In some embodiments, the present disclosure provides use of a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih) according to any one of the embodiments disclosed herein, or a stereoisomer, or a pharmaceutically acceptable salt thereof, for treatment of a disease or disorder associated with NLRP3 activities in a subject in need of treatment. In some embodiments, the present disclosure provides use of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih) according to any one of the embodiments disclosed herein, or a stereoisomer, or a pharmaceutically acceptable salt 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 associated with NLRP3 activities is a neurodegenerative disorder, a metabolic ailment, an inflammatory syndrome, an autoinflammatory disease, cancer, or a hereditary disease. In some embodiments, the disease or condition is a neurodegenerative disorder selected from Parkinson’s disease or Alzheimer’s disease. In some embodiments, the disease or condition is a metabolic ailment selected from type 2 diabetes or atherosclerosis. In some embodiments, the disease or condition is an inflammatory disease selected from gout flares, osteoarthritis, ulcerative colitis, and Crohn’s disease. In some embodiments, the disease or condition is an autoinflammatory disease selected from multiple sclerosis or rheumatoid arthritis. In some embodiments, the disease or condition is a cancer, which is lung cancer. In some embodiments, the disease or condition is a hereditary disease, which is Cryopyrin- associated periodic syndrome. 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 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 an 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 C_2-10 alkenylene, more preferably C_2-8 alkenylene, sometimes more preferably C_2-6 alkenylene, and sometimes even more prefereably C_2-4 alkenylene. 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 -NH₂ group. The term "alkylthio" refers to alkyl-S-. The term “alkylamino” refers to “alkyl-NH-”, or sometimes dialkyl amino (-NR^aR^b), where the two alkyl groups (R^a and R^b) can be the same or different. Sometimes preferably, the alkyl group is a C₁-C₆ alkyl, and sometimes more preferably, the alkyl is a C₁-C₄ alkyl. Examples of alkylamino include, but are not limited to, CH₃-NH-, -N(CH₃)₂, -N(CH₂CH₃)₂, - NHCH₂CH₃, -N(CH₃)(CH₂CH₃), -NH-Bu^t, -N(CH₃)(Bu^t), 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 -NO₂ group. 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). 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-C₆ alkyl, halogen, C₁-C₆ alkoxy, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ alkylthio, C₁-C₆ alkylamino, di-(C₁-C₆ alkyl)amino, thiol, hydroxyl, nitro, cyano, amino, C₃- C₆ cycloalkyl, 5- to 10-membered heterocyclyl, C₆-C₁₀ aryl, 5- to 10-membered heteroaryl, C₃- C6 cycloalkoxy, C₁-C₆ cycloalkylthio, 5- to 10-membered heterocyclylthio and oxo group. In some embodiments, sometimes preferably, the substituents are independently selected from C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylamino, di-(C₁-C₆ alkyl)amino, thiol, hydroxyl, nitro, cyano, amino, and oxo group. In some embodiments, sometimes more preferably, the substituents are independently selected from C₁-C₄ alkyl, halogen, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)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-C₆ alkyl,” “C_1-6 alkyl,” “C_1-6alkyl,” 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 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 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 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, 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. 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., with ³H and ¹⁴C) 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 invention is meant to encompass all suitable isotopic variations of the compounds disclosed. 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. 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, bentonite, 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 alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia 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 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, pigs, horses, sheep, goats, monkeys, chimpanzees, and so on, preferably humans. The term “disease,” “disorder,” and “condition,” or the like, as used herein, are often used interchangeably. 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. 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 P. G. M. 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 AgOTf = silver trifluoromethanesulfonate AIBN = azodiisobutyronitrile Boc = t-butyloxy carbonyl BPO = benzoyl peroxide CyJohn Phos = (2-biphenyl)dicyclohexylphosphine 4CzPN-Bu = 3,4,5,6-tetrakis(3,6-di-t-Butylcarbazol-9-yl)-1,2-dicyanobenzene DCM = dichloromethane DIEA or DIPEA = diisopropylethylamine DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide dppfO2 = 1,1'-bis(diphenylphosphino)ferrocene dioxide DTBMP = 2,6-di-tert-butyl-4-methylpyridine EtOH = ethanol EtOAc = ethyl acetate FA = formic acid HBpin = pinacolborane HCHO = formaldehyde HPLC = high performance liquid chromatography hr or h= hour K₂S₂O₈ = potassium persulfate LC-MS = liquid chromatography – mass spectrometry M= mol/L. m-CPBA = m-chloroperoxybenzoic acid Me = methyl MeCN = acetonitrile MeOH = methanol MOMCl = chloromethyl methyl ether MsCl = methane sulfonyl chloride NaBH₃CN = sodium cyanoborohydride NaH = sodium hydride NMR = nuclear magnetic resonance NIS = N-iodosuccinimide NOE = nuclear Overhauser effect NBS = N-bromosuccinimide 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 Ruphos = 2-dicyclohexylphosphino-2,6'-diisopropoxy-1,1'-biphenyl Ruphos Pd G3 = methanesulfonato(2-dicyclohexylphosphino-2,6'-di-i-propoxy-1,1'- biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) Sat. = saturated SFC = supercritical fluid chromatography SPhos = 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl SPhos Pd G2 = chloro(2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl)[2-(2- amino-1,1-biphenyl)]palladium(II) TBAF = tetrabutylammonium fluoride TBSCl = tert-butyldimethylsilyl chloride TEA = triethylamine Tert-butyl XPhos = 2-di-t-butylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl TFA = trifluoracetic acid THF = tetrahydrofuran TLC = thin layer chromatography TMAD = N,N,N,N'-tetramethylazodicarboxamide TMSCl = chlorotrimethylsilane 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 CaH₂ under 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; dt, doublet of triplets; bs, broad signal. Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were run with electrospray ionization (ESI) on a 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, 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 one of the following solvent systems: H₂O, MeCN, and 0.1% FA in H₂O or H₂O, MeOH, and 0.1% FA in H₂O or H₂O, MeCN, and 0.1% NH₄OH/NH₄HCO₃ in H₂O or H₂O, MeCN, and 0.1% NH₄OH/NH₄HCO₃ in H₂O. Specific elution gradients were based on the retention times obtained from an analytical LC-MS, however, in general all elution gradients of H₂O and MeCN or MeOH were run over a 20-minute 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 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 C₁₈ Column (3.0 x 33 mm, 3 μm) at 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: stereoisomeric 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 / CO₂ or 0.05% diethylamine in isopropanol / CO₂ with 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/CO₂ or 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:

In general scheme 1, formulae II were prepared by deprotonation of formulae I with appropriate base and solvent (e.g., LiHMDS, THF) and subsequent substitution with bromoacetate. Treatment of formulae II with hydrazine hydrate and then with appropriate oxidant (e.g., CuX2) gave formulae IV. Chlorination of formulae IV with POCl₃ and substitution with appropriate substituted piperidine nucleophile reagent (such as amine, thioalcohol, alcohol, etc..) gave formulae VI. Deprotection of formulae VI and functionalization with appropriate conditions (such as: alkylation, reductive amination, acylation, etc..) afforded macrocycle I.

In general scheme 2, formulae VIII were prepared under Suzuki coupling conditions (such as, Ruphos Pd G3, base and solvent) at appropriate temperature. Ring-closing metathesis of formulae VIII with appropriate catalyst (e.g., Grubbs catalyst I, II, III, Hoveyda Grubbs catalyst I) gave formulae IX. Hydrogenation of formulae IX with appropriate catalyst (e.g., Pd/C, Pd(OH)₂, etc.) under H₂ atmosphere produced formulae X. Deprotection of formulae X and functionalization with appropriate conditions (such as: alkylation, reductive amination, acylation, etc.) afforded macrocycle II. General Scheme 3

In general scheme 3, formulae XIII were prepared from formulae XI under Miyaura Borylation conditions (e.g., Bis(pinacolato)diboron, Pd(dppf)Cl₂, KOAc in 1,4-dioxane) and subsequent Suzuki coupling (e.g., Ruphos Pd G3, Na₂CO₃, 1,4-dioxane/H₂O). Deprotection of formulae XIII and functionalization under appropriate conditions (such as: alkylation, reductive amination, acylation, etc.) afforded macrocycle III. General Scheme 4

In general scheme 4, formulae XV were prepared under Suzuki coupling conditions (such as, Ruphos Pd G3, base and solvent) at appropriate temperature. Deprotection of formulae XV with appropriate reagent (such as TBAF to remove TBS group) gave the diol formulae XVI. One alcohol from the diol formulae XVI were converted to the corresponding halogen or OMs/OTos and treatment of the intermediate with appropriate base (such as, NaH, AgOTf/lutidine) in appropriate solvent gave the formulae XVII. Deprotection of formulae XVII and functionalization with appropriate conditions (such as: alkylation, reductive amination, acylation, etc.) afforded macrocycle IV. General Scheme 5

In general scheme 5, formulae XIX were prepared using Minisci reaction (oxidant induced or photoinduced, such as K₂S₂O₈, AgNO₃) from formulae XVIII. Deprotection of formulae XIX and functionalization with appropriate conditions (such as alkylation, acylation or substitution with other electrophiles, etc.) gave formulae XXI. Deprotection of formulae XXI and functionalization with appropriate conditions (alkylation, reductive amination, acylation, etc.) afforded Macrocycle V. General Scheme 6

formulae XXII formulae XXIII formulae XXIV

In general Scheme 6, deprotection of formulae XXIII (prepared according to the above general scheme) gives formulae XVIII. Treatment of formulae XVIII with chlorination reagent (such as POCl₃, SOCl₂, etc.) or Tf₂O give formulae XXIV. Formulae XXV are prepared from transition-metal catalyzed cross-coupling reaction (Suzuki reaction, Stille reaction, etc.) or SnAr reaction (with nucleophile) from appropriate reagents. Deprotection of formulae XXV and functionalization with appropriate conditions (if needed, such as alkylation, reductive amination, acylation, etc.) afford Macrocycle VI. Examples of Preparative Intermediates Intermediate 1 Tert-butyl (R)-3-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloropyridazin-3- yl)amino)piperidine-1-carboxylate

Step 1: Tert-butyldimethyl(pent-4-yn-1-yloxy)silane To a solution of pent-4-yn-1-ol (10 g, 118 mmol) in DCM (100 mL) was added imidazole (12.1 g, 178 mmol) followed by portion-wise addition of TBSCl (21.5 g, 142.6 mmol) at 0 °C and the mixture was stirred under N₂ atmosphere at RT for 16 hrs. The mixture was diluted with DCM, 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, 0–3 % EtOAc in PE) to give the title compound (18 g) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 3.70 (t, J = 6.0 Hz, 2H), 2.29 – 2.25 (m, 2H), 1.93 (t, J = 2.6 Hz, 1H), 1.76 – 1.69 (m, 2H), 0.89 (s, 9H), 0.06 (s, 6H). Step 2: 4-(3-((Tert-butyldimethylsilyl)oxy)propyl)-3,6-dichloropyridazine To a solution of 3,6-dichloro-1,2,4,5-tetrazine (6 g, 39.7 mmol) in toluene (50 mL) was added tert-butyldimethyl(pent-4-yn-1-yloxy)silane (11.8 g, 59.6 mmol) at RT and the mixture was stirred under N₂ atmosphere at 100 °C for 16 hrs. The mixture was 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 (11 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 7.40 (s, 1H), 3.69 – 3.66 (m, 2H), 2.85 – 2.81 (m, 2H), 1.91 – 1.84 (m, 2H), 0.84 (s, 9H), 0.05 (s, 6H). Step 3: Tert-butyl (R)-3-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloropyridazin-3- yl)amino)piperidine-1-carboxylate To a solution of 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-3,6-dichloropyridazine (11 g, 34.2 mmol) in DMSO (100 mL) was added tert-butyl (R)-3-aminopiperidine-1-carboxylate (20.6 g, 102.7 mmol) and DIEA (13.2 g, 102.7 mmol) at RT and the mixture was stirred under N₂ atmosphere at 150 °C for 8 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 (6 g) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 6.52 (s, 1H), 4.78 (s, 1H), 3.92 – 3.91 (m, 1H), 3.69 – 3.66 (m, 3H), 3.45 – 3.36 (m, 3H), 2.69 – 2.66 (m, 2H), 1.96 – 1.92 (m, 1H), 1.85 – 1.79 (m, 2H), 1.74 – 1.68 (m, 3H), 1.42 (s, 9H), 0.90 (s, 9H), 0.06 (s, 6H). LC-MS (ESI) m/z: 485.4 (M+H)⁺. Intermediate 2 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6- chloropyridazin-3-yl)amino)piperidine-1,2-dicarboxylate

Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6- chloropyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a solution of 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-3,6-dichloropyridazine (10 g, 31.1 mmol) in DMSO (100 mL) were added 1-(tert-butyl) 2-ethyl (2S,5R)-5- aminopiperidine-1,2-dicarboxylate (prepared following the procedure in WO2020216766, Intermediate 3) (11.1 g, 40.4 mmol) and NaF (2.6 g, 62.2 mmol) at RT. The mixture was stirred under N₂ atmosphere at 130 °C for 48 hrs. 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 dryness. The residue was purified by flash chromatography (silica gel, 0–35% EtOAc in PE) to give the title compound (3.5 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 6.50 (s, 1H), 4.91 – 4.71 (m, 2H), 4.23 – 4.10 (m, 4H), 3.67 (t, J = 6.0 Hz, 2H), 3.31 – 3.22 (m, 1H), 2.67 (t, J = 7.5 Hz, 2H), 2.14 – 1.92 (m, 3H), 1.85 – 1.78 (m, 2H), 1.65 – 1.55 (m, 1H), 1.45 – 1.42 (m, 9H), 1.29 (t, J = 7.1 Hz, 3H), 0.90 (s, 9H), 0.06 (s, 6H). LC-MS (ESI) m/z: 557.4 (M+H)⁺. Intermediate 3 5-Methoxy-7-(methoxymethoxy)benzo[c][1,2]oxaborol-1(3H)-ol

1_{2 3} Intermediate 3 Step 1: Methyl 2-bromo-5-methoxy-3-(methoxymethoxy)benzoate To a solution of methyl 2-bromo-3-hydroxy-5-methoxybenzoate (prepared following the procedure from Synlett (2022), 33(11), 1087-1091) (5.5 g, 21 mmol) in DCM (60 mL) was added DIPEA (8.2 g, 63.6 mmol) followed by drop-wise addition of MOMCl (3.4 g, 42 mmol) at 0 °C. The mixture was stirred at RT for 3 hrs and was then 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, 0–30%, EtOAc in PE) to give the title compound (5 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 6.88 (d, J = 2.8 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 5.24 (s, 2H), 3.93 (s, 3H), 3.80 (s, 3H), 3.51 (s, 3H). LC-MS (ESI) (m/z): 305 (M+H)⁺. Step 2: Methyl 5-methoxy-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate To a solution of methyl 2-bromo-5-methoxy-3-(methoxymethoxy)benzoate (1.8 g, 5.92 mmol) in 1,4-dioxane (20 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g, 8.59 mmol), TEA (1.8 g, 17.8 mmol), SPhos (487 mg, 1.18 mmol) and Pd(MeCN)₂Cl₂ (153 mg, 0.591 mmol) under N₂ at RT. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 60 °C overnight. The mixture was diluted with EtOAc and the organic layer was separated and 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 (1.5 g) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.16 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 5.15 (s, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 3.45 (s, 3H), 1.42 (s, 12H). LC-MS (ESI) (m/z): 353 (M+H)⁺. Step 3: 5-Methoxy-7-(methoxymethoxy)benzo[c][1,2]oxaborol-1(3H)-ol To a solution of methyl 5-methoxy-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate (6 g, 17.0 mmol) in THF (60 mL) was added LiBH4 (26 mL, 52.0 mmol, 2 M in THF) drop-wisely at 0 °C and the mixture was stirred under N₂ at RT overnight. The mixture was quenched with sat. aq. NH₄Cl solution at 0 °C 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 (3.6 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 6.54 (s, 1H), 6.47 (s, 1H), 5.24 (s, 2H), 5.00 (s, 2H), 3.83 (s, 3H), 3.56 (s, 3H). LC-MS (ESI) (m/z): 225 (M+H)⁺. Intermediate 4 7-(Methoxymethoxy)-5-(trifluoromethoxy)benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: 3-Hydroxy-5-(trifluoromethoxy)benzoic acid To a solution of 3-bromo-5-(trifluoromethoxy)benzoic acid (18 g, 63.2 mmol) in 1,4- dioxane (54 mL) and water (54 mL) were added NaOH (10.1 g, 252 mmol), Pd2(dba)3 (1.16 g, 1.26 mmol) and tert-butyl XPhos (1.34 g, 3.16 mmol) at RT under N₂ atmosphere. The reaction mixture was degassed with N₂ three times and stirred at 100 °C for 3 hrs. The mixture was diluted with water and washed with EtOAc twice. The aqueous layer was acidified with 2N aq. HCl solution to pH~2 and extracted with DCM/MeOH (v/v= 5/1) three times. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under the reduced pressure to give the title compound (12 g) as a solid. LC-MS (ESI) (m/z): 220.8 (M-H)-. Step 2: Methyl 3-hydroxy-5-(trifluoromethoxy)benzoate To a mixture of 3-hydroxy-5-(trifluoromethoxy)benzoic acid (12 g, 54.1 mmol) in MeOH (240 mL) was added TMSCl (9.34 mL, 108 mmol) and the mixture was stirred at 70 °C overnight. The mixture was 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 (11 g) as a solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 7.37 (s, 1H), 7.26 (s, 1H), 7.00 (s, 1H), 3.86 (s, 3H). Step 3: Methyl 2-bromo-3-hydroxy-5-(trifluoromethoxy)benzoate To a solution of methyl 3-hydroxy-5-(trifluoromethoxy)benzoate (5.6 g, 23.7 mmol) in CCl₄ (112 mL) and water (16.8 mL) was added NBS (4.22 g, 23.7 mmol) in portions at 0 °C. The mixture was stirred under N₂ atmosphere at RT for 16 hrs. The layers were separated and the aqueous layer was 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 flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (3.2 g) as a solid, the regio-chemistry was confirmed by NOE and HMBC.¹H NMR (400 MHz, DMSO-d₆) δ 11.37 (s, 1H), 7.11 (d, J = 1.9 Hz, 1H), 7.03 (d, J = 1.9 Hz, 1H), 3.85 (s, 3H). Step 4: Methyl 2-bromo-3-(methoxymethoxy)-5-(trifluoromethoxy)benzoate To a solution of methyl 2-bromo-3-hydroxy-5-(trifluoromethoxy)benzoate (3.5 g, 11.1 mmol) in DCM (40 mL) was added DIPEA (4.3 g, 33.3 mmol) followed by drop-wise addition of MOMCl (1.34 g, 16.7 mmol) at 0 °C and the mixture was stirred at RT for 3 hrs. The reaction 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, 0–30%, EtOAc in PE) to give the title compound (3.3 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 7.22 (d, J = 1.6 Hz, 1H), 7.16 (d, J = 2.2 Hz, 1H), 5.27 (s, 2H), 3.95 (s, 3H), 3.52 (s, 3H). LC-MS (ESI) (m/z): 359/361 (M+H)⁺. Step 5: Methyl 3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethoxy)benzoate To a solution of methyl 2-bromo-3-(methoxymethoxy)-5-(trifluoromethoxy)benzoate (2 g, 5.59 mmol) in 1,4-dioxane (20 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (2.8 g, 11.0 mmol), KOAc (1.6 g, 16.3 mmol) and Pd(dppf)Cl₂ (409 mg, 0.559 mmol) under N₂ atmosphere at RT. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 120 °C for 2 hrs. The mixture was filtered and the filtrate was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (1.1 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J = 0.8 Hz, 1H), 7.08 (d, J = 1.0 Hz, 1H), 5.17 (s, 2H), 3.91 (s, 3H), 3.46 (s, 3H), 1.43 (s, 12H). LC-MS (ESI) (m/z): 407 (M+H)⁺. Step 6: 7-(methoxymethoxy)-5-(trifluoromethoxy)benzo[c][1,2]oxaborol-1(3H)-ol The title compound was prepared following methods and protocols as those described in Intermediate 3 Step 3 as a solid.¹H NMR (400 MHz, CDCl₃) δ 6.87 (s, 1H), 6.85 (s, 1H), 5.26 (s, 2H), 5.05 (s, 2H), 3.57 (s, 3H). LC-MS (ESI) (m/z): 279 (M+H)⁺. Intermediate 5 3-(Methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)benzyl acetate

Step 1: 2-(2-(Methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane To a mixture of 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (prepared following the procedure in WO2023178099, Example 20) (5 g, 14.4 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.25 g,72.2 mmol) in 1,4-dioxane (100 mL) were added TEA (10 mL, 72.2 mmol), CyJohn Phos (0.51 g, 1.5 mmol) and Pd(OAc)₂ (0.32 g, 1.5 mmol) successively under N₂ atmosphere, the mixture was degassed with N₂ three times and stirred under N₂ atmosphere 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 dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (2.2 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 7.05 (bs, 2H), 5.16 (s, 2H), 3.47 (s, 3H), 2.39 (s, 3H), 1.39 (s, 12H). Step 2: 2-(2-(Bromomethyl)-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane To a solution of 2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (1.2 g, 3.5 mmol) in CCl₄ (24 mL) was added NBS (0.68 g, 3.8 mmol) and AIBN (0.06 g, 0.35 mmol) and the mixture was stirred under N₂ atmosphere at 80 °C for 5 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 compound (1.1 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 7.26 (s, 1H), 7.19 (s, 1H), 5.18 (s, 2H), 4.57 (s, 2H), 3.49 (s, 3H), 1.42 (s, 12H). Step 3: 3-(Methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5- (trifluoromethyl)benzyl acetate To a mixture of 2-(2-(bromomethyl)-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.471 mmol) in DMSO (4 mL) was added KOAc (92.3 mg, 0.941 mmol) at RT and the mixture was stirred at 30 °C 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, 0–20% EtOAc in PE) to give the title compound (80 mg) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.27 (s, 1H), 7.22 (s, 1H), 5.18 (s, 2H), 5.12 (s, 2H), 3.48 (s, 3H), 2.10 (s, 3H), 1.39 (s, 12H). Intermediate 6 5-(Difluoromethoxy)-7-(methoxymethoxy)benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Methyl 3-(benzyloxy)-5-hydroxybenzoate To a solution of methyl 3,5-dihydroxybenzoate (50 g, 298 mmol) in DMF (500 mL) was added K₂CO₃ (41.1 g, 298 mmol) followed by drop-wise addition of BnBr (40.7 g, 238 mmol) at 0 °C 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, 0–40%, EtOAc in PE) to give the title compound (35 g) as an oil. LC-MS (ESI) (m/z): 259 (M+H)⁺. Step 2: Methyl 5-(benzyloxy)-2-bromo-3-hydroxybenzoate To a solution of methyl 3-(benzyloxy)-5-hydroxybenzoate (30 g, 116 mmol) in DCM (300 mL) was added NBS (21.7 g, 122 mmol) in portions at 0 °C and the mixture was stirred at RT overnight. 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 (18 g) as an oil. ¹H NMR (400 MHz, DMSO-d₆) δ 10.62 (s, 1H), 7.44 – 7.34 (m, 5H), 6.78 (d, J = 2.8 Hz, 1H), 6.71 (d, J = 2.9 Hz, 1H), 5.08 (s, 2H), 3.82 (s, 3H). LC-MS (ESI) (m/z): 337/339 (M+H)⁺. Step 3: Methyl 5-(benzyloxy)-2-bromo-3-(methoxymethoxy)benzoate To a solution of methyl 2-bromo-3-hydroxy-5-methoxybenzoate (18 g, 53.4 mmol) in DCM (180 mL) was added DIPEA (20.7 g, 160 mmol) followed by drop-wise addition of MOMCl (6.4 g, 80.1 mmol) at 0 °C 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, 0–20% EtOAc in PE) to give the title compound (12 g) as a solid.¹H NMR (400 MHz, DMSO-d6) δ 7.48 – 7.34 (m, 5H), 7.03 (d, J = 2.8 Hz, 1H), 6.99 (d, J = 2.8 Hz, 1H), 5.32 (s, 2H), 5.13 (s, 2H), 3.85 (s, 3H), 3.40 (s, 3H). Step 4: Methyl 5-(benzyloxy)-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate To a mixture of methyl 5-(benzyloxy)-2-bromo-3-(methoxymethoxy)benzoate (5 g, 13.1 mmol) in 1,4-dioxane (50 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.4 g, 26.2 mmol), TEA (4.0 g, 39.3 mmol), S-Phos (539 mg, 2.6 mmol) and Pd(MeCN)₂Cl₂ (340 mg, 1.3 mmol) under N₂ temperature at RT. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere 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 (3.7 g) as a solid.¹H NMR (400 MHz, DMSO-d₆) δ 7.48 – 7.33 (m, 5H), 7.18 (d, J = 2.1 Hz, 1H), 6.94 (d, J = 2.1 Hz, 1H), 5.19 (s, 2H), 5.14 (s, 2H), 3.83 (s, 3H), 3.36 (s, 3H), 1.31 (s, 12H). Step 5: Methyl 5-hydroxy-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2- yl)benzoate To a solution of methyl 5-(benzyloxy)-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzoate (3.7 g, 8.6 mmol) in MeOH (40 mL) was added Pd/C (400 mg, 10% wt.) under N₂ temperature and the mixture was stirred with a H₂ balloon at RT overnight. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (2.4 g) as an oil. LC/MS (ESI) m/z: 339.2 (M+H)⁺. Step 6: Methyl 5-(difluoromethoxy)-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate To a mixture of methyl 5-hydroxy-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate (2 g, 5.9 mmol) and Cs₂CO₃ (5.78 g, 17.7 mmol) in DMF (20 mL) was added sodium chlorodifluoroacetate (1.82 g, 11.8 mmol) at RT. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 80 °C for 2 hrs. The mixture was cooled to RT, diluted with ice/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, 0–20% EtOAc in PE) to give the title compound (700 mg, 31% yield) as colorless oil.¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H), 6.92 (s, 1H), 6.64 (t, J = 73.5 Hz, 1H), 5.10 (s, 2H), 3.85 (s, 3H), 3.40 (s, 3H), 1.36 (s, 12H). Step 7: 5-(difluoromethoxy)-7-(methoxymethoxy)benzo[c][1,2]oxaborol-1(3H)-ol The title compound was prepared following methods and protocols as those described in Intermediate 3 Step 3 as a solid.¹H NMR (400 MHz, CDCl₃) δ 6.76 (s, 1H), 6.75 (s, 1H), 6.55 (t, J = 73.5 Hz, 1H), 5.25 (s, 2H), 5.03 (s, 2H), 3.57 (s, 3H). LC-MS (ESI) (m/z): 261 (M+H)⁺. Intermediate 7 (R)-11-methoxy-3-(piperidin-3-ylamino)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-13-ol TFA salt

Step 1: Tert-butyl (3R)-3-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-(2- (hydroxymethyl)-4-methoxy-6-(methoxymethoxy)phenyl)pyridazin-3- yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6- chloropyridazin-3-yl)amino)piperidine-1-carboxylate (Intermediate 1, 6 g, 12.4 mmol) in 1,4- dioxane (80 mL) and water (8 mL) was added 5-methoxy-7- (methoxymethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (Intermediate 3, 2.8 g, 12.5 mmol), K₃PO₄ (8 g, 37.7 mmol) and SPhos Pd G₂ (1.8 g, 2.50 mmol) under N₂ atmosphere at RT. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 100 °C for 2 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 flash chromatography (silica gel, 0– 70% EtOAc in PE) to give the title compound (4.6 g) as a solid. LC-MS (ESI) (m/z): 647 (M+H)⁺. Step 2: Tert-butyl (3R)-3-((6-(2-(hydroxymethyl)-4-methoxy-6- (methoxymethoxy)phenyl)-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1- carboxylate To a solution of tert-butyl (3R)-3-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-(2- (hydroxymethyl)-4-methoxy-6-(methoxymethoxy)phenyl)pyridazin-3-yl)amino)piperidine-1- carboxylate (4.64 g, 7.18 mmol) in THF (50 mL) was added TBAF (14.3 mL, 14.3 mmol, 1M in THF) at 0 °C and the mixture was stirred at 25 °C for 3 hrs. The mixture was diluted with EtOAc, washed with sat. aq. NH₄Cl solution five times, dried over anhydrous Na₂SO₄, filtered, and concentrated under the reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–6% MeOH in DCM) to give the title compound (3.1 g) as a solid. LC-MS (ESI) m/z: 533 (M+H)⁺. Step 3: Tert-butyl (3R)-3-((6-(2-(bromomethyl)-4-methoxy-6-(methoxymethoxy)phenyl)- 5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (3R)-3-((6-(2-(hydroxymethyl)-4-methoxy-6- (methoxymethoxy)phenyl)-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1- carboxylate (500 mg, 0.940 mmol) in DCM (50 mL) was added CBr₄ (468 mg, 1.41 mmol) and PPh₃ (296 mg, 1.13 mmol) under N₂ atmosphere at -20 °C, the mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 30 °C for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–7% MeOH in DCM) to give the title compound (380 mg) as a solid. LC-MS (ESI) m/z: 595/597 (M+H)⁺. Step 4: Tert-butyl (R)-3-((11-methoxy-13-(methoxymethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (3R)-3-((6-(2-(bromomethyl)-4-methoxy-6- (methoxymethoxy)phenyl)-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1- carboxylate (380 mg, 0.640 mmol) in chloroform (25 mL) was added DTBMP (263 mg, 1.28 mmol) and AgOTf (247 mg, 0.96 mmol) at 0 °C under N₂ atmosphere, the mixture was degassed with N₂ three times and stirred under N₂ atmosphere at RT for 1 hour. The mixture was filtered through a pad of Celite and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–7% MeOH in DCM) to give the title compound (190 mg) as a solid. LC-MS (ESI) m/z: 515 (M+H)⁺. Step 5: (R)-11-methoxy-3-(piperidin-3-ylamino)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol TFA salt To a solution of tert-butyl (R)-3-((11-methoxy-13-(methoxymethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (190 mg, 0.370 mmol) in DCM (2 mL) was added TFA (1 mL) at 0 °C and the mixture was stirred at RT for 0.5 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (120 mg) as an oil, which was used directly in the next reaction without purification. LC-MS (ESI) m/z: 371 (M+H)⁺. The Intermediates listed in Error! Reference source not found.1 were prepared following the methods and protocols as those described for the synthesis of Intermediate 7 from Intermediate 4, Intermediate 5 or Intermediate 6.

Intermediate 11 5-(Benzyloxy)-7-(methoxymethoxy)benzo[c][1,2]oxaborol-1(3H)-ol

To a solution of methyl 5-(benzyloxy)-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzoate (Intermediate 6 Compound 5, 5 g, 11.7 mmol) in THF (50 mL) was added LiBH₄ (8.8 mL, 35.1 mmol, 4 M in THF) drop-wisely at 0 °C and the mixture was stirred under N₂ at RT overnight. The reaction was quenched with ice-water and extracted with DCM twice. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness to give the title compound (3.4 g) as a solid, which was used directly in the next reaction without purification. ¹H NMR (400 MHz, CDCl₃) δ 7.43 – 7.40 (m, 3H), 7.39 – 7.38 (m, 1H), 7.38 – 7.36 (m, 1H), 6.64 – 6.62 (m, 1H), 6.62 – 6.60 (m, 1H), 5.23 (s, 2H), 5.08 (s, 2H), 4.99 (s, 2H), 3.55 (s, 3H). LC/MS (ESI) (m/z): 300.7 (M+H)⁺. Intermediate 12

Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((6-chloro-5-(3-hydroxypropyl)pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((5-(3-((tert- butyldimethylsilyl)oxy)propyl)-6-chloropyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (5 g, 8.99 mmol) in THF (50 mL) was added TBAF (18 mL, 18 mmol, 1 M in THF) at 0 °C and the mixture was stirred at 30 °C for 3 hrs. The mixture was diluted with EtOAc, washed with sat. aq. NH₄Cl solution five times, dried over anhydrous Na₂SO₄, filtered, and concentrated under the reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–5% MeOH in DCM) to give the title compound (3.1 g) as a solid. LC-MS (ESI) m/z: 443 (M+H)⁺. Step 2: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-((benzyloxy)methyl)-6-chloro-5-(3- hydroxypropyl)pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a mixture of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-chloro-5-(3- hydroxypropyl)pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (50 mg, 0.11 mmol) and 2- (benzyloxy)acetic acid (36 mg, 0.22 mmol) in DMSO (0.6 mL) were added BPO (55 mg, 0.22 mmol), 4CzPN-Bu (1.4 mg, 0.001 mmol) and 4A molecular sieves (10 mg) under N₂ atmosphere. The reaction mixture was degassed with N₂ three times and stirred at RT under 18W White LED irradiation 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, 0–50% EtOAc in PE) to give the title compound (460 mg) as a solid. LC/MS (ESI) m/z: 563.3 (M+H)⁺. Step 3: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-((benzyloxy)methyl)-5-(3-((tert- butyldimethylsilyl)oxy)propyl)-6-chloropyridazin-3-yl)amino)piperidine-1,2- dicarboxylate To a mixture of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-((benzyloxy)methyl)-6-chloro-5- (3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (460 mg, 0.82 mmol) in DCM (50 mL) was added imidazole (225 mg, 3.3 mmol) and TBSCl (247 mg, 1.6 mmol) at 0 °C. The mixture was stirred under N₂ atmosphere 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, 0–40% EtOAc in PE) to afford the title compound (380 mg) as a solid. LC/MS (ESI) m/z: 677.4 (M+H)⁺. EXAMPLES Example 1 (R)-10-cyclopropyl-3-((1-methylpiperidin-3-yl)amino)-5,6,7,8- tetrahydrobenzo[7,8]cycloocta[1,2-c]pyridazin-12-ol formic salt (partial)

Step 1: (E)-6-(3-bromo-5-methoxyphenyl)hex-5-enoic acid To a solution of (4-carboxybutyl)triphenylphosphonium bromide (49.5 g, 0.111 mol) in THF (500 mL) was added potassium tert-butoxide (31.3 g, 0.279 mol) under N₂ atmosphere at RT and the mixture was stirred at RT for 1 hr. A solution of 3-bromo-5- methoxybenzaldehyde (20 g, 93 mmol) in THF (300 mL) was added to the above mixture, and the resulting mixture was stirred at RT overnight. The mixture was acidified with 1N aq. HCl at 0 °C 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, 0–40% EtOAc in PE) to give the title compound (19 g) as a solid. LC-MS (ESI) (m/z): 299/301 (M+H)⁺. Step 2: 6-(3-Bromo-5-methoxyphenyl)hexanoic acid To a solution of (E)-6-(3-bromo-5-methoxyphenyl)hex-5-enoic acid (19 g, 63.5 mmol) in EtOAc (200 mL) was added PtO₂ (1 g, 8.1 mmol), the mixture was degassed with N₂ three times and stirred under a H₂ balloon at RT for 1 hr. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (18 g) as a solid. LC-MS (ESI) m/z: 301/303 (M+H)⁺. Step 3: 2-Bromo-4-methoxy-7,8,9,10-tetrahydrobenzo[8]annulen-5(6H)-one A solution of 6-(3-bromo-5-methoxyphenyl)hexanoic acid (10 g, 0.66 mmol) in Eaton's Reagent (100 mL) was stirred at RT overnight. The mixture was poured into sat. aq. NaHCO₃ solution 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, 0–20% EtOAc in PE) to give the title compound (1.05 g) as an oil.¹H NMR (400 MHz, CDCl₃) δ 6.93 (d, J = 0.8 Hz, 1H), 6.89 (s, 1H), 3.77 (s, 3H), 2.67 – 2.63 (m, 2H), 2.60 – 2.56 (m, 2H), 1.74 – 1.67 (m, 4H), 1.60 – 1.57 (m, 2H). LC-MS (ESI) (m/z): 283/285 (M+H)⁺. Step 4: Ethyl 2-(2-bromo-4-methoxy-5-oxo-5,6,7,8,9,10-hexahydrobenzo[8]annulen-6- yl)acetate To a solution of 2-bromo-4-methoxy-7,8,9,10-tetrahydrobenzo[8]annulen-5(6H)-one (750 mg, 2.65 mmol) in THF (8 mL) was added HMPA (0.60 mL, 3.44 mmol) followed by drop-wise addition of LiHMDS (1.99 mL, 3.97 mmol, 2M in THF) at 0 °C and the mixture was stirred under N₂ atmosphere at 0 °C for 30 mins. Then ethyl bromoacetate (663 mg, 3.97 mmol) was added and the mixture was stirred under N₂ atmosphere at RT 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 under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (600 mg) as an oil. LC-MS (ESI) (m/z): 369/371 (M+H)⁺. Step 5: 10-Bromo-12-methoxy-4,4a,5,6,7,8-hexahydrobenzo[7,8]cycloocta[1,2- c]pyridazin-3(2H)-one To a solution of ethyl 2-(2-bromo-4-methoxy-5-oxo-5,6,7,8,9,10- hexahydrobenzo[8]annulen-6-yl)acetate (500 mg, 1.35 mmol) in EtOH (5 mL) was added hydrazinium hydroxide solution (5 mL, 85% wt.) and the mixture was stirred at 80 °C for 5 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 to give the title compound (250 mg) as a solid. LC-MS (ESI) (m/z): 337/339 (M+H)⁺. Step 6: 10-Bromo-12-methoxy-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2-c]pyridazin- 3(2H)-one To a solution of 10-bromo-12-methoxy-4,4a,5,6,7,8- hexahydrobenzo[7,8]cycloocta[1,2-c]pyridazin-3(2H)-one (250 mg, 0.74 mmol) in MeCN (3 mL) was added cupric chloride (199 mg, 1.48 mmol). The mixture was stirred at 80 °C for 2 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 flash chromatography (silica gel, 0–5% MeOH in DCM) to give the title compound (150 mg) as a solid. LC-MS (ESI) (m/z): 335/337 (M+H)⁺. Step 7: 10-Bromo-3-chloro-12-methoxy-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2- c]pyridazine A solution of 10-bromo-12-methoxy-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2- c]pyridazin-3(2H)-one (150 mg, 0.45 mmol) in POCl₃ (4 mL) was stirred at 100 °C for 1 hr. The mixture was concentrated to dryness. The residue was diluted with ice-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 give the title compound (130 mg) as an oil, which was directly used in the next reaction without purification. LC-MS (ESI) (m/z): 353/355 (M+H)⁺. Step 9: Tert-butyl (R)-3-((10-bromo-12-methoxy-5,6,7,8-tetrahydrobenzo[7,8]- cycloocta[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate To a mixture of 10-bromo-3-chloro-12-methoxy-5,6,7,8-tetrahydrobenzo[7,8]- cycloocta[1,2-c]pyridazine (130 mg, 0.37 mmol) and tert-butyl (R)-3-aminopiperidine-1- carboxylate (81 mg, 0.41 mmol) in DMSO (2 mL) was added cesium fluoride (84 mg, 0.55 mmol) and the mixture was stirred at 120 °C 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 dryness. The residue was purified by flash chromatography (silica gel, 0–5% MeOH in DCM) to give the title compound (110 mg) as a solid. LC-MS (ESI) (m/z): 517/519 (M+H)⁺. Step 10: Tert-butyl (R)-3-((10-cyclopropyl-12-methoxy-5,6,7,8-tetrahydrobenzo- [7,8]cycloocta[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate To a mixture of tert-butyl (R)-3-((10-bromo-12-methoxy-5,6,7,8-tetrahydrobenzo- [7,8]cycloocta[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (110 mg, 0.24 mmol) and cyclopropylboronic acid (18 mg, 0.21 mmol) in toluene (3 mL) and water (0.5 mL) were added K₃PO₄ (158 mg, 0.74 mmol), tricyclohexyl phosphine (12 mg, 0.04 mmol) and palladium acetate (4 mg, 0.02 mmol) under N₂ atmosphere. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 80 °C overnight. 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, 0–5% MeOH in DCM) to give the title compound (80 mg) as a solid. LC-MS (ESI) (m/z): 479.3 (M+H)⁺. Step 11: (R)-10-cyclopropyl-3-(piperidin-3-ylamino)-5,6,7,8- tetrahydrobenzo[7,8]cycloocta[1,2-c]pyridazin-12-ol To a solution of tert-butyl (R)-3-((10-cyclopropyl-12-methoxy-5,6,7,8- tetrahydrobenzo[7,8]cycloocta[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (80 mg, 0.17 mmol) in DCM (1 mL) was added boron tribromide (42 mg, 0.17 mmol) at -78 °C under N₂ atmosphere and the mixture was stirred at RT for 30 mins. The mixture was quenched with sat. aq. NaHCO₃ solution at 0 °C and extracted with DCM three times. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness to give the crude title compound (50 mg) as a solid. LC-MS (ESI) (m/z): 365 (M+H)⁺ . Step 12: (R)-10-cyclopropyl-3-((1-methylpiperidin-3-yl)amino)-5,6,7,8- tetrahydrobenzo[7,8]cycloocta[1,2-c]pyridazin-12-ol To a mixture of (R)-10-cyclopropyl-3-(piperidin-3-ylamino)-5,6,7,8- tetrahydrobenzo[7,8]cycloocta[1,2-c]pyridazin-12-ol (50 mg, 0.137 mmol) and 37% aq. HCHO (0.3 mL) in MeOH (1 mL) was added sodium cyanoborohydride (17 mg, 0.27 mmol) at 0 °C. The mixture was stirred at RT for 30 mins. The mixture was quenched with ice water. The mixture was purified by prep-HPLC (YMC-Actus Triart C18250*20mm, 20–95% MeCN in H₂O with 0.1% FA) to afford the title compound (3.9 mg) as a solid.¹H NMR (400 MHz, DMSO-d₆) δ 6.70 (d, J = 3.1 Hz, 1H), 6.55 (d, J = 7.9 Hz, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 4.09 – 3.97 (m, 1H), 2.92 – 2.84 (m, 1H), 2.62 – 2.55 (m, 2H), 2.07 (s, 3H), 2.03 – 1.96 (m, 3H), 1.90 – 1.80 (m, 4H), 1.79 – 1.68 (m, 2H), 1.60 – 1.42 (m, 2H), 1.34 – 1.29 (m, 2H), 0.96 – 0.90 (m, 2H), 0.88 – 0.79 (m, 1H), 0.68 – 0.61 (m, 2H). LC-MS (ESI) m/z: 379.1 (M+H)⁺. Example 2 9-Cyclopropyl-3-(((R)-1-methylpiperidin-3-yl)amino)-6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazin-11-ol formic salt (partial)

The title compound was prepared following methods and protocols as those described for the synthesis of Example 1 from (3-carboxypropyl)triphenylphosphonium bromide as starting material.¹H NMR (400 MHz, DMSO-d6) δ 6.93 (d, J = 7.7 Hz, 1H), 6.84 (s, 1H), 6.55 (d, J = 1.4 Hz, 1H), 6.52 (d, J = 1.5 Hz, 1H), 4.13 – 4.03 (m, 1H), 2.99 – 2.88 (m, 1H), 2.68 – 2.59 (m, 1H), 2.42 (t, J = 6.9 Hz, 2H), 2.34 (t, J = 7.0 Hz, 2H), 2.25 (s, 3H), 2.15 – 1.99 (m, 4H), 1.90 – 1.82 (m, 2H), 1.77 – 1.71 (m, 1H), 1.62 – 1.53 (m, 1H), 1.38 – 1.29 (m, 1H), 0.97 – 0.90 (m, 2H), 0.73 – 0.67 (m, 2H). LC-MS (ESI) m/z: 365 (M+H)⁺. Example 3 (R)-3-((1-methylpiperidin-3-yl)amino)-10-(trifluoromethyl)-5,6,7,8- tetrahydrobenzo[7,8]cycloocta[1,2-c]pyridazin-12-ol formic salt (partial)

Step 1: Tert-butyl (R)-3-((6-chloro-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine- 1-carboxylate To a solution of tert-butyl (R)-3-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6- chloropyridazin-3-yl)amino)piperidine-1-carboxylate (Intermediate 1, 6 g, 12.4 mmol) in THF (60 mL) was added TBAF (8.08 g, 261.5 mmol) and the mixture was stirred at RT for 3 hrs. The mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with sat. aq. NH₄Cl and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–80% EtOAc in PE) to give the title compound (4 g) as a solid. LC-MS (ESI) m/z: 371.2 (M+H)⁺. Step 2: Tert-butyl (R)-3-((6-chloro-5-(3-oxopropyl)pyridazin-3-yl)amino)piperidine-1- carboxylate To a solution of tert-butyl (R)-3-((6-chloro-5-(3-hydroxypropyl)pyridazin-3- yl)amino)piperidine-1-carboxylate (4 g, 10.8 mmol) in DCM (40 mL) was added Dess-Martin reagent (11.4 g, 27.0 mmol) at 0 °C and the mixture was stirred at RT for 4 hrs. The mixture was quenched with sat. aq. NaHCO₃ solution and filtered. The filtrate was extracted with DCM three times. The combined organic layers were washed with brine and 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 (2.6 g) as an oil. LC-MS (ESI) m/z: 369.4 (M+H)⁺. Step 3: Tert-butyl (R)-3-((5-(but-3-yn-1-yl)-6-chloropyridazin-3-yl)amino)piperidine-1- carboxylate To a solution of tert-butyl (R)-3-((6-chloro-5-(3-oxopropyl)pyridazin-3- yl)amino)piperidine-1-carboxylate (2.6 g, 7.05 mmol) in MeOH (30 mL) was added K₂CO₃ (1.95 g, 14.1 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.62 g, 8.46 mmol) at 0 °C and the mixture was stirred under N₂ atmosphere at RT 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, 0–35 % EtOAc in PE) to give the title compound (1.5 g) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 6.64 (s, 1H), 4.91 (s, 1H), 3.94 – 3.87 (m, 1H), 3.70 – 3.68 (m, 1H), 3.47 – 3.37 (m, 2H), 2.84 – 2.81 (m, 2H), 2.58 – 2.54 (m, 2H), 1.99 – 1.93 (m, 1H), 1.74 – 1.73 (m, 4H), 1.61 – 1.55 (m, 1H), 1.43 (s, 9H). LC-MS (ESI) m/z: 365.1 (M+H)⁺. Step 4: Tert-butyl (R)-3-((5-(but-3-en-1-yl)-6-chloropyridazin-3-yl)amino)piperidine-1- carboxylate To a solution of tert-butyl (R)-3-((5-(but-3-yn-1-yl)-6-chloropyridazin-3- yl)amino)piperidine-1-carboxylate (1.5 g, 4.11 mmol) in EtOAc (15 mL) was added Lindlar Pd catalyst (0.17 g, 0.411 mmol) at 0 °C, the mixture was degassed with N₂ three times and stirred under a H₂ balloon at 0 °C for 2 hrs. The mixture was filtered, and the filtrate was concentrated under the reduced pressure to dryness. The residue was purified by prep-HPLC (C18, 0–55% acetonitrile in H₂O with 0.1% FA) to give the title compound (1.1 g) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 6.59 (s, 1H), 5.87 – 5.77 (m, 1H), 5.10 – 5.04 (m, 2H), 4.10 – 3.97 (m, 1H), 3.83 – 3.68 (m, 2H), 3.53 – 3.50 (m, 1H), 3.35 – 3.23 (m, 2H), 2.73 – 2.69 (m, 2H), 2.42 – 2.37 (m, 2H), 1.97 – 1.92 (m, 1H), 1.78 – 1.68 (m, 2H), 1.60 – 1.54 (m, 1H), 1.42 (s, 9H). LC-MS (ESI) m/z: 367.2 (M+H)⁺. Step 5: Tert-butyl (3R)-3-((6-(2-allyl-6-(methoxymethoxy)-4-(trifluoromethyl)-phenyl)-5- (but-3-en-1-yl)pyridazin-3-yl)amino)piperidine-1-carboxylate To a mixture of tert-butyl (R)-3-((5-(but-3-en-1-yl)-6-chloropyridazin-3- yl)amino)piperidine-1-carboxylate (900 mg, 2.46 mmol) and 2-(2-allyl-6-(methoxymethoxy)- 4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.19 g, 3.20 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Na₂CO₃ (0.78 g, 7.38 mmol), RuPhos (0.114 g, 0.246 mmol) and RuPhos Pd G3 (0.206 g, 0.246 mmol) under N₂ atmosphere, the mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 120 °C for 5 hrs. 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 dryness. The residue was purified by flash chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (0.26 g) as a solid. LC-MS (ESI) m/z: 577.4 (M+H)⁺. Step 6: Tert-butyl (R,Z)-3-((12-(methoxymethoxy)-10-(trifluoromethyl)-5,6- dihydrobenzo[7,8]cycloocta[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (3R)-3-((6-(2-allyl-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-5-(but-3-en-1-yl)pyridazin-3-yl)amino)piperidine-1-carboxylate (100 mg, 0.174 mmol) in toluene (100 mL) was added Grubbs II catalyst (17.7 mg, 0.021 mmol) at 0 °C under N₂ atmosphere. The mixture was stirred at 100 °C for 6 hrs. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (C18, 0–40% acetonitrile in H₂O with 0.1% FA) to give the title compound (15 mg) as a solid. LC-MS (ESI) m/z: 535.2 (M+H)⁺. Step 7: Tert-butyl (R)-3-((12-(methoxymethoxy)-10-(trifluoromethyl)-5,6,7,8- tetrahydrobenzo[7,8]cycloocta[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (R,Z)-3-((12-(methoxymethoxy)-10-(trifluoromethyl)-5,6- dihydrobenzo[7,8]cycloocta[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (15 mg, 0.028 mmol) in MeOH (2 mL) was added Pd/C (3 mg, 10% wt.) under N₂ temperature and the mixture was stirred under a H₂ balloon at RT for 1 hr. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (12 mg) as a solid. LC-MS (ESI) m/z: 537.2 (M+H)⁺. Step 8: (R)-3-(piperidin-3-ylamino)-10-(trifluoromethyl)-5,6,7,8- tetrahydrobenzo[7,8]cycloocta[1,2-c]pyridazin-12-ol To a solution of tert-butyl (R)-3-((12-(methoxymethoxy)-10-(trifluoromethyl)-5,6,7,8- tetrahydrobenzo[7,8]cycloocta[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (12 mg, 0.022 mmol) in 1,4-dioxane (0.5 mL) was added HCl/1,4-dioxane (0.5 mL, 4 M) and the mixture was stirred at RT for 20 mins. The mixture was basified with sat. aq. NaHCO₃ solution 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 (7 mg) as a solid. LC-MS (ESI) (m/z): 393.2 (M+H)⁺. Step 9: (R)-3-((1-methylpiperidin-3-yl)amino)-10-(trifluoromethyl)-5,6,7,8- tetrahydrobenzo[7,8]cycloocta[1,2-c]pyridazin-12-ol To a mixture of (R)-3-(piperidin-3-ylamino)-10-(trifluoromethyl)-5,6,7,8- tetrahydrobenzo[7,8]cycloocta[1,2-c]pyridazin-12-ol (7 mg, 0.018 mmol) and 37% aq. HCHO (0.2 mL) in MeOH (1 mL) was added AcOH (2.2 mg, 0.036 mmol) and NaBH3CN (3.4 mg, 0.054 mmol) at 0 °C 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% FA) to give the title compound (2 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.09 (s, 1H), 7.04 (s, 1H), 6.85 (s, 1H), 4.30 – 4.22 (m, 1H), 2.84 – 2.78 (m, 2H), 2.74 – 2.67 (m, 2H), 2.65 – 2.63 (m, 3H), 2.21 – 2.01 (m, 7H), 1.89 – 1.79 (m, 1H), 1.64 – 1.45 (m, 4H). LC-MS (ESI) (m/z): 407.5 (M+H)⁺. Example 4 (R)-3-((1-methylpiperidin-3-yl)amino)-12-(trifluoromethyl)-5,6,7,8,9,10- hexahydrobenzo[9,10]cyclodeca[1,2-c]pyridazin-14-ol formic salt (partial)

Step 1: 3,6-Dichloro-4-(pent-4-yn-1-yl)pyridazine To a solution of 3,6-dichloro-1,2,4,5-tetrazine (5 g, 33.1 mmol) in toluene (50 mL) was added hepta-1,6-diyne (9.16 g, 99.4 mmol) at 25 °C under N₂ atmosphere. The mixture was stirred at 100 °C for 4 hrs. The mixture was 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 (5.5 g) as an oil.¹H NMR (400 MHz, CDCl₃) δ 7.41 (s, 1H), 2.89 – 2.85 (m, 2H), 2.33 – 2.29 (m, 2H), 2.06 – 2.05 (m, 1H), 1.93 – 1.86 (m, 2H). Step 2: Tert-butyl (R)-3-((6-chloro-5-(pent-4-yn-1-yl)pyridazin-3-yl)amino)piperidine-1- carboxylate To a mixture of 3,6-dichloro-4-(pent-4-yn-1-yl)pyridazine (5.5 g, 25.7 mmol) and tert- butyl (R)-3-aminopiperidine-1-carboxylate (7.71 g, 38.6 mmol) in DMSO (60 mL) was added CsF (7.81 g, 51.4 mmol). The mixture was stirred at 120 °C 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 dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (4.2 g) as a solid. LC-MS (ESI) (m/z): 379 (M+H)⁺. Step 3: Tert-butyl (R)-3-((6-chloro-5-(pent-4-en-1-yl)pyridazin-3-yl)amino)piperidine-1- carboxylate To a solution of tert-butyl (R)-3-((6-chloro-5-(pent-4-yn-1-yl)pyridazin-3- yl)amino)piperidine-1-carboxylate (1.4 g, 3.69 mmol) in THF (8 mL) and EtOAc (8 mL) was added Lindlar catalyst (0.15 g, 0.37 mmol) at 0 °C, the mixture was degassed with N₂ atmosphere three times and stirred under H₂ balloon at 0 °C for 2 hrs. The mixture was filtered, and the filtrate was concentrated under the reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Pack ODS-AQ /S-5um/12 nm 250*20mm, 0–55% acetonitrile in H₂O with 0.1% FA) to give the title compound (1.1 g) as an oil.¹H NMR (400 MHz, CDCl₃) δ 6.60 (s, 1H), 5.87 – 5.77 (m, 1H), 5.09 – 5.02 (m, 2H), 3.83 – 3.72 (m, 2H), 3.54 – 3.51 (m, 1H), 3.40 – 3.18 (m, 4H), 2.64 – 2.60 (m, 2H), 2.19 – 2.13 (m, 2H), 2.00 – 1.96 (m, 1H), 1.77 – 1.70 (m, 3H), 1.62 – 1.55 (m, 1H), 1.43 (s, 9H). Step 4: 2-(Methoxymethoxy)-1-nitro-4-(trifluoromethyl)benzene To a solution of 2-nitro-5-(trifluoromethyl)phenol (20 g, 96.6 mmol) in DCM (200 mL) were added DIPEA (37.4 g, 289.7 mmol) followed by drop-wise addition of MOMCl (11.7 g, 144.8 mmol) at 0 °C and the mixture was stirred under N₂ atmosphere at RT 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, 0–20 % EtOAc in PE) to give the title compound (21 g) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.29 (d, J = 8.4 Hz, 1H), 5.27 (s, 2H), 3.47 (s, 3H). Step 5: 2-(Methoxymethoxy)-4-(trifluoromethyl)aniline To a solution of 2-(methoxymethoxy)-1-nitro-4-(trifluoromethyl)benzene (21 g, 83.6 mmol) in MeOH (200 mL) was added Pd/C (0.9 g, 10% wt.) under N₂ temperature and the mixture was stirred with a H₂ balloon at RT overnight. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (17.5 g) as an oil. LC-MS (ESI) m/z: 222.3 (M+H)⁺. Step 6: 2-Iodo-6-(methoxymethoxy)-4-(trifluoromethyl)aniline To a solution of 2-(methoxymethoxy)-4-(trifluoromethyl)aniline (17.5 g, 79.1 mmol) in AcOH (180 mL) was added NIS (16.1 g, 71.2 mmol) and the mixture was stirred at RT for 16 hrs. The mixture was diluted with water and neutralized with sat. aq. NaHCO₃ solution and extracted with EtOAc three times. 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 gel, 0–10% EtOAc in PE) to give the title compound (19 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J = 0.8 Hz, 1H), 7.22 (d, J = 1.4 Hz, 1H), 5.23 (s, 2H), 4.59 (bs, 2H), 3.50 (s, 3H). LC-MS (ESI) m/z: 347.9 (M+H)⁺. Step 7: 2-Allyl-6-(methoxymethoxy)-4-(trifluoromethyl)aniline To a solution of 2-iodo-6-(methoxymethoxy)-4-(trifluoromethyl)aniline (8 g, 23 mmol) in toluene (60 mL) were added allyltributylstannane (11.4 g, 34.6 mmol) and Pd(PPh₃)₄ (2.66 g, 2.30 mmol) at RT under N₂ atmosphere. The mixture was stirred under N₂ atmosphere at 100 °C 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– 35% EtOAc in PE) to give the title compound (5.6 g) as an oil.¹H NMR (400 MHz, CDCl₃) δ 7.18 (d, J = 1.4 Hz, 1H), 7.03 (s, 1H), 5.98 – 5.88 (m, 1H), 5.22 (s, 2H), 5.19 – 5.11 (m, 2H), 3.51 (s, 3H), 3.34 – 3.33 (m, 2H). LC-MS (ESI) m/z: 262 (M+H)⁺. Step 8: 3-Allyl-2-iodo-5-(trifluoromethyl)phenol To a solution of 2-allyl-6-(methoxymethoxy)-4-(trifluoromethyl)aniline (5.5 g, 21.05 mmol) in MeCN (30 mL) were added conc. HCl (60 mL) at 0 °C and the mixture was stirred at 0 °C for 10 mins. A solution of NaNO₂ (0.69 g, 10.0 mmol) in water (20 mL) was added drop-wisely to the above mixture at 0 °C and the mixture was stirred at 0 °C for 1 hr. Then a solution of KI (6.99 g, 42.1 mmol) in water (40 mL) was added drop-wisely at 0 °C and the resulting mixture was stirred at RT for 16 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with sat. aq. Na₂S₂O₃ solution 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 (4.3 g) as an oil.¹H NMR (400 MHz, CDCl₃) δ 7.10 (s, 1H), 7.04 (s, 1H), 5.98 – 5.88 (m, 1H), 5.22 – 5.10 (m, 2H), 3.54 (d, J = 6.4 Hz, 2H). LC-MS (ESI) m/z: 327.0 (M-H)-. Step 9: 1-Allyl-2-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzene To a solution of 3-allyl-2-iodo-5-(trifluoromethyl)phenol (4.3 g, 13.1 mmol) in DCM (40 mL) were added DIPEA (5.07 g, 39.3 mmol) followed by drop-wise addition of MOMCl (1.59 g, 19.7 mmol) at 0 °C and the mixture was stirred under N₂ atmosphere 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, 0–10 % EtOAc in PE) to give the title compound (4.6 g) as an oil.¹H NMR (400 MHz, CDCl₃) δ 7.14 – 7.13 (m, 2H), 6.00 – 5.90 (m, 1H), 5.29 (s, 2H), 5.21 – 5.11 (m, 2H), 3.61 – 3.60 (m, 2H), 3.53 (s, 3H). Step 10: 2-(2-Allyl-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane To a solution of 1-allyl-2-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzene (4.6 g, 12.4 mmol) in THF (40 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.17 g, 24.8 mmol), CuI (0.24 g, 1.24 mmol) and NaH (0.74 g, 18.6 mmol, 60% dispersion in mineral oil) successively at 0 °C under N₂ atmosphere and the mixture was stirred at RT for 1 hr. The mixture was quenched with ice-water 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 flash chromatography (silica gel, 0–8% EtOAc in PE) to give the title compound (4 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 7.10 – 7.08 (m, 2H), 6.00 – 5.90 (m, 1H), 5.17 (s, 2H), 5.10 – 5.03 (m, 2H), 3.47 (s, 3H), 3.44 – 3.42 (m, 2H), 1.39 (s, 12H). Step 11: Tert-butyl (3R)-3-((6-(2-allyl-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)- 5-(pent-4-en-1-yl)pyridazin-3-yl)amino)piperidine-1-carboxylate To a mixture of tert-butyl (R)-3-((6-chloro-5-(pent-4-en-1-yl)pyridazin-3- yl)amino)piperidine-1-carboxylate (0.58 g, 1.53 mmol) and 2-(2-allyl-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.74 g, 1.99 mmol) in 1,4- dioxane (5 mL) and water (1 mL) was added Na₂CO₃ (0.49 g, 4.59 mmol), RuPhos (71.4 mg, 0.15 mmol) and RuPhos Pd G3 (0.128 g, 0.153 mmol) under N₂ atmosphere, the mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 120 °C for 4 hrs. 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 dryness. The residue was purified by flash chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (0.48 g) as a solid. LC-MS (ESI) m/z: 591.7 (M+H)⁺. Step 12: Tert-butyl (R,Z)-3-((14-(methoxymethoxy)-12-(trifluoromethyl)-5,6,7,10- tetrahydrobenzo[9,10]cyclodeca[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (3R)-3-((6-(2-allyl-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-5-(pent-4-en-1-yl)pyridazin-3-yl)amino)piperidine-1-carboxylate (200 mg, 0.34 mmol) in toluene (200 mL) was added Hoveyda-Grubbs II catalyst (31.8 mg, 0.051 mmol) at 0 °C under N₂ atmosphere. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 100 °C for 6 hrs. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Pack ODS-AQ /S-5um/12 nm 250*20mm, 0–40% acetonitrile in H₂O with 0.1% FA) to give the title compound (38 mg) as an oil. LC-MS (ESI) m/z: 563.3 (M+H)⁺. Step 13: Tert-butyl (R)-3-((14-(methoxymethoxy)-12-(trifluoromethyl)-5,6,7,8,9,10- hexahydrobenzo[9,10]cyclodeca[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (R,Z)-3-((14-(methoxymethoxy)-12-(trifluoromethyl)- 5,6,7,10-tetrahydrobenzo[9,10]cyclodeca[1,2-c]pyridazin-3-yl)amino)piperidine-1- carboxylate (38 mg, 0.068 mmol) in MeOH (2 mL) was added Pd/C (7 mg, 10% wt.) under N₂ temperature and the mixture was stirred with a H₂ balloon at RT for 1 hr. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (25 mg) as an oil. LC-MS (ESI) m/z: 565.3 (M+H)⁺. Step 14: (R)-3-(piperidin-3-ylamino)-12-(trifluoromethyl)-5,6,7,8,9,10- hexahydrobenzo[9,10]cyclodeca[1,2-c]pyridazin-14-ol To a solution of tert-butyl (R)-3-((14-(methoxymethoxy)-12-(trifluoromethyl)- 5,6,7,8,9,10-hexahydrobenzo[9,10]cyclodeca[1,2-c]pyridazin-3-yl)amino)piperidine-1- carboxylate (25 mg, 0.044 mmol) in 1,4-dioxane (0.5 mL) was added HCl/1,4-dioxane (0.2 mL, 4 M) and the mixture was stirred at RT for 20 mins. The mixture was basified with sat. aq. NaHCO₃ solution 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 (13 mg) as a solid. LC-MS (ESI) (m/z): 421.5 (M+H)⁺. Step 15: (R)-3-((1-methylpiperidin-3-yl)amino)-12-(trifluoromethyl)-5,6,7,8,9,10- hexahydrobenzo[9,10]cyclodeca[1,2-c]pyridazin-14-ol To a mixture of (R)-3-(piperidin-3-ylamino)-12-(trifluoromethyl)-5,6,7,8,9,10- hexahydrobenzo[9,10]cyclodeca[1,2-c]pyridazin-14-ol (13 mg, 0.031 mmol) and 37% aq. HCHO (0.2 mL) in MeOH (1 mL) was added AcOH (3.8 mg, 0.062 mmol) and NaBH₃CN (5.8 mg, 0.09 mmol) at 0 °C 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*20mm, 5–95% MeCN in H₂O with 0.1% FA) to give the title compound (7 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.14 (s, 1H), 6.97 (s, 1H), 6.86 (s, 1H), 4.36 – 4.21 (m, 1H), 3.61 – 3.47 (m, 1H), 3.20 – 3.09 (m, 1H), 2.90 – 2.72 (m, 2H), 2.69 (s, 3H), 2.66 – 2.54 (m, 2H), 2.50 – 2.41 (m, 1H), 2.39 – 2.30 (m, 1H), 2.17 – 1.99 (m, 2H), 1.93 – 1.80 (m, 1H), 1.76 – 1.60 (m, 3H), 1.58 – 1.44 (m, 2H), 1.33 – 1.21 (m, 2H), 0.77 – 0.61 (m, 2H). LC-MS (ESI) (m/z): 435.5 (M+H)⁺. Example 5 (R)-3-((1-methylpiperidin-3-yl)amino)-11-(trifluoromethyl)-6,7,8,9-tetrahydro-5H- benzo[8,9]cyclonona[1,2-c]pyridazin-13-ol

Step 1: 2-Bromo-3-iodo-5-(trifluoromethyl)phenol To a solution of 2-iodo-6-(methoxymethoxy)-4-(trifluoromethyl)aniline (19 g, 54.7 mmol, intermediate 8 of example 4) in MeCN (80 mL) was added aq. HBr (30 mL, 40% wt.) at 0 °C. The mixture was stirred at 0 °C for 20 mins and a solution of NaNO₂ (3.97 g, 57.5 mmol) in water (20 mL) was added drop-wisely at 0 °C. The mixture was stirred at 0 °C for 1 hr and a solution of CuBr₂ (24.3 g, 109.4 mmol) in MeCN was added drop-wisely at 0 °C. The resulting mixture was stirred at RT for 16 hrs. The mixture was 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 gel, 0–20% EtOAc in PE) to give the title compound (17 g) as an oil. LC-MS (ESI) m/z: 365.0 (M-H)-. Step 2: 2-Bromo-1-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzene To a solution of 2-bromo-3-iodo-5-(trifluoromethyl)phenol (17 g, 46.3 mmol) in DCM (180 mL) were added DIPEA (17.9 g, 139 mmol) followed by drop-wise addition of MOMCl (5.6 g, 69.5 mmol) at 0 °C and the mixture was stirred under N₂ atmosphere at RT 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, 0–10 % EtOAc in PE) to give the title compound (16 g) as an oil.¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 1.1 Hz, 1H), 7.34 (d, J = 1.2 Hz, 1H), 5.27 (s, 2H), 3.52 (s, 3H). Step 3: 4-(5-(2-Bromo-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)pent-4-yn-1-yl)- 3,6-dichloropyridazine To a mixture of 3,6-dichloro-4-(pent-4-yn-1-yl)pyridazine (5.4 g, 25.1 mmol) and 2- bromo-1-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzene (13.4 g, 32.6 mmol) in DMSO (15 mL) were added TEA (15 mL), CuI (0.48 g, 2.51 mmol) and Pd(PPh₃)4 (2.90 g, 2.511 mmol) at RT under N₂ atmosphere. The mixture was stirred at RT for 2 hrs. The mixture was filtered, and the filtrate 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 compound (10 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 5.30 (s, 2H), 3.53 (s, 3H), 3.02 – 2.98 (m, 2H), 2.63 – 2.60 (m, 2H), 2.07 – 1.99 (m, 2H). LC-MS (ESI) m/z: 499.2 (M+H)⁺. Step 4: 2-Bromo-3-(5-(3,6-dichloropyridazin-4-yl)pent-1-yn-1-yl)-5- (trifluoromethyl)phenol To a solution of 4-(5-(2-bromo-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)pent- 4-yn-1-yl)-3,6-dichloropyridazine (8.5 g, 17.1 mmol) in 1,4-dioxane (30 mL) was added HCl/1,4-dioxane (8.5 mL, 4 M) at 0 °C. The mixture was stirred at RT for 3 hrs. The mixture was basified with sat. aq. NaHCO₃ 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 give the title compound (7.2 g) as a solid. LC-MS (ESI) (m/z): 452.9 (M+H)⁺. Step 5: 4-(5-(2-Bromo-3-methoxy-5-(trifluoromethyl)phenyl)pent-4-yn-1-yl)-3,6- dichloropyridazine To a solution of 2-bromo-3-(5-(3,6-dichloropyridazin-4-yl)pent-1-yn-1-yl)-5- (trifluoromethyl)phenol (7.1 g, 15.6 mmol) in MeCN (70 mL) were added K₂CO₃ (6.48 g, 46.9 mmol) and MeI (3.03 g, 23.5 mmol) at RT. The mixture was stirred under N₂ atmosphere at RT 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 under the reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–20% EtOAc in PE) to give the title compound (6.5 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.32 (d, J = 1.1 Hz, 1H), 7.01 (d, J = 1.2 Hz, 1H), 3.96 (s, 3H), 3.02 – 2.98 (m, 2H), 2.60 (t, J = 6.6 Hz, 2H), 2.06 – 1.99 (m, 2H). LC-MS (ESI) (m/z): 468.9 (M+H)⁺. Step 6: Tert-butyl (R)-3-((5-(5-(2-bromo-3-methoxy-5-(trifluoromethyl)phenyl)-pent-4- yn-1-yl)-6-chloropyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of 4-(5-(2-bromo-3-methoxy-5-(trifluoromethyl)phenyl)pent-4-yn-1-yl)- 3,6-dichloropyridazine (6.1 g, 13.0 mmol) in DMSO (60 mL) were added tert-butyl (R)-3- aminopiperidine-1-carboxylate (5.22 g, 26.1 mmol) and KF (2.27 g, 39.1 mmol) at RT under N₂ atmosphere. The mixture was stirred at 110 °C for 6 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 the reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–45% EtOAc in PE) to give the title compound (3.2 g, 39% yield) as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 7.20 (s, 1H), 6.88 (s, 1H), 3.95 (s, 3H), 3.92 – 3.88 (m, 1H), 3.76 – 3.38 (m, 3H), 3.27 – 3.23 (m, 1H), 2.90 – 2.86 (m, 2H), 2.61 (t, J = 6.7 Hz, 2H), 2.05 – 1.95 (m, 4H), 1.58 – 1.51 (m, 2H), 1.40 – 1.28 (m, 9H). LC-MS (ESI) (m/z): 631/633 (M+H)⁺. Step 7: Tert-butyl (R)-3-((5-(5-(2-bromo-3-methoxy-5-(trifluoromethyl)phenyl)-pentyl)- 6-chloropyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((5-(5-(2-bromo-3-methoxy-5- (trifluoromethyl)phenyl)pent-4-yn-1-yl)-6-chloropyridazin-3-yl)amino)piperidine-1- carboxylate (3.2 g, 5.06 mmol) in MeOH (30 mL) was added PtO2 (0.11 g, 0.50 mmol) under N₂ temperature and the mixture was stirred with a H₂ balloon at RT for 5 hrs. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (2.4 g) as an oil. LC-MS (ESI) m/z: 637.4 (M+H)⁺. Step 8: Tert-butyl (R)-3-((6-chloro-5-(5-(3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)pentyl)pyridazin-3-yl)amino)piperidine-1- carboxylate To a mixture of tert-butyl (R)-3-((5-(5-(2-bromo-3-methoxy-5- (trifluoromethyl)phenyl)pentyl)-6-chloropyridazin-3-yl)amino)piperidine-1-carboxylate (1.8 g, 2.83 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.44 g, 5.66 mmol) in 1,4-dioxane (20 mL) were added KOAc (0.83 g, 8.49 mmol) and Pd(dppf)Cl₂.DCM (0.23 g, 0.28 mmol) under N₂ atmosphere, the mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 100 °C for 2 hrs. 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 dryness. The residue was purified by flash chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (1.2 g) as a solid. LC-MS (ESI) m/z: 683.4 (M+H)⁺. Step 9: Tert-butyl (R)-3-((13-methoxy-11-(trifluoromethyl)-6,7,8,9-tetrahydro-5H- benzo[8,9]cyclonona[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((6-chloro-5-(5-(3-methoxy-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)pentyl)pyridazin-3-yl)amino)piperidine- 1-carboxylate (1.2 g, 1.76 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added Na₂CO₃ (0.56 g, 5.27 mmol), RuPhos (0.08 g, 0.176 mmol) and RuPhos Pd G3 (0.15 g, 0.176 mmol) under N₂ atmosphere, the mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 120 °C for 2 hrs. 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 dryness. The residue was purified by flash chromatography (silica gel, 0–40% EtOAc in PE) to give the title compound (0.15 g) as a solid. LC-MS (ESI) m/z: 521.4 (M+H)⁺. Step 10: (R)-13-methoxy-N-(piperidin-3-yl)-11-(trifluoromethyl)-6,7,8,9-tetrahydro-5H- benzo[8,9]cyclonona[1,2-c]pyridazin-3-amine To a solution of tert-butyl (R)-3-((13-methoxy-11-(trifluoromethyl)-6,7,8,9-tetrahydro- 5H-benzo[8,9]cyclonona[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (150 mg, 0.288 mmol) in 1,4-dioxane (2 mL) was added HCl/1,4-dioxane (1 mL, 4 M) and the mixture was stirred at RT for 30 mins. The mixture was basified with sat. aq. NaHCO₃ 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 give the title compound (100 mg) as a solid. LC-MS (ESI) (m/z): 421.3 (M+H)⁺. Step 11: (R)-13-methoxy-N-(1-methylpiperidin-3-yl)-11-(trifluoromethyl)-6,7,8,9- tetrahydro-5H-benzo[8,9]cyclonona[1,2-c]pyridazin-3-amine To a mixture of (R)-13-methoxy-N-(piperidin-3-yl)-11-(trifluoromethyl)-6,7,8,9- tetrahydro-5H-benzo[8,9]cyclonona[1,2-c]pyridazin-3-amine (100 mg, 0.24 mmol) and 37% aq. HCHO (0.2 mL) in MeOH (2 mL) was added AcOH (28.9 mg, 0.48 mmol) and NaBH₃CN (45.2 mg, 0.72 mmol) at 0 °C 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 give the title compound (80 mg) as an oil. LC-MS (ESI) (m/z): 435.3 (M+H)⁺. Step 12: (R)-3-((1-methylpiperidin-3-yl)amino)-11-(trifluoromethyl)-6,7,8,9-tetrahydro- 5H-benzo[8,9]cyclonona[1,2-c]pyridazin-13-ol To a solution of (R)-13-methoxy-N-(1-methylpiperidin-3-yl)-11-(trifluoromethyl)- 6,7,8,9-tetrahydro-5H-benzo[8,9]cyclonona[1,2-c]pyridazin-3-amine (80 mg, 0.184 mmol) in DCM (2 mL) was added BBr3 (184 mg, 0.736 mmol) at -78 °C. The mixture was stirred at -78 °C to RT for 1 hr. The mixture was slowly quenched with sat. aq. NaHCO₃ solution at 0 °C and extracted with DCM three times. 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*20mm, 5–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (7 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.10 (s, 1H), 7.04 (s, 1H), 6.89 (s, 1H), 4.40 – 4.35 (m, 1H), 3.45 – 3.35 (m, 1H), 3.05 – 2.96 (m, 1H), 2.88 – 2.86 (m, 3H), 2.77 – 2.65 (m, 3H), 2.22 – 2.05 (m, 4H), 1.98 – 1.89 (m, 1H), 1.82 – 1.74 (m, 1H), 1.63 – 1.61 (m, 2H), 1.44 – 1.23 (m, 5H). LC-MS (ESI) (m/z): 421.5 (M+H)⁺. Example 6 (R)-3-((1-methylpiperidin-3-yl)amino)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol

Step 1: 1-(Bromomethyl)-2-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzene To a mixture of 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (500 mg, 1.45 mmol) and AIBN (47 mg, 0.29 mmol) in DCE (6 mL)was added NBS (385 mg, 2.17 mmol) under N₂ atmosphere and the reaction mixture was stirred at 80 °C for 18 hours. 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 chromatography (silica gel, 0–5% EtOAc in PE) to give the title compound (550 mg) as an oil.¹H NMR (400 MHz, CDCl₃) δ 7.39 (s, 1H), 7.20 (s, 1H), 5.30 (s, 2H), 4.67 (s, 2H), 3.53 (s, 3H). Step 2: Tert-butyl (R)-3-((6-chloro-5-(3-((2-iodo-3-(methoxymethoxy)-5- (trifluoromethyl)benzyl)oxy)propyl)pyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((6-chloro-5-(3-hydroxypropyl)pyridazin-3- yl)amino)piperidine-1-carboxylate (174 mg, 0.47 mmol) in THF (6 mL) was added NaH (28 mg, 0.70 mmol, 60% dispersion in mineral oil) at 0 °C. After the addition, the mixture was stirred at 0 °C for 20 minutes. 1-(bromomethyl)-2-iodo-3-(methoxymethoxy)-5- (trifluoromethyl)benzene (200 mg, 0.47 mmol) was added to the above mixture at 0 °C and the resulting mixture was stirred at 25 °C for 15 hours. The mixture was poured into ice-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 chromatography (silica gel, 0–4% MeOH in DCM) to give the title compound (146 mg) as a solid. LC-MS (ESI) m/z: 715 (M+1)⁺. Step 3: Tert-butyl (R)-3-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate To a mixture of tert-butyl (R)-3-((6-chloro-5-(3-((2-iodo-3-(methoxymethoxy)-5- (trifluoromethyl)benzyl)oxy)propyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (120 mg, 0.19 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (64 mg, 0.25 mmol) in 1,4-dioxane (6 mL) was added KOAc (49 mg, 0.50 mmol), Pd(dppf)Cl₂ (12 mg, 0.017 mmol) under N₂ atmosphere. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 100 °C for 2 hours. To the above mixture, water (1 mL), K₂CO₃ (69 mg, 0.50 mmol) and RuPhos Pd G3 (14 mg, 0.017 mmol) were added successively under N₂ atmosphere and the resulting mixture was stirred under N₂ atmosphere at 90 °C for 1 hour. 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% MeOH in DCM) to give the title compound (40 mg) as a solid. LC-MS (ESI) m/z: 553 (M+H)⁺. Step 4: (R)-3-(piperidin-3-ylamino)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol hydrochloride A solution of tert-butyl (R)-3-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (40 mg, 0.08 mmol) in DCM (1 mL) and HCl/1,4-dioxane (1 mL, 4M) was stirred at RT for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness to give the title compound (45 mg) as a solid, which was used directly in the next step without further purification. LC-MS (ESI) m/z: 409 (M+H)⁺. Step 5: (R)-3-((1-methylpiperidin-3-yl)amino)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol To a mixture of (R)-3-(piperidin-3-ylamino)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol (45 mg, 0.08 mmol) and paraformaldehyde (7.4 mg, 0.25 mmol) in MeOH (1 mL) was added AcOH (0.001 mL, 0.012 mmol) and NaBH3CN (11.5 mg, 0.18 mmol) at 0 °C under N₂ atmosphere and the mixture was stirred at 25 °C for 0.5 hour. The mixture was quenched with sat. aq. NaHCO₃ solution 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, 5–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (2 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 7.13 (s, 1H), 6.74 (s, 1H), 4.62 – 4.58 (m, 2H), 4.29 (d, J = 13.4 Hz, 1H), 4.18 – 4.12 (m, 1H), 3.78 – 3.76 (m, 1H), 3.22 – 3.14 (m, 1H), 2.84 – 2.76 (m, 1H), 2.65 – 2.60 (m, 1H), 2.40 (s, 3H), 2.36 – 2.29 (m, 1H), 2.14 – 2.08 (m, 1H), 2.07 – 2.02 (m, 1H), 1.90 – 1.84 (m, 1H), 1.77 – 1.69 (m, 3H), 1.49 – 1.40 (m, 1H), 1.35 – 1.28 (m, 1H). LC-MS (ESI) (m/z): 423 (M+H)⁺. Example 7 Methyl (R)-3-(3-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidin-1-yl)propanoate

Step 1: Tert-butyl (R)-3-((4-((benzyloxy)methyl)-13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (80 mg, 0.018 mmol) in MeCN (4 mL) and water (4 mL) were added 2-(benzyloxy)acetic acid (36.1 mg, 0.217 mmol), K₂S₂O₈ (58.9 mg, 0.217 mmol) and AgNO₃ (4.9 mg, 0.029 mmol) successively at RT. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 60 °C for 12 hrs. The mixture was cooled to RT, diluted with ice-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, 0–90% EtOAc in PE) to give the title compound (30 mg, 25% yield) as an oil. LC-MS (ESI) m/z: 673.5 (M+H)⁺. Step 2: Tert-butyl (R)-3-((4-(hydroxymethyl)-13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((4-((benzyloxy)methyl)-13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1-carboxylate (30 mg, 0.045 mmol) in MeOH (2 mL) was added Pd/C (5 mg, 10% wt.) under N₂ temperature and the mixture was stirred under a H₂ balloon at 35 °C for 1 hr. The mixture was filtered, and the filtrate was concentrated to dryness to give the title compound (25 mg, 96% yield) as an oil. LC-MS (ESI) m/z: 583.4 (M+H)⁺. Step 3: (R)-4-(hydroxymethyl)-3-(piperidin-3-ylamino)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol To a solution of tert-butyl (R)-3-((4-(hydroxymethyl)-13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1-carboxylate (25 mg, 0.043 mmol) in DCM (1 mL) was added TFA (0.5 mL) and the mixture was stirred at RT for 1 hr. The mixture was concentrated under reduced pressure to give the title compound (18 mg, 96% yield) as an oil. LC-MS (ESI) (m/z): 439.1 (M+H)⁺. Step 4: Methyl (R)-3-(3-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidin-1-yl)propanoate To a solution of (R)-4-(hydroxymethyl)-3-(piperidin-3-ylamino)-11-(trifluoromethyl)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol (18 mg, 0.041 mmol) in MeOH (1 mL) were added Cs₂CO₃ (26.8 mg, 0.082 mmol) and methyl acrylate (5.3 mg, 0.062 mmol) at 0 °C. The mixture was stirred at RT for 30 mins. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*21 mm, 20–95% MeCN in H₂O with 0.1% NH₄OH) to give the title compound (6 mg, 28% yield) as a solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.15 (v br s, 1H), 7.20 (s, 1H), 7.17 (s, 1H), 6.21 – 6.11 (m, 1H), 5.52 – 5.49 (m, 1H), 4.63 – 4.35 (m, 3H), 4.27 – 4.20 (m, 2H), 3.61 and 3.59 (s, 3H), 3.18 – 3.12 (m, 2H), 2.88 – 2.76 (m, 2H), 2.67 – 2.55 (m, 2H), 2.48 – 2.41 (m, 2H), 2.37 – 2.24 (m, 2H), 2.03 – 1.96 (m, 1H), 1.85 – 1.65 (m, 3H), 1.59 – 1.46 (m, 4H). LC-MS (ESI) (m/z): 525.2 (M+H)⁺. Example 8 (R)-3-(3-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidin-1-yl)propanoic acid, partial formic acid salt

Example 7 ^{Example 8} Step 1: (R)-3-(3-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidin-1-yl)propanoic acid, partial formic acid salt To a solution of methyl (R)-3-(3-((13-hydroxy-4-(hydroxymethyl)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidin- 1-yl)propanoate (2 mg, 0.004 mmol) in a mixture of THF (0.6 mL), MeOH (0.3 mL) and water (0.2 mL) was added LiOH (1.6 mg, 0.04 mmol) at RT and the mixture was stirred at RT for 30 mins. The mixture was filtered, and the residue was purified by prep-HPLC (YMC-Actus Triart C18250*21.2 mm, 10–95% MeCN in H₂O with 0.1% FA) to give the title compound (1 mg, 51% yield) as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.14 (s, 1H), 4.92 – 4.89 (m, 1H), 4.83 – 4.79 (m, 2H), 4.74 – 4.65 (m, 1H), 4.59 – 4.49 (m, 2H), 4.30 – 4.26 (m, 1H), 3.82 – 3.74 (m, 1H), 3.66 – 3.52 (m, 1H), 3.27 – 3.16 (m, 3H), 3.03 – 2.97 (m, 1H), 2.65 – 2.50 (m, 2H), 2.19 – 2.02 (m, 4H), 1.98 – 1.80 (m, 2H), 1.73 – 1.61 (m, 2H). LC-MS (ESI) (m/z): 511.2 (M+H)⁺. Example 9 Methyl (R)-3-(3-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidin-1-yl)propanoate, partial formic salt

Step 1: Methyl (R)-3-(3-((13-hydroxy-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidin-1-yl)propanoate, partial formic acid salt To a mixture of (R)-11-methoxy-3-(piperidin-3-ylamino)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol TFA salt (Intermediate 7, 60 mg, 0.124 mmol), Cs₂CO₃ (160 mg, 0.48 mmol) in MeOH (2 mL) was added methyl prop-2-enoate (15.4 mg, 0.16 mmol) at 0 °C and the mixture was stirred at 25 °C for 20 mins. The mixture was filtered and the filtrate was purified by prep-HPLC (YMC-Actus Triart C18250*21 mm, 10– 95% MeCN in H₂O with 0.1% FA) to give the title compound (20 mg) as a solid. ¹H NMR (400 MHz, CD₃OD) δ 6.71 (s, 1H), 6.48 – 6.42 (m, 2H), 4.59 – 4.54 (m, 1H), 4.17 – 4.11 (m, 1H), 4.11 – 4.02 (m, 1H), 3.80 (s, 3H), 3.75 – 3.71 (m, 1H), 3.67 (s, 3H), 3.18 – 3.00 (m, 2H), 2.78 – 2.68 (m, 3H), 2.61 – 2.54 (m, 3H), 2.32 – 2.24 (m, 1H), 2.23 – 2.13 (m, 2H), 1.99 – 1.91 (m, 1H), 1.84 – 1.78 (m, 1H), 1.75 – 1.65 (m, 3H), 1.51 – 1.40 (m, 1H). LC-MS (ESI) m/z: 457 (M+H)⁺. The examples listed in Error! Reference source not found.2 were prepared following the methods and protocols as those described for the synthesis of Example 9 from Intermediate 7, Intermediate 8, Intermediate 9 or Intermediate 10. Table 2. Examples Prepared Using Procedure for Example 9

Example 20 (R)-3-(3-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin- 3-yl)amino)piperidin-1-yl)propanoic acid

To a solution of methyl (R)-3-(3-((13-hydroxy-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidin-1-yl)propanoate (15 mg, 0.033 mmol) in MeOH (1 mL) and water (0.2 mL) was added LiOH (2.8 mg, 0.066 mmol) and the mixture was stirred at RT for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*21 mm, 20–95% MeCN in H₂O with 0.1% NH₃.H₂O) to give the title compound (9 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.71 (s, 1H), 6.41 (s, 1H), 6.29 (s, 1H), 4.56 – 4.51 (m, 1H), 4.11 – 4.03 (m, 2H), 3.78 (s, 3H), 3.72 – 3.66 (m, 1H), 3.41 – 3.36 (m, 1H), 3.07 – 2.95 (m, 1H), 2.77 – 2.69 (m, 3H), 2.60 – 2.54 (m, 1H), 2.40 (t, J = 7.6 Hz, 2H), 2.31 – 2.15 (m, 3H), 1.98 – 1.92 (m, 1H), 1.82 – 1.76 (m, 1H), 1.74 – 1.64 (m, 3H), 1.48 – 1.39 (m, 1H). LC-MS (ESI) m/z: 443.3 (M+H)⁺. Example 21 (R)-11-methoxy-3-((1-methylpiperidin-3-yl)amino)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol

Step 1: (R)-11-methoxy-3-((1-methylpiperidin-3-yl)amino)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol To a mixture of (R)-11-methoxy-3-(piperidin-3-ylamino)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol (Intermediate 7, 10 mg, 0.027 mmol) and 37% aq. HCHO (4.4 mg, 0.054 mmol) in MeOH (1 mL) was added AcOH (one drop) and NaBH₃CN (5 mg, 0.081 mmol) at 0 °C and the mixture was stirred at RT for 30 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, 5–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (0.43 mg) as a solid. LC-MS (ESI) (m/z): 385 (M+H)⁺. Example 22 (R)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol

Step 1: (R)-3-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-3-yl)amino)-11- methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol To a mixture of (R)-11-methoxy-3-(piperidin-3-ylamino)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol (Intermediate 7, 20 mg, 0.054 mmol) and 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (19 mg, 0.108 mmol) in MeOH (1 mL) was added AcOH (one drop) and NaBH₃CN (10 mg, 0.162 mmol) at 0 °C and the mixture was stirred at RT for 30 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 give the title compound (15 mg) as a solid. LC-MS (ESI) (m/z): 529 (M+H)⁺. Step 2: (R)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol To a solution of (R)-3-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-3- yl)amino)-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol (15 mg, 0.028 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) at 0 °C and the mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (0.4 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.73 (s, 1H), 6.47 & 6.46 (s, 1H), 6.44 & 6.43 (s, 1H), 4.63 – 4.51 (m, 2H), 4.19 – 4.09 (m, 2H), 3.80 (s, 3H), 3.76 – 3.67 (m, 3H), 3.12 – 3.04 (m, 1H), 2.79 – 2.69 (m, 1H), 2.65 – 2.55 (m, 3H), 2.47 – 2.39 (m, 1H), 2.35 – 2.26 (m, 1H), 2.23 – 2.16 (m, 1H), 1.98 – 1.89 (m, 1H), 1.88 – 1.81 (m, 1H), 1.76 – 1.68 (m, 3H), 1.57 – 1.50 (m, 1H). LC-MS (ESI) (m/z): 415 (M+H)⁺. Example 23 Ethyl (2S,5R)-5-((4-cyano-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Step 1: 5-(3-(Benzyloxy)propyl)-3,6-dichloropyridazine-4-carbonitrile To a solution of 3,6-dichloropyridazine-4-carbonitrile (5.0 g, 28.9 mmol) in MeCN (50 mL) and water (50 mL) were added 4-(benzyloxy)butanoic acid (8.42 g, 43.4 mmol), K₂S₂O₈ (8.42 g, 43.4 mmol) and AgNO₃ (983 mg, 5.78 mmol). The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 60 °C for 16 hrs. The mixture was cooled 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, 0–30% EtOAc in PE) to give the title compound (6.51 g) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.35 – 7.28 (m, 5H), 4.45 (s, 2H), 3.63 (t, J = 5.6 Hz, 2H), 3.13 (t, J = 7.2 Hz, 2H), 2.12 – 2.05 (m, 2H). LC-MS (ESI) m/z: 322.1 (M+H)⁺. Step 2: 3,6-Dichloro-5-(3-hydroxypropyl)pyridazine-4-carbonitrile To a solution of 5-(3-(benzyloxy)propyl)-3,6-dichloropyridazine-4-carbonitrile (12.0 g, 37.4 mmol) in DCM (240 mL) was added BCl₃ (74.8 mL, 74.8 mmol, 1 M in DCM) drop- wisely at -10 °C and the mixture was stirred at -10 °C for 2 hrs. The reaction mixture was poured into ice-cooled saturated aq. NaHCO₃ solution 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, 0–50% EtOAc in PE) to give the title compound (4.80 g) as an oil. LC-MS (ESI) m/z: 232.3 (M+H)⁺. Step 3: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((6-chloro-4-cyano-5-(3- hydroxypropyl)pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a solution of 3,6-dichloro-5-(3-hydroxypropyl)pyridazine-4-carbonitrile (4.8 g, 20.8 mmol) in EtOH (50 mL) was added 1-(tert-butyl) 2-ethyl (2S,5R)-5-aminopiperidine-1,2- dicarboxylate (6.22 g, 22.9 mmol) at RT and the mixture was stirred at 60 °C for 12 hrs. The mixture was 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 (3.6 g) as a solid. LC-MS (ESI) (m/z): 468.4 (M+H)⁺. Steps 4-7: Ethyl (2S,5R)-5-((4-cyano-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate The title compound was prepared following methods and protocols as those described in Intermediate 7 Steps 1, 3, 4, and 5 as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.83 (s, 1H), 6.79 (s, 1H), 4.56 – 4.51 (m, 1H), 4.23 – 4.17 (m, 3H), 3.83 – 3.79 (m, 1H), 3.44 – 3.36 (m, 3H), 2.96 – 2.90 (m, 1H), 2.29 – 2.12 (m, 4H), 2.05 – 2.00 (m, 1H), 1.92 – 1.81 (m, 2H), 1.69 – 1.65 (m, 1H), 1.64 – 1.58 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 522.2 (M+H)⁺. Example 24 Ethyl (2S,5R)-5-((13-hydroxy-4-(((methoxycarbonyl)amino)methyl)-11- (trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-2-carboxylate

Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-(aminomethyl)-13-(methoxymethoxy)-11- (trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-cyano-13-(methoxymethoxy)-11- (trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (60 mg, 0.090 mmol) in MeOH (3 mL) were added one drop of FA and Raney Ni (20 mg) under N₂ temperature and the mixture was stirred under a H₂ balloon at RT for 6 hrs. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (60 mg) as a solid. LC-MS (ESI) m/z: 670.3 (M+H)⁺. Step 2: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-(((methoxycarbonyl)amino)methyl)-13- (methoxymethoxy)-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-(aminomethyl)-13- (methoxymethoxy)-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (60 mg, 0.090 mmol) in DCM (2 mL) was added TEA (27 mg, 0.27 mmol) followed by methyl chloroformate (13 mg, 0.14 mmol) under N₂ temperature at 0 °C and the mixture was stirred under N₂ at RT for 1.5 hrs. The reaction was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to dryness to give the title compound (40 mg) as a solid. LC-MS (ESI) (m/z): 728 (M+H)⁺. Step 3: Ethyl (2S,5R)-5-((13-hydroxy-4-(((methoxycarbonyl)amino)methyl)-11- (trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4- (((methoxycarbonyl)amino)methyl)-13-(methoxymethoxy)-11-(trifluoromethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (40 mg, 0.05 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) at 0 °C and the mixture was stirred at 25 °C for 20 mins. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18, 20–95% MeCN in water with 0.1% NH₃ ^.H₂O) to give the title compound (3.61 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.82 (s, 1H), 6.80 (s, 1H), 4.57 – 4.53 (m, 1H), 4.34 – 4.20 (m, 6H), 3.92 – 3.76 (m, 3H), 3.71 (s, 3H), 3.36 – 3.34 (m, 1H), 3.12 – 3.02 (m, 1H), 2.80 – 2.65 (m, 1H), 2.42 – 2.25 (m, 2H), 2.19 – 2.09 (m, 1H), 1.86 – 1.67 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m/z: 584.3 (M+H)⁺. Example 25 Ethyl (2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-(acetoxymethyl)-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-5-(3-((tert-butyldimethylsilyl)oxy)propyl)pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a mixture of 3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 5-(trifluoromethyl)benzyl acetate (Intermediate 5, 50 mg, 0.124 mmol) and 1-(tert-butyl) 2- ethyl (2R,5S)-5-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloropyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (Intermediate 2, 68.9 mg, 0.124 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added K₃PO₄ (78.8 mg, 0.371 mmol) and SPhos Pd G2 (17.8 mg, 0.025 mmol) at RT under N₂ atmosphere, the mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 100 °C 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– 60% EtOAc in PE) to give the title compound (55 mg) as an oil. LC-MS (ESI) m/z: 799 (M+H)⁺. Step 2: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-(2- (hydroxymethyl)-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a mixture of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-(acetoxymethyl)-6- (methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-(3-((tert- butyldimethylsilyl)oxy)propyl)pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (55 mg, 0.069 mmol) in EtOH (2 mL) was added K₂CO₃ (19.1 mg, 0.138 mmol) at RT and the mixture was stirred at 30 °C for 1 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to dryness to give the title compound (40 mg) as a solid. LC-MS (ESI) m/z: 757 (M+H)⁺. Step 3: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-(hydroxymethyl)-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate To a mixture of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((5-(3-((tert- butyldimethylsilyl)oxy)propyl)-6-(2-(hydroxymethyl)-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (40 mg, 0.053 mmol) in THF (1 mL) was added TBAF (0.106 mL, 0.106 mmol, 1 M in THF) at RT and the mixture was stirred at RT for 1 hr. 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, 0–5% MeOH in DCM) to give the title compound (30 mg) as a solid. LC-MS (ESI) m/z: 643.4 (M+H)⁺. Step 4: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-(bromomethyl)-6-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate To a mixture of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-(hydroxymethyl)-6- (methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-(3-hydroxypropyl)pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (30 mg, 0.047 mmol) in DCM (5 mL) was added 4A molecular sieves (20 mg), PPh₃ (19.1 mg, 0.138 mmol) and CBr₄ (23.2 mg, 0.070 mmol) at - 78 °C. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 30 °C for 30 mins. The mixture was filtered and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–15% MeOH in DCM) to give the title compound (15 mg) as a solid. LC-MS (ESI) m/z: 705/707 (M+H)⁺. Step 5: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate To a mixture of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-(bromomethyl)-6- (methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-(3-hydroxypropyl)pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (15 mg, 0.021 mmol) in chloroform (2 mL) was added DTBMP (10.9 mg, 0.053 mmol) and AgOTf (8.2 mg, 0.032 mmol) at RT. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at RT for 1 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–15% MeOH in DCM) to give the title compound (9 mg) as a solid. LC-MS (ESI) m/z: 625 (M+H)⁺. Step 6: Ethyl (2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (9 mg, 0.014 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) and the mixture was stirred at RT for 2 hrs. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 10–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (1.4 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.12 (s, 1H), 6.73 (s, 1H), 4.613 & 4.609 (d, both J = 13.4 Hz, 1H), 4.29 ( d, J = 13.4 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.95 – 3.89 (m, 1H), 3.79 – 3.75 (m, 1H), 3.49 – 3.41 (m, 2H), 3.37 – 3.34 (m, 1H), 2.65 – 2.59 (m, 1H), 2.47 – 2.41 (m, 1H), 2.28 – 2.23 (m, 1H), 2.17 – 2.09 (m, 2H), 1.77 – 1.70 (m, 2H), 1.63 – 1.51 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 481.4 (M+H)⁺. Example 26 Ethyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-2-carboxylate, partial formic acid

Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-(2- (hydroxymethyl)-4-methoxy-6-(methoxymethoxy)phenyl)pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((5-(3-((tert- butyldimethylsilyl)oxy)propyl)-6-chloropyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (Intermediate 2, 1.3 g, 2.34 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was added 5- methoxy-7-(methoxymethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (Intermediate 3, 786 mg, 3.51 mmol), K₃PO₄ (1.5 g, 7.08 mmol) and SPhos Pd G₂ (337 mg, 0.467 mmol) under N₂ atmosphere at RT. The mixture was degassed with N₂ three times and stirred under N₂ at 100 °C for 1.5 hrs. The mixture was diluted with water 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, 0–70% EtOAc in PE) to give the title compound (1.4 g) as a solid. LC-MS (ESI) (m/z): 719 (M+H)⁺. Step 2: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-(hydroxymethyl)-4-methoxy-6- (methoxymethoxy)phenyl)-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((5-(3-((tert- butyldimethylsilyl)oxy)propyl)-6-(2-(hydroxymethyl)-4-methoxy-6- (methoxymethoxy)phenyl)pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (1.3 g, 1.81 mmol) in THF (15 mL) was added TBAF (1 g, 2.68 mmol, 70% wt. in water) under N₂ temperature at 0 °C and the mixture was stirred under N₂ at RT for 3 hrs. The reaction was quenched with sat. aq. NH₄Cl solution at 0 °C 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, 0–10% MeOH in DCM) to give the title compound (800 mg) as a solid. LC-MS (ESI) (m/z): 605 (M+H)⁺. Step 3: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-(bromomethyl)-4-methoxy-6- (methoxymethoxy)phenyl)-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-(hydroxymethyl)-4-methoxy-6- (methoxymethoxy)phenyl)-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate (800 mg, 1.32 mmol) in DCM (32 mL) was added 4A molecular sieves (250 mg), CBr₄ (657 mg, 1.98 mmol) and PPh₃ (415 mg, 1.58 mmol) successively under N₂ atmosphere at -78 °C. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 30 °C for 30 mins. The mixture was filtered and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–15% MeOH in DCM) to give the title compound (480 mg) as a solid. LC-MS (ESI) (m/z): 667 (M+H)⁺. Step 4: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-(bromomethyl)-4-methoxy-6- (methoxymethoxy)phenyl)-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate (500 mg, 0.751 mmol) in chloroform (5 mL) was added AgOTf (290 mg, 1.13 mmol) and DTBMP (385 mg, 1.88 mmol) under N₂ temperature at RT and the mixture was stirred under N₂ atmosphere at RT overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–15% MeOH in DCM) to give the title compound (248 mg) as a solid. LC-MS (ESI) (m/z): 587 (M+H)⁺. Step 5: Ethyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate, partial TFA salt To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (50 mg, 0.085 mmol) in DCM (1 mL) was added HCl in 1,4-dioxane (1 mL, 4 M) and the mixture was stirred at RT for 2 hrs. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*21 mm, 10–95% MeCN in H₂O with 0.1% FA) to give the title compound (6 mg) as a solid. ¹H NMR (400 MHz, CD₃OD) δ 6.87 (s, 1H), 6.50 – 6.46 (m, 2H), 4.56 & 4.55 (d, both J = 13.4 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.23 – 4.14 (m, 2H), 4.02 – 3.96 (m, 1H), 3.82 (s, 3H), 3.81 – 3.75 (m, 2H), 3.40 – 3.34 (m, 1H), 2.83 – 2.74 (m, 1H), 2.69 – 2.62 (m, 1H), 2.47 – 2.39 (m, 1H), 2.32 – 2.21 (m, 2H), 1.95 – 1.85 (m, 1H), 1.81 – 1.69 (m, 3H), 1.34 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m/z: 443.3 (M+H)⁺. Example 27

The title compound was prepared following methods and protocols as those described for the synthesis of Intermediate 7 as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.78 (br s, 1H), 7.24 (t, J = 74.1 Hz, 1H), 6.68 (s, 1H), 6.64 & 6.63 (s, 1H), 6.57 & 6.56 (s, 1H), 6.40 (d, J = 7.5 Hz, 1H), 4.35 & 4.33 (d, both J = 13.1 Hz, 1H), 4.15 – 4.06 (m, 3H), 3.86 – 3.74 (m, 1H), 3.66 – 3.59 (m, 1H), 3.29 – 3.25 (m, 2H), 3.24 – 3.13 (m, 2H), 2.49 – 2.43 (m, 1H), 2.37 – 2.28 (m, 1H), 2.12 – 2.05 (m, 1H), 2.00 – 1.88 (m, 2H), 1.67 – 1.40 (m, 4H), 1.21 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m/z: 479.3 (M+H)⁺. Example 28 Isopropyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Step 1: (2S,5R)-1-(tert-butoxycarbonyl)-5-((11-methoxy-13-(methoxymethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((11-methoxy-13-(methoxymethoxy)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate (50 mg, 0.085 mmol) in MeOH (1 mL) and water (0.5 mL) was added LiOH (6.1 mg, 0.255 mmol) at RT and the mixture was stirred at RT for 3 hrs. The mixture was acidified with 1 N aq. HCl 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 to give the title compound (30 mg) as a solid. LC-MS (ESI) (m/z): 559 (M+H)⁺. Step 2: Isopropyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate To a solution of (2S,5R)-1-(tert-butoxycarbonyl)-5-((11-methoxy-13- (methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-2-carboxylic acid (30 mg, 0.054 mmol) in isopropyl alcohol (1.5 mL) was added SOCl₂ (0.1 mL) at RT and the mixture was stirred at 70 °C for 2 hrs. The mixture was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (5 mg) as a solid.¹H NMR (400 MHz, DMSO-d6)) δ 9.30 (s, 1H), 6.55 & 6.54 (s, 1H), 6.46 (s, 1H), 6.403 & 6.399 (s, 1H), 6.34 (d, J = 7.6 Hz, 1H), 4.99 – 4.89 (m, 1H), 4.33 & 4.32 (d, J = 12.8 Hz, 1H), 4.05 (d, J = 12.8 Hz, 1H), 3.85 – 3.77 (m, 1H), 3.76 (s, 3H), 3.63 – 3.56 (m, 1H), 3.30 – 3.16 (m, 4H), 2.48 – 2.42 (m, 1H), 2.38 – 2.29 (m, 1H), 2.12 – 2.05 (m, 1H), 2.00 – 1.92 (m, 2H), 1.67 – 1.38 (m, 4H), 1.22 (d, J = 6.1 Hz, 3H), 1.21 (d, J = 6.1 Hz, 3H). LC-MS (ESI) (m/z): 457.2 (M+H)⁺. Example 29 Isopropyl (2R,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Step 1: (2R,5R)-1-(tert-butoxycarbonyl)-5-((11-methoxy-13-(methoxymethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((11-methoxy-13-(methoxymethoxy)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate (90 mg, 0.154 mmol) in EtOH (1 mL) was added EtONa/EtOH solution (1 mL, 20% wt.) at RT. The mixture was stirred at 30 °C for 6 hrs. The mixture was acidified with 1 N aq. 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 chiral SFC to give (2S,5R)-1-(tert-butoxycarbonyl)-5- ((11-methoxy-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-2-carboxylic acid (60 mg, peak 1, Rt= 4.156 min) and (2R,5R)-1-(tert- butoxycarbonyl)-5-((11-methoxy-13-(methoxymethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid (15 mg, peak 2, Rt= 8.972 min) as solids. Chiral SFC condition: Column: (R,R)-WHELK, 250×30mm I.D., 5µm; Mobile phase: A= CO₂ and B= IPA (0.1% 2mol/L DEA in MeOH); Gradient: B 33%; Flow rate: 60 mL/min. LC/MS (ESI) m/z: 559.3 (M+H)⁺. Step 2: Isopropyl (2R,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate To a solution of (2R,5R)-1-(tert-butoxycarbonyl)-5-((11-methoxy-13- (methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-2-carboxylic acid (15 mg, 0.027 mmol) in EtOH (1 mL) was added SOCl₂ (0.05 mL) and the mixture was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*21 mm, 10–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (3.8 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.73 (s, 1H), 6.46 (d, J = 2.3 Hz, 1H), 6.43 (d, J = 2.3 Hz, 1H), 5.09 – 5.03 (m, 1H), 4.57 – 4.54 (m, 2H), 4.13 (d, J = 13.1 Hz, 1H), 4.06 – 4.02 (m, 1H), 3.80 (s, 3H), 3.74 – 3.71 (m, 1H), 3.49 – 3.47 (m, 1H), 3.06 – 3.03 (m, 1H), 2.60 – 2.55 (m, 1H), 2.21 – 2.16 (m, 1H), 2.06 – 2.00 (m, 1H), 1.95 – 1.86 (m, 4H), 1.74 – 1.68 (m, 2H), 1.282 (d, J = 6.2 Hz, 3H), 1.275 (d, J = 6.3 Hz, 3H). LC-MS (ESI) m/z: 457.3 (M+H)⁺. Example 30 Ethyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)-1-methylpiperidine-2-carboxylate

Step 1: Ethyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)-1-methylpiperidine-2- carboxylate To a mixture of ethyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate (10 mg, 0.022 mmol) and 37% aq. HCHO (0.1 mL) in MeOH (1 mL) were added AcOH (2.7 mg, 0.045 mmol) and NaBH₃CN (4.3 mg, 0.068 mmol) at 0 °C 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 (2.2 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.72 & 6.71 (s, 1H), 6.46 (d, J = 2.2 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 4.55 (d, J = 13.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.13 (d, J = 13.1 Hz, 1H), 4.12 – 4.05 (m, 1H), 3.80 (s, 3H), 3.74 – 3.71 (m, 1H), 3.38 – 3.34 (m, 2H), 2.78 – 2.75 (m, 1H), 2.60 – 2.55 (m, 1H), 2.28 (s, 3H), 2.24 – 2.15 (m, 2H), 2.08 – 1.99 (m, 2H), 1.82 – 1.68 (m, 3H), 1.42 – 1.39 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 457.2 (M+H)⁺. Example 31 (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid

To a solution of ethyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate (10 mg, 0.02 mmol) in MeOH (0.2 mL) and water (0.2 mL) was added LiOH (2.7 mg, 0.11 mmol) at 0 °C and the mixture was stirred at RT for 1 hr. The mixture was purified by prep-HPLC (YMC – Actus TriartC18250*20 mm, 5 µm, 30–95% MeCN in water with 0.1% NH₄HCO₃) to give the title compound (1.2 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.70 (s, 1H), 6.46 (d, J = 2.2 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 4.55 & 4.54 (d, both J = 13.1 Hz, 1H), 4.21 – 4.03 (m, 2H), 3.80 (s, 3H), 3.76 – 3.61 (m, 2H), 3.41 – 3.33 (m, 2H), 2.67 – 2.54 (m, 2H), 2.38 – 2.29 (m, 1H), 2.25 – 2.15 (m, 2H), 1.81 – 1.57 (m, 4H). LC-MS (ESI) (m/z): 415.1 (M+H)⁺. Example 32 (2S,5R)-5-((13-Hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)-1-methylpiperidine-2-carboxylic acid O O

Example 30 ^{Example 32} To a mixture of ethyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)-1-methylpiperidine-2-carboxylate (15.0 mg, 0.033 mmol) in MeOH (0.5 mL) and water (0.5 mL) was added LiOH (6.9 mg, 0.164 mmol) at 0 °C and the mixture was stirred at RT for 3 hrs. The mixture was filtered and the filtrate was purified by prep-HPLC (YMC – Actus Triart C18250*20 mm, 5 µm, 15–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (2 mg) as a solid. ¹H NMR (400 MHz, CD₃OD) δ 6.72 (s, 1H), 6.47 (d, J = 2.3 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 4.54 (d, J = 13.2 Hz, 1H), 4.25 – 4.15 (m, 1H), 4.13 ( d, J = 13.2 Hz, 1H), 3.80 (s, 3H), 3.76 – 3.63 (m, 2H), 3.38 – 3.34 (m, 2H), 2.75 (br s, 3H), 2.62 – 2.42 (m, 2H), 2.33 – 2.26 (m, 1H), 2.23 – 2.16 (m, 2H), 1.94 – 1.83 (m, 1H), 1.73 – 1.68 (m, 2H), 1.62 – 1.53 (m, 1H). LC-MS (ESI) (m/z): 429.4 (M+H)⁺. Example 33 & Example 34 Ethyl (2R,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-2-carboxylate & Ethyl (2R,5R)-5-((13-hydroxy-11- methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)-1- methylpiperidine-2-carboxylate

The title compounds were prepared following methods and protocols as those described for the synthesis of Example 29 & Example 30 as a solid. Example 33: LC-MS (ESI) (m/z): 443.2 (M+H)⁺. Example 34: ¹H NMR (400 MHz, CD₃OD) δ 6.75 (s, 1H), 6.463 & 6.458 (s, 1H), 6.436 & 6.433 (s, 1H), 4.56 & 4.55 (d, both J = 13.3 Hz, 1H), 4.24 – 4.17 (m, 3H), 4.13 (d, d, J = 13.2 Hz, 1H), 3.80 (s, 3H), 3.75 – 3.70 (m, 1H), 3.37 – 3.34 (m, 1H), 3.03 – 2.98 (m, 2H), 2.65 – 2.56 (m, 2H), 2.34 & 2.33 (s, 3H), 2.22 – 2.15 (m, 1H), 1.96 – 1.83 (m, 3H), 1.76 – 1.69 (m, 3H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 457.3 (M+H)⁺. Example 35 (2R,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid

The title compound was prepared following methods and protocols as those described for the synthesis of Example 31 as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.80 (s, 1H), 6.47 – 6.45 (m, 2H), 4.55 & 4.54 (d, both J = 13.2 Hz, 1H), 4.29 – 4.24 (m, 1H), 4.15 & 4.14 (d, both J = 13.3 Hz, 1H), 3.81 (s, 3H), 3.77 – 3.72 (m, 1H), 3.70 – 3.67 (m, 1H), 3.58 – 3.53 (m, 1H), 3.38 – 3.32 (m, 2H), 2.64 – 2.58 (m, 1H), 2.30 – 2.10 (m, 3H), 2.07 – 1.99 (m, 1H), 1.90 – 1.84 (m, 1H), 1.73 – 1.71 (m, 2H). LC-MS (ESI) (m/z): 415.3 (M+H)⁺. Example 36 (2R,5R)-5-((13-Hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)-1-methylpiperidine-2-carboxylic acid

The title compound was prepared following methods and protocols as those described for the synthesis of Example 32 as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.01 (s, 1H), 6.49 (s, 2H), 4.56 & 4.55 (d, both J = 13.4 Hz, 1H), 4.35 – 4.30 (m, 1H), 4.175 & 4.170 (d, J = 13.7 & 13.5 Hz, 1H), 3.82 (s, 3H), 3.82 – 3.77 (m, 2H), 3.58 – 3.53 (m, 1H), 3.38 – 3.33 (m, 2H), 2.91 (s, 3H), 2.73 – 2.65 (m, 1H), 2.32 – 2.16 (m, 3H), 2.06 – 1.99 (m, 1H), 1.94 – 1.87 (m, 1H), 1.80 – 1.71 (m, 2H). LC-MS (ESI) (m/z): 429.3 (M+H)⁺. Example 37 Methyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-2-carboxylate

The title compound was prepared following methods and protocols as those described for the synthesis of Example 28 as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.71 (s, 1H), 6.48 (s, 1H), 6.45 (s, 1H), 4.60 – 4.55 (m, 1H), 4.17 – 4.12 (m, 1H), 3.95 – 3.88 (m, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.75 – 3.71 (m, 1H), 3.46 – 3.36 (m, 3H), 2.61 – 2.55 (m, 1H), 2.48 – 2.42 (m, 1H), 2.28 – 2.14 (m, 3H), 1.75 – 1.52 (m, 4H). LC-MS (ESI) (m/z): 429.2 (M+H)⁺. Example 38 Methyl (2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

The title compound was prepared following methods and protocols as those described for the synthesis of Example 28 as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.12 (s, 1H), 6.72 (s, 1H), 4.605 & 4.600 (d, J = 13.3 Hz, 1H), 4.26 (d, J = 13.4 Hz, 1H), 3.95 – 3.89 (m, 1H), 3.78 – 3.74 (m, 1H), 3.74 (s, 3H), 3.48 – 3.34 (m, 3H), 2.63 – 2.60 (m, 1H), 2.47 – 2.41 (m, 1H), 2.26 – 2.23 (m, 1H), 2.17 – 2.06 (m, 2H), 1.75 – 1.70 (m, 2H), 1.66 – 1.51 (m, 2H). LC-MS (ESI) (m/z): 467.2 (M+H)⁺. Example 39 Ethyl (2S,5R)-5-((13-hydroxy-4-(hydroxymethyl)-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Steps 1-4: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-((benzyloxy)methyl)-11-methoxy-13- (methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate The title compound was prepared following methods and protocols as those described in Intermediate 7 Steps 1-4 as a solid. LC-MS (ESI) m/z: 707 (M+H)⁺. Step 5: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-(hydroxymethyl)-11-methoxy-13- (methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazine-3- yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-((benzyloxy)methyl)-11-methoxy- 13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazine-3- yl)amino)piperidine-1,2-dicarboxylate (110 mg, 0.20 mmol) in MeOH (2 mL) was added Pd/C (5 mg, 10% wt.) under N₂ atmosphere and the mixture was stirred under a H₂ balloon at 45 °C for 6 hrs. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (85 mg) as a solid. LC-MS (ESI) m/z: 617 (M+H)⁺. Step 6: Ethyl (2S,5R)-5-((13-hydroxy-4-(hydroxymethyl)-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-(hydroxymethyl)-11-methoxy-13- (methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazine-3- yl)amino)piperidine-1,2-dicarboxylate (35 mg, 0.057 mmol) in DCM (2 mL) was added TFA (1 mL) at 0 °C and the mixture was stirred at RT for 8 hours. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*21 mm, 20–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (2.3 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.47 (d, J = 2.3 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 4.80 – 4.73 (m, 2H), 4.63 – 4.58 (m, 1H), 4.57 – 4.51 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.16 – 4.10 (m, 1H), 3.81 (s, 3H), 3.75 – 3.70 (m, 1H), 3.55 – 3.49 (m, 1H), 3.42 – 3.36 (m, 2H), 2.97 – 2.90 (m, 1H), 2.50 – 2.43 (m, 1H), 2.32 – 2.25 (m, 1H), 2.19 – 2.12 (m, 2H), 1.70 – 1.57 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m/z: 473.2 (M+H)⁺. Example 40 Ethyl (2S,5R)-5-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate Example 41 Ethyl (2S,5R,S_a)-5-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate Example 42 Ethyl (2S,5R,R_a)-5-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-((benzyloxy)methyl)-13-(methoxymethoxy)- 11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (45 mg, 0.072 mmol) in MeCN (1 mL) and water (1 mL) were added 2-(benzyloxy)acetic acid (15.6 mg, 0.094 mmol), K₂S₂O₈ (29.3 mg, 0.108 mmol) and AgNO₃ (2.5 mg, 0.014 mmol) successively at RT. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 60 °C for 6 hrs. The mixture was cooled to RT, diluted with ice/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, 0–5% MeOH in DCM) to give the title compound (20 mg) as an oil. LC-MS (ESI) m/z: 745.4 (M+H)⁺. Step 2: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-(hydroxymethyl)-13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-((benzyloxy)methyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (20 mg, 0.027 mmol) in MeOH (2 mL) was added Pd/C (5 mg, 10% wt.) and one drop of FA under N₂ temperature and the mixture was stirred under a H₂ balloon at 35 °C for 4 hrs. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (16 mg) as an oil. LC-MS (ESI) m/z: 655.3 (M+H)⁺. Step 3: Ethyl (2S,5R)-5-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-(hydroxymethyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (16 mg, 0.043 mmol) in DCM (1 mL) was added TFA (0.5 mL) and the mixture was stirred at RT for 1 hr. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give Example 40 (1.5 mg) as a solid, which was further resolved by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5–95% MeCN in H₂O with 0.1% NH₃.H₂O) to give Example 41 (eluted second) and Example 42 (eluted first) as solids. The structures of epimers arising from axial chirality such as in Examples 41 and 42 were tentatively assigned based on more active epimer having similar confirmation as that observed for Example 6 in its Cyro-EM structure bound to NLRP3 protein. This interpretation of the data was also consistent with computational docking results. This assignment method was also used for other examples. Example 40: ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.13 (s, 1H), 4.81 – 4.74 (m, 2H), 4.63 – 4.56 (m, 2H), 4.30 – 4.28 (d, J = 13.4 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.19 – 4.13 (m, 1H), 3.79 – 3.74 (m, 1H), 3.54 – 3.50 (m, 1H), 3.40 – 3.37 (m, 1H), 3.00 – 2.95 (m, 1H), 2.53 – 2.45 (m, 1H), 2.32 – 2.25 (m, 1H), 2.21 – 2.16 (m, 1H), 2.09 – 2.02 (m, 2H), 1.69 – 1.55 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 511.3 (M+H)⁺. Example 41: LC-MS (ESI) (m/z): 511.3 (M+H)⁺. Example 42: ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.13 (s, 1H), 4.81 – 4.77 (m, 1H), 4.61 – 4.57 (m, 2H), 4.30 – 4.27 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.16 – 4.10 (m, 1H), 3.78 – 3.75 (m, 1H), 3.54 – 3.51 (m, 1H), 3.41 – 3.38 (m, 1H), 3.34 – 3.33 (m, 1H), 3.00 – 2.96 (m, 1H), 2.53 – 2.47 (m, 1H), 2.29 – 2.26 (m, 1H), 2.17 – 2.13 (m, 1H), 2.10 – 2.03 (m, 1H), 1.71 – 1.57 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 511.3 (M+H)⁺. LC-MS (ESI) (m/z): 511.3 (M+H)⁺. Example 43 Ethyl (2S,5R)-5-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

The title compound was prepared following methods and protocols as those described in Example 39 Steps 4–9 from Intermediate 3 & Intermediate 12 as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.81 (s, 1H), 6.78 (s, 1H), 4.83 – 4.75 (m, 2H), 4.63 – 4.54 (m, 2H), 4.24 – 4.17 (m, 3H), 4.17 – 4.09 (m, 1H), 3.81 – 3.73 (m, 1H), 3.55 – 3.48 (m, 1H), 3.42 – 3.37 (m, 1H), 3.01 – 2.94 (m, 1H), 2.54 – 2.45 (m, 1H), 2.33 – 2.25 (m, 1H), 2.19 – 2.07 (m, 2H), 1.73 – 1.56 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 527.2 (M+H)⁺. Example 44 Ethyl (2S,5R)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-((carbamoyloxy)methyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a mixture of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-(hydroxymethyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (60 mg, 0.091 mmol) and TEA (28.1 mg, 0.275 mmol) in DCM (2 mL) was added trichloroacetyl isocyanate (25.7 mg, 0.136 mmol) at 0 °C and the mixture stirred at RT for 1 hr. The mixture was concentrated under reduced pressure to dryness. The residue was dissolved in MeOH (1 mL) and the resulting mixture was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure to dryness to give the title compound (40 mg) as a solid. LC-MS (ESI) m/z: 698.3 (M+H)⁺. Step 2: Ethyl (2S,5R)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-(trifluoromethyl)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2- carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-((carbamoyloxy)methyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (40 mg, 0.057 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) and the mixture was stirred at RT for 1 hr. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (8 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 7.14 (s, 1H), 5.275 & 5.269 (d, both J = 13.1 Hz, 1H), 5.079 & 5.075 (d, both J = 13.1 Hz, 1H), 4.61 – 4.57 (m, 1H), 4.29 (d, J = 13.5 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.20 – 4.12 (m, 1H), 3.79 – 3.76 (m, 1H), 3.55 – 3.41 (m, 2H), 3.13 – 3.09 (m, 1H), 2.53 – 2.47 (m, 1H), 2.28 – 2.26 (m, 1H), 2.21 – 2.03 (m, 3H), 1.82 – 1.59 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 554.2 (M+H)⁺. Example 45 Ethyl (2S,5R)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

The title compound was prepared following methods and protocols as those described for the synthesis of Example 44 as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.46 (s, 1H), 6.44 (s, 1H), 5.28 – 5.24 (m, 1H), 5.08 – 5.04 (m, 1H), 4.57 – 4.50 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.16 – 4.08 (m, 2H), 3.80 (s, 3H), 3.76 – 3.68 (m, 1H), 3.53 – 3.46 (m, 1H), 3.41 – 3.35 (m, 2H), 3.10 – 3.02 (m, 1H), 2.54 – 2.46 (m, 1H), 2.31 – 2.12 (m, 3H), 1.79 – 1.57 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 516.4 (M+H)⁺. Example 46 (R)-13-fluoro-N-(1-methylpiperidin-3-yl)-11-(trifluoromethyl)-7,8-dihydro-5H- benzo[8,9][1,4]dioxonino[7,6-c]pyridazin-3-amine, partial formic acid salt

Step 1: Tert-butyldimethyl(2-(prop-2-yn-1-yloxy)ethoxy)silane To a solution of 2-(prop-2-yn-1-yloxy)ethan-1-ol (30 g, 299 mmol) in DCM (240 mL) were added imidazole (30.6 g, 449 mmol) and TBSCl (54.2 g, 359 mmol) at 0 °C and the mixture was stirred at RT overnight. The mixture was diluted with water and extracted with DCM twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under the reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–10% EtOAc in PE) to give the title compound (50.6 g) as an oil. ¹H NMR (400 MHz, CD₃OD) δ 4.19 – 4.18 (m, 2H), 3.80 – 3.77 (m, 2H), 3.60 – 3.58 (m, 2H), 2.81 – 2.80 (m, 1H), 0.91 (s, 9H), 0.09 (s, 6H). Step 2: 4-((2-((Tert-butyldimethylsilyl)oxy)ethoxy)methyl)-3,6-dichloropyridazine To a solution of tert-butyldimethyl(2-(prop-2-yn-1-yloxy)ethoxy)silane (28 g, 132 mmol) in toluene (200 mL) was added 3,6-dichloro-1,2,4,5-tetrazine (10 g, 66 mmol) at RT under N₂ atmosphere and the mixture was stirred at 100 °C overnight. The mixture was 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 (10 g) as an oil. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 4.63 (s, 2H), 3.87 – 3.84 (m, 2H), 3.73 – 3.71 (m, 2H), 0.90 (s, 9H), 0.08 (s, 6H). LC-MS (ESI) m/z: 337.3 (M+H)⁺. Step 3: Tert-butyl (R)-3-((5-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-6- chloropyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of 4-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-3,6- dichloropyridazine (5.7 g, 16.9 mmol) in DMSO (80 mL) was added DIPEA (6.55 g, 50.7 mmol) and tert-butyl (R)-3-aminopiperidine-1-carboxylate (6.77 g, 33.8 mmol) at RT. The mixture was stirred at 150 °C 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 the reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (2.6 g) as an oil. LC-MS (ESI) (m/z): 501.2 (M+H)⁺. Step 4: Tert-butyl (3R)-3-((5-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-6-(2- fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-1- carboxylate To a solution of tert-butyl (R)-3-((5-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)- 6-chloropyridazin-3-yl)amino)piperidine-1-carboxylate (3.2 g, 6.4 mmol) in 1,4-dioxane (30 mL) and water (6 mL) were added (2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (1.72 g, 7.68 mmol), RuPhos (298 mg, 0.64 mmol), RuPhos Pd G3 (535 mg, 0.64 mmol) and Na₂CO₃ (2.04 g, 19.2 mmol) at RT under N₂ atmosphere. The mixture was degassed with N₂ three times and stirred under N₂ atmosphere at 100 °C for 4 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 the reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–30% EtOAc in PE) to give the title compound (2.51 g) as a solid.¹H NMR (400 MHz, CDCl₃) δ 7.16 (s, 1H), 7.07 (s, 1H), 6.94 – 6.91 (m, 1H), 4.97 (bs, 1H), 4.45 (s, 2H), 4.13 – 4.06 (m, 1H), 3.77 – 3.74 (m, 2H), 3.56 – 3.53 (m, 2H), 3.50 – 3.38 (m, 3H), 2.02 – 1.97 (m, 1H), 1.80 – 1.74 (m, 2H), 1.64 – 1.58 (m, 2H), 1.43 (s, 9H), 0.86 (s, 9H), 0.03 (s, 6H). LC-MS (ESI) (m/z): 645.3 (M+H)⁺. Step 5: Tert-butyl (3R)-3-((6-(2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)-5-((2- hydroxyethoxy)methyl)pyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (3R)-3-((5-((2-((tert- butyldimethylsilyl)oxy)ethoxy)methyl)-6-(2-fluoro-6-hydroxy-4- (trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (580 mg, 0.899 mmol) in THF (6 mL) was added TBAF (469 mg, 1.80 mmol) at 0 °C and the mixture was stirred at RT for 4 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, 0–50% EtOAc in PE) to give the title compound (357 mg) as an oil. LC-MS (ESI) (m/z): 531.5 (M+H)⁺. Step 6: Tert-butyl (R)-3-((13-fluoro-11-(trifluoromethyl)-7,8-dihydro-5H- benzo[8,9][1,4]dioxonino[7,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate To the solution of tert-butyl (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-1-carboxylate (130 mg, 0.245 mmol) in THF (3 mL) were added tri-tert-butylphosphine (99.3 mg, 0.491 mmol) and TMAD (84.5 mg, 0.491 mmol) under N₂ atmosphere. The reaction mixture was degassed with N₂ three times and stirred at 50 °C for 8 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. The residue was purified by prep-TLC (PE: EtOAc =1: 1) to give the title compound (14 mg) as a solid. LC-MS (ESI) m/z: 513.5 (M+H)⁺. Step 7: (R)-13-fluoro-N-(piperidin-3-yl)-11-(trifluoromethyl)-7,8-dihydro-5H- benzo[8,9][1,4]dioxonino[7,6-c]pyridazin-3-amine To a solution of tert-butyl (R)-3-((13-fluoro-11-(trifluoromethyl)-7,8-dihydro-5H- benzo[8,9][1,4]dioxonino[7,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (14 mg, 0.023 mmol) in 1,4-dioxane (0.5 mL) was added HCl in 1,4-dioxane (0.5 mL, 4 M) and the mixture was stirred at RT for 1 hr. The mixture was concentrated under reduced pressure to give the title compound (10 mg) as an oil. LC-MS (ESI) m/z: 413.2 (M+H)⁺. Step 8: (R)-13-fluoro-N-(1-methylpiperidin-3-yl)-11-(trifluoromethyl)-7,8-dihydro-5H- benzo[8,9][1,4]dioxonino[7,6-c]pyridazin-3-amine, Formic acid salt To a solution of (R)-13-fluoro-N-(piperidin-3-yl)-11-(trifluoromethyl)-7,8-dihydro- 5H-benzo[8,9][1,4]dioxonino[7,6-c]pyridazin-3-amine (10 mg, 0.024 mmol) in MeOH (0.5 mL) were added 37% aq. HCHO (0.1 mL), AcOH (2.9 mg, 0.048 mmol) and NaBH₃CN (4.6 mg, 0.073 mmol) successively and the mixture was stirred under N₂ atmosphere at RT for 30 mins. The reaction mixture concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*21 mm, 5–95% MeCN in H₂O with 0.1% FA) to give the title compound (0.5 mg) as a solid. LC-MS (ESI) m/z: 427.2 (M+H)⁺. Example 47 Ethyl (2S,5R,R_a)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-(trifluoromethoxy)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2- carboxylate Example 48 Ethyl (2S,5R,S_a)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-(trifluoromethoxy)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2- carboxylate

The title compound was prepared following methods and protocols as those described for the synthesis of Example 44 and purified by prep-HPLC (Welch-Ultimate AQ-C18, 21.2*250 mm, 5μm, 10–95% MeCN in H₂O with 0.1% NH₄HCO₃) to afford Example 47 (eluted first) and Example 48 (eluted second) as solids. Example 47: ¹H NMR (400 MHz, CD₃OD) δ 6.80 (s, 1H), 6.77 (s, 1H), 5.26 (d, J = 13.1 Hz, 1H), 5.07 (d, J = 13.1 Hz, 1H), 4.58 – 4.54 (m, 2H), 4.19 (q, J = 7.2 Hz, 2H), 4.16 – 4.08 (m, 1H), 3.80 – 3.74 (m, 1H), 3.51 – 3.47 (m, 1H), 3.42 – 3.35 (m, 2H), 3.13 – 3.07 (m, 1H), 2.50 (dd, J = 12.2, 10.3 Hz, 1H), 2.29 – 2.21 (m, 1H), 2.19 – 2.08 (m, 2H), 1.80 – 1.70 (m, 2H), 1.68 – 1.56 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 570.3 (M+H)⁺. Example 48: ¹H NMR (400 MHz, CD₃OD) δ 6.81 (s, 1H), 6.77 (s, 1H), 5.26 (d, J = 13.2 Hz, 1H), 5.06 (d, J = 13.1 Hz, 1H), 4.58 – 4.53 (m, 2H), 4.19 (q, J = 7.2 Hz, 2H), 4.16 – 4.11 (m, 1H), 3.80 – 3.74 (m, 1H), 3.51 – 3.46 (m, 1H), 3.41 – 3.33 (m, 2H), 3.12 – 3.07 (m, 1H), 2.49 (dd, J = 12.2, 10.4 Hz, 1H), 2.29 – 2.23 (m, 1H), 2.18 – 2.08 (m, 2H), 1.80 – 1.70 (m, 2H), 1.68 – 1.58 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). LC- MS (ESI) (m/z): 570.3 (M+H)⁺. Example 49 Ethyl (2S,5R,R_a)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate Example 50 Ethyl (2S,5R,S_a)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

The epimers of Example 44 was separated by prep-HPLC (WELCH ultimate XB-C18 250*21.2 mm, 5–90% MeCN in H₂O with 0.1% NH₄HCO₃) to afford Example 49 (eluted first) and Example 50 (eluted second) as solids. Example 49: δ ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.14 (s, 1H), 5.27 (d, J = 13.2 Hz, 1H), 5.08 (d, J = 13.1 Hz, 1H), 4.59 (d, J = 13.4 Hz, 1H), 4.29 (d, J = 13.5 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.16 – 4.11 (m, 1H), 3.79 – 3.76 (m, 1H), 3.51 – 3.46 (m, 1H), 3.42 – 3.39 (m, 1H), 3.34 – 3.32 (m, 1H), 3.13 – 3.09 (m, 1H), 2.55 – 2.49 (m, 1H), 2.29 – 2.24 (m, 1H), 2.18 – 2.05 (m, 2H), 1.80 – 1.60 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 554.3 (M+H)⁺. Example 50: ¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 7.14 (s, 1H), 5.28 (d, J = 13.1 Hz, 1H), 5.07 (d, J = 13.2 Hz, 1H), 4.58 (d, J = 13.5 Hz, 1H), 4.28 (d, J = 13.5 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.18 – 4.11 (m, 1H), 3.79 – 3.76 (m, 1H), 3.53 – 3.49 (m, 1H), 3.43 – 3.40 (m, 1H), 3.35 – 3.33 (m, 1H), 3.13 – 3.09 (m, 1H), 2.55 – 2.49 (m, 1H), 2.29 – 2.24 (m, 1H), 2.20 – 2.16 (m, 1H), 2.12 – 2.05 (m, 1H), 1.85 – 1.60 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 554.3 (M+H)⁺. Example 51 Ethyl (2S,5R,R_a)-5-((11-(difluoromethoxy)-13-hydroxy-4-(hydroxymethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate Example 52 Ethyl (2S,5R,S_a)-5-((11-(difluoromethoxy)-13-hydroxy-4-(hydroxymethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Steps 1-4: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((11-(difluoromethoxy)-13-(methoxymethoxy)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate The title compound was prepared following methods and protocols as those described for the synthesis of Example 26 from Intermediate 2 and Intermediate 6 as starting materials. LC-MS (ESI) (m/z): 623.3 (M+H)⁺. Step 5: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((11-(difluoromethoxy)-4-(hydroxymethyl)-13- (methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((11-(difluoromethoxy)-13- (methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (150 mg, 0.24 mmol) in MeOH (10 mL) were added H₂O2 (54 mg, 0.48 mmol, 30% wt. in H₂O), TFA (55 mg, 0.48 mmol) and dppfO2 (13.8 mg, 0.024 mmol) at RT. The reaction mixture was degassed under N₂ three times and irradiated with 50W 390 nM LEDs at 40 °C for 18 hrs. The mixture was quenched with sat. aq. Na₂S₂O₃ solution and neutralized with sat. aq. Na₂CO₃ solution. The mixture was 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 flash chromatography (silica gel, 0–10% MeOH in DCM) to give the title compound (48 mg) as an oil. LC-MS (ESI) (m/z): 544 (M+H)⁺. Step 6: Ethyl (2S,5R,R_a)-5-((11-(difluoromethoxy)-13-hydroxy-4-(hydroxymethyl)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2- carboxylate & ethyl (2S,5R,S_a)-5-((11-(difluoromethoxy)-13-hydroxy-4- (hydroxymethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((11-(difluoromethoxy)-4- (hydroxymethyl)-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (48 mg, 0.073 mmol) in 1,4-dioxane (1 mL) was added HCl/1,4-dioxane (1 mL, 4 M) solution at RT and the mixture was stirred at RT for 2 hrs. The mixture was concentrated to dryness and the residue was purified by prep-HPLC (Welch-Ultimate AQ-C18, 21.2*250 mm, 5μm, 10–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give Example 51 (6 mg, eluted first) and Example 52 (5 mg, eluted second) as solids. Example 51: ¹H NMR (400 MHz, CD₃OD) δ 6.86 (t, J = 74.0 Hz, 1H), 6.67 (d, J = 2.1 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 4.78 (d, J = 13.2 Hz, 1H), 4.56 (dd, J = 13.0, 11.1 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 4.18 – 4.09 (m, 2H), 3.78 – 3.71 (m, 1H), 3.55 – 3.50 (m, 1H), 3.44 – 3.33 (m, 2H), 3.00 – 2.93 (m, 1H), 2.48 (dd, J = 12.1, 10.2 Hz, 1H), 2.31 – 2.23 (m, 1H), 2.18 – 2.09 (m, 2H), 1.70 – 1.55 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 509.2 (M+H)⁺. Example 52: ¹H NMR (400 MHz, CD₃OD) δ 6.85 (t, J = 71.9 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 4.75 (d, J = 13.2 Hz, 1H), 4.60 (d, J = 13.2 Hz, 1H), 4.53 (d, J = 13.2 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.18 – 4.12 (m, 2H), 3.77 – 3.72 (m, 1H), 3.55 – 3.50 (m, 1H), 3.43 – 3.33 (m, 2H), 2.98 – 2.92 (m, 1H), 2.48 (dd, J = 12.3, 10.2 Hz, 1H), 2.31 – 2.25 (m, 1H), 2.18 – 2.08 (m, 2H), 1.69 – 1.57 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 509.2 (M+H)⁺. Example 53 Ethyl (2S,5R,R_a)-5-((13-hydroxy-4-(hydroxymethyl)-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate Example 54 Ethyl (2S,5R,S_a)-5-((13-hydroxy-4-(hydroxymethyl)-11-methoxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

The epimers of Example 39 were separated by prep-HPLC (WELCH ultimate XB-C18 250*21.2 mm, 5–90% MeCN in H₂O with 0.1% NH₄HCO₃) to afford Example 53 (eluted first) and Example 54 (eluted second) as solids. Example 53: ¹H NMR (400 MHz, CD₃OD) δ 6.47 (d, J = 2.3 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 4.81 – 4.75 (m, 1H), 4.60 – 4.51 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.17 – 4.10 (m, 2H), 3.81 (s, 3H), 3.76 – 3.69 (m, 1H), 3.57 – 3.51 (m, 1H), 3.45 – 3.39 (m, 1H), 3.38 – 3.33 (m, 1H), 2.98 – 2.90 (m, 1H), 2.55 – 2.47 (m, 1H), 2.32 – 2.24 (m, 1H), 2.21 – 2.13 (m, 2H), 1.71 – 1.56 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 473.2 (M+H)⁺. Example 54: ¹H NMR (400 MHz, CD₃OD) δ 6.47 (d, J = 2.3 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 4.79 – 4.72 (m, 1H), 4.64 – 4.50 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.17 – 4.10 (m, 2H), 3.81 (s, 3H), 3.76 – 3.69 (m, 1H), 3.58 – 3.51 (m, 1H), 3.44 – 3.39 (m, 1H), 3.39 – 3.35 (m, 1H), 2.99 – 2.88 (m, 1H), 2.55 – 2.43 (m, 1H), 2.35 – 2.23 (m, 1H), 2.22 – 2.11 (m, 2H), 1.74 – 1.54 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 473.2 (M+H)⁺. Example 55 Ethyl (2S,5R)-5-((11-cyclopropyl-13-hydroxy-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Step 1-4: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((11-(benzyloxy)-13-(methoxymethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate The title compound was prepared following methods and protocols as those described in Intermediate 7 Steps 1-4 as a solid. LC-MS (ESI) m/z: 663.3 (M+H)⁺. Step 5: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((11-hydroxy-13-(methoxymethoxy)-6,7,8,9- tetrahydro-5H-benzo[8,9]cyclonona[1,2-c]pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((11-(benzyloxy)-13- (methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (500 mg, 0.755 mmol) in EtOH (5 mL) was added Pd/C (50 mg, 10% wt.) at RT under N₂ atmosphere and the mixture was stirred under a H₂ balloon at RT for 4 hrs. The mixture was filtered and the filtrate was concentrated under reduced pressure to dryness to give the title compound (400 mg) as a solid, which was used directly in the next reaction without purification. LC/MS (ESI) (m/z): 573.3 (M+H)⁺. Step 6: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((13-(methoxymethoxy)-11- (((trifluoromethyl)sulfonyl)oxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((11-hydroxy-13-(methoxymethoxy)- 6,7,8,9-tetrahydro-5H-benzo[8,9]cyclonona[1,2-c]pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate (150 mg, 0.262 mmol) in DMF (3 mL) were added TEA (79 mg, 0.782 mmol) and N,N-bis(trifluoromethylsulfonyl)aniline (140 mg, 0.392 mmol) and the mixture was stirred at 60 °C 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, 0–60% EtOAc in PE) to give the title compound (141 mg) as a solid. LC/MS (ESI) m/z: 705.3 (M+H)⁺. Step 7: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((11-cyclopropyl-13-(methoxymethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((13-(methoxymethoxy)-11- (((trifluoromethyl)sulfonyl)oxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (130 mg, 0.185 mmol) in 1,4-dioxane (5 mL) and water (1 mL) were added cyclopropylboronic acid (32 mg, 0.372 mmol), K₂CO₃ (76 mg, 0.551 mmol) and Pd(dppf)Cl₂ (14 mg, 0.019 mmol) under N₂ atmosphere. The mixture was degassed with N₂ three times and stirred under N₂ at 80 °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– 50% EtOAc in PE) to give the title compound (71 mg,) as a solid. LC/MS (ESI) (m/z): 597.4 (M+H)⁺. Step 8: Ethyl (2S,5R)-5-((11-cyclopropyl-13-hydroxy-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((11-cyclopropyl-13- (methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (70 mg, 0.117 mmol) in 1,4-dioxane (2 mL) was added HCl/1,4-dioxane (2 mL) at 0 °C and the mixture was stirred at RT for 2 hrs. The mixture was concentrated to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 5–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (20 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 6.72 (s, 1H), 6.60 (s, 1H), 6.57 (s, 1H), 4.55 (dd, J = 13.0, 3.8 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 4.14 (d, J = 12.8 Hz, 1H), 4.04 – 3.94 (m, 1H), 3.75 – 3.69 (m, 1H), 3.59 – 3.51 (m, 2H), 3.37 – 3.33 (m, 1H), 2.61 – 2.47 (m, 2H), 2.28 – 2.12 (m, 3H), 1.92 – 1.86 (m, 1H), 1.77 – 1.65 (m, 3H), 1.64 – 1.53 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.02 – 0.95 (m, 2H), 0.74 – 0.66 (m, 2H). LC/MS (ESI) (m/z): 453.3 (M+H)⁺. Example 56 ((2S,5R)-5-((13-Hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidin-2-yl)methyl carbamate

Step 1: Tert-butyl (2S,5R)-2-(hydroxymethyl)-5-((13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (130 mg, 0.21 mmol) in THF (5 mL) was added LiBH4 (13.6 mg, 0.62 mmol) at 0 °C and the mixture was stirred at 60 °C for 2 hrs. The mixture was quenched with saturated aq. NaHCO₃ 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, 0–5% MeOH in DCM) to give the title compound (60 mg) as an oil. LC-MS (ESI) m/z: 583.3 (M+H)⁺. Step 2: Tert-butyl (2S,5R)-2-((carbamoyloxy)methyl)-5-((13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1-carboxylate To a mixture of tert-butyl (2S,5R)-2-(hydroxymethyl)-5-((13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1-carboxylate (60 mg, 0.10 mmol) and TEA (30.6 mg, 0.3 mmol) in DCM (2 mL) was added trichloroacetyl isocyanate (28.2 mg, 0.15 mmol) at 0 °C. The reaction mixture was stirred at RT for 1 hr. Then the mixture was concentrated under reduced pressure to dryness. The residue was dissolved in MeOH (1 mL) and the resulting mixture was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure to give the title compound (40 mg) as an oil. LC-MS (ESI) m/z: 626.3 (M+H)⁺. Step 3: ((2S,5R)-5-((13-Hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidin-2-yl)methyl carbamate To a solution of tert-butyl (2S,5R)-2-((carbamoyloxy)methyl)-5-((13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1-carboxylate (20 mg, 0.03 mmol) in DCM (1 mL) was added TFA (0.5 mL) and the mixture was stirred at RT for 1 hr. The mixture was concentrated to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18250*21 mm, 10–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (6 mg) as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.12 (s, 1H), 6.71 (s, 1H), 4.62 – 4.59 (m, 1H), 4.30 – 4.27 (m, 1H), 4.07 – 4.03 (m, 1H), 3.97 – 3.90 (m, 2H), 3.78 – 3.75 (m, 1H), 3.49 – 3.48 (m, 1H), 3.27 – 3.20 (m, 1H), 2.86 – 2.81 (m, 1H), 2.63 – 2.60 (m, 1H), 2.46 – 2.41 (m, 1H), 2.25 – 2.22 (m, 1H), 2.12 – 2.07 (m, 1H), 1.84 – 1.81 (m, 1H), 1.74 – 1.69 (m, 2H), 1.49 – 1.41 (m, 2H). LC-MS (ESI) (m/z): 482.2 (M+H)⁺. Example 57 ((2S,5R)-5-((13-Hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)-1-methylpiperidin-2-yl)methyl carbamate

E_{xample 56 Example 57} The title compound was prepared following methods and protocols as those described in Example 13 Steps 13 as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.13 (s, 1H), 6.72 (s, 1H), 4.62 – 4.58 (m, 1H), 4.30 – 4.27 (m, 1H), 4.22 – 4.12 (m, 3H), 3.78 – 3.76 (m, 1H), 3.46 – 3.43 (m, 1H), 3.28 – 3.25 (m, 1H), 2.64 – 2.60 (m, 1H), 2.50 (s, 3H), 2.44 – 2.42 (m, 1H), 2.22 – 2.17 (m, 2H), 2.11 – 2.08 (m, 1H), 1.93 – 1.89 (m, 1H), 1.73 – 1.66 (m, 3H), 1.50 – 1.42 (m, 1H). LC-MS (ESI) (m/z): 496.3 (M+H)⁺. Example 58 3-(((3R,6S)-6-(Hydroxymethyl)piperidin-3-yl)amino)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol

The title compound was prepared following methods and protocols as those described in Example 56 as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.15 (s, 1H), 7.11 (s, 1H), 6.72 (s, 1H), 4.62 – 4.58 (m, 1H), 4.30 – 4.26 (m, 1H), 4.00 – 3.93 (m, 1H), 3.78 – 3.75 (m, 1H), 3.58 – 3.54 (m, 1H), 3.49 – 3.45 (m, 2H), 3.26 – 3.23 (m, 1H), 2.73 – 2.67 (m, 1H), 2.63 – 2.59 (m, 1H), 2.50 – 2.43 (m, 1H), 2.25 – 2.22 (m, 1H), 2.14 – 2.07 (m, 1H), 1.84 – 1.81 (m, 1H), 1.73 – 1.70 (m, 2H), 1.50 – 1.37 (m, 2H). LC-MS (ESI) (m/z): 439.2 (M+H)⁺. Example 59 3-(((3R,6S)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)-11-(trifluoromethyl)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-13-ol

1_{Example 59} The title compound was prepared following methods and protocols as those described in Example 13 Steps 13 as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.12 (s, 1H), 6.72 (s, 1H), 4.62 – 4.58 (m, 1H), 4.30 – 4.27 (m, 1H), 4.16 – 4.11 (m, 1H), 3.78 – 3.75 (m, 1H), 3.68 – 3.67 (m, 2H), 3.43 – 3.38 (m, 1H), 3.27 – 3.25 (m, 1H), 2.63 – 2.60 (m, 1H), 2.49 (s, 3H), 2.29 – 2.19 (m, 3H), 2.13 – 2.07 (m, 1H), 1.95 – 1.90 (m, 1H), 1.74 – 1.65 (m, 3H), 1.47 – 1.38 (m, 1H). LC-MS (ESI) (m/z): 453.2 (M+H)⁺. Example 60 2-Hydroxyethyl (2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Step 1: (2S,5R)-1-(tert-butoxycarbonyl)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)- 5,6,7, 9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2- carboxylic acid To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (100 mg, 0.16 mmol) in MeOH (3 mL) and water (0.6 mL) was added LiOH (33.6 mg, 0.8 mmol) and the mixture was stirred at RT for 2 hrs. The mixture was acidified with 2 N aq. 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, 0–5% MeOH in DCM) to give the title compound (60 mg) as a solid. LC-MS (ESI) m/z: 597.4 (M+H)⁺. Step 2: 1-(Tert-butyl) 2-(2-hydroxyethyl) (2S,5R)-5-((13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a solution of (2S,5R)-1-(tert-butoxycarbonyl)-5-((13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-2-carboxylic acid (60 mg, 0.10 mmol) in DCM (2 mL) were added ethylene glycol (9.4 mg, 0.15 mmol), EDCI (38.6 mg, 0.2 mmol) and DMAP (6.1 mg, 0.05 mmol) at RT and the mixture was stirred at RT for 2 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 under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0–10% MeOH in DCM) to give the title compound (40 mg) as an oil. LC-MS (ESI) m/z: 641.5 (M+H)⁺. Step 3: 2-Hydroxyethyl (2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-(2-hydroxyethyl) (2S,5R)-5-((13-(methoxymethoxy)- 11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (40 mg, 0.06 mmol) in DCM (1 mL) was added TFA (1 mL) and the mixture was stirred at RT for 1 hr. The mixture was concentrated to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18250*21 mm, 20–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give the title compound (13 mg) as a solid. ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.13 (s, 1H), 6.73 (s, 1H), 4.62 – 4.58 (m, 1H), 4.30 – 4.27 (m, 1H), 4.25 – 4.22 (m, 2H), 4.05 – 3.97 (m, 1H), 3.79 – 3.75 (m, 3H), 3.59 – 3.54 (m, 2H), 3.28 – 3.25 (m, 1H), 2.65 – 2.60 (m, 1H), 2.56 – 2.50 (m, 1H), 2.29 – 2.23 (m, 2H), 2.14 – 2.07 (m, 1H), 1.77 – 1.68 (m, 3H), 1.64 – 1.54 (m, 1H). LC-MS (ESI) (m/z): 497.3 (M+H)⁺. Example 61 3-Hydroxypropyl (2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)ami OnTBoS)piperidine-2-carboxy OHlate

The title compound was prepared following methods and protocols as those described in Example 60 as a solid.¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 7.13 (s, 1H), 6.73 (s, 1H), 4.65 – 4.57 (m, 1H), 4.33 – 4.22 (m, 3H), 3.98 – 3.88 (m, 1H), 3.81 – 3.74 (m, 1H), 3.65 (t, J = 6.2 Hz, 2H), 3.49 – 3.42 (m, 1H), 3.41 – 3.35 (m, 1H), 3.29 – 3.24 (m, 1H), 2.67 – 2.58 (m, 1H), 2.50 – 2.41 (m, 1H), 2.29 – 2.22 (m, 1H), 2.20 – 2.05 (m, 2H), 1.92 – 1.84 (m, 2H), 1.77 – 1.69 (m, 2H), 1.68 – 1.51 (m, 2H). LC-MS (ESI) (m/z): 511.2 (M+H)⁺. Example 62 Ethyl (2S,5R,R_a)-5-((13-hydroxy-11-(trifluoromethyl)-4-(ureidomethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate Example 63 Ethyl (2S,5R,S_a)-5-((13-hydroxy-11-(trifluoromethyl)-4-(ureidomethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-4- (ureidomethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-(aminomethyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (prepared following methods and protocols as those described for the synthesis of Example 24) (40 mg, 0.06 mmol) in DCM (2 mL) were added TEA (18.6 mg, 0.18 mmol) and 2,2,2-trichloroacetyl isocyanate (17.3 mg, 0.09 mmol) at 0 °C and the mixture reaction was stirred at RT for 1 hr. The mixture was concentrated under reduced pressure to dryness. The residue was dissolved in EtOH and K₂CO₃ (16.9 mg, 0.12 mmol) was added. The resulting mixture was stirred at 40 °C for 2 hrs. The mixture was filtered and the filtrate was concentrated under reduced pressure to dryness to give the title compound (30 mg) as an oil. LC-MS (ESI) m/z: 697.3 (M+H)⁺. Step 2: Ethyl (2S,5R,R_a)-5-((13-hydroxy-11-(trifluoromethyl)-4-(ureidomethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate and Ethyl (2S,5R,S_a)-5-((13-hydroxy-11-(trifluoromethyl)-4-(ureidomethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((13-(methoxymethoxy)-11- (trifluoromethyl)-4-(ureidomethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (30 mg, 0.04 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4M) and the mixture was stirred at RT for 1 hr. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (WELCH ultimate XB-C18250*21.2 mm, 10–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give Example 62 (6 mg, eluted first) and Example 63 (5 mg, eluted second) as solids. Example 62: ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.14 (s, 1H), 4.61 (d, J = 13.3 Hz, 1H), 4.40 – 4.35 (m, 2H), 4.29 (d, J = 13.2 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.15 – 4.10 (m, 1H), 3.82 – 3.77 (m, 1H), 3.55 – 3.51 (m, 1H), 3.46 – 3.42 (m, 1H), 3.33 – 3.33 (m, 1H), 3.06 – 3.01 (m, 1H), 2.55 – 2.49 (m, 1H), 2.26 – 2.22 (m, 1H), 2.19 – 2.16 (m, 1H), 2.11 – 2.03 (m, 1H), 1.74 – 1.61 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 553.2 (M+H)⁺. Example 63: ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.14 (s, 1H), 4.60 (d, J = 13.4 Hz, 1H), 4.40 – 4.35 (m, 2H), 4.29 (d, J = 13.4 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.17 – 4.08 (m, 1H), 3.82 – 3.77 (m, 1H), 3.51 – 3.47 (m, 1H), 3.43 – 3.40 (m, 1H), 3.34 – 3.33 (m, 1H), 3.05 – 3.01 (m, 1H), 2.51 – 2.45 (m, 1H), 2.28 – 2.24 (m, 1H), 2.19 – 2.16 (m, 1H), 2.12 – 2.05 (m, 1H), 1.73 – 1.60 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 553.2 (M+H)⁺. Example 64 Ethyl (2S,5R,R_a)-5-((4-(acetamidomethyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate Example 65 Ethyl (2S,5R,S_a)-5-((4-(acetamidomethyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-(acetamidomethyl)-13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-(aminomethyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (50 mg, 0.077 mol) in DCM (1 mL) was added TEA (23 mg, 0.231 mol) and acetyl chloride (7.2 mg, 0.092 mol) at RT and the mixture was stirred at RT for 1 hr. 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 compound (30 mg) as a solid. LC-MS (ESI) (m/z): 696.4 (M+H)⁺. Step 2: Ethyl (2S,5R)-5-((4-(acetamidomethyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate To a solution of ethyl (2S,5R)-5-((4-(acetamidomethyl)-13-hydroxy-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-2-carboxylate (30 mg, 0.043 mmol) in DCM (1 mL) was added HCl/1,4- dioxane solution (1 mL, 4 M) at room temperature and the mixture was stirred at RT for 1 hr. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC- Actus Triart C18250*20 mm, 15–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give Example 64 (4 mg, eluted first) and Example 65 (4 mg, eluted second) as solids. Example 64: ¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 7.15 (s, 1H), 4.62 (d, J = 13.3 Hz, 1H), 4.53 (d, J = 15.2 Hz, 1H), 4.30 (d, J = 13.9 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 4.21 – 4.13 (m, 1H), 3.85 – 3.76 (m, 1H), 3.65 – 3.55 (m, 2H), 3.39 – 3.26 (m, 1H), 3.11 – 3.02 (m, 1H), 2.65 – 2.55 (m, 1H), 2.28 – 2.20 (m, 2H), 2.16 – 2.08 (m, 1H), 2.01 (s, 3H), 1.77 – 1.59 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m/z: 552.3 (M+H)⁺. Example 65: ¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 7.15 (s, 1H), 4.61 (d, J = 13.3 Hz, 1H), 4.51 (d, J = 15.2 Hz, 1H), 4.36 – 4.27 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 4.22 – 4.15 (m, 1H), 3.84 – 3.76 (m, 1H), 3.67 – 3.54 (m, 2H), 3.36 – 3.31 (m, 1H), 3.11 – 3.02 (m, 1H), 2.59 – 2.44 (m, 1H), 2.34 – 2.24 (m, 2H), 2.16 – 2.08 (m, 1H), 2.01 (s, 3H), 1.80 – 1.63 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m/z: 552.3 (M+H)⁺. Example 66 Ethyl (2S,5R,R_a)-5-((13-hydroxy-4-(3-methoxy-3-oxopropyl)-11-(trifluoromethyl)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2- carboxylate Example 67 Ethyl (2S,5R,S_a)-5-((13-hydroxy-4-(3-methoxy-3-oxopropyl)-11-(trifluoromethyl)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2- carboxylate

St

11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-(hydroxymethyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (500 mg, 0.76 mmol) in DCM (5 mL) was added Dess-Martin (421 mg, 0.99 mmol) at 0 °C and the reaction mixture was stirred at RT for 3 hrs. The mixture was quenched with sat. aq. NaHCO₃ solution 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 flash chromatography (silica gel, 0–50% EtOAc in PE) to give the title compound (400 mg) as a solid. LC-MS (ESI) (m/z): 653.4 (M+H)⁺. Step 2: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-formyl-13-(methoxymethoxy)-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (180 mg, 0.28 mmol) in DCM (5 mL) was added methyl (triphenylphosphoranylidene)acetate (111 mg, 0.33 mmol) at RT and the reaction mixture was stirred at RT for 2 hrs. The mixture was 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 (120 mg) as a solid. LC-MS (ESI) (m/z): 709.4 (M+H)⁺. Step 3: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-(3-methoxy-3-oxopropyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-((E)-3-methoxy-3-oxoprop-1-en- 1-yl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (120 mg, 0.17 mmol) in EtOH (3 mL) was added Pd/C (20 mg, 10% wt.) under N₂ temperature and the mixture was stirred with a H₂ balloon at RT for 1 hr. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (70 mg) as a solid. LC-MS (ESI) m/z: 711.3 (M+H)⁺. Step 4: Ethyl (2S,5R)-5-((13-hydroxy-4-(3-methoxy-3-oxopropyl)-11-(trifluoromethyl)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2- carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-(3-methoxy-3-oxopropyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (50 mg, 0.07 mmol) in DCM (2 mL) was added HCl/1,4-dioxane (1 mL, 4M) and the mixture was stirred at RT for 1 hr. The mixture was 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 Example 66 (7 mg, eluted first) and Example 67 (6 mg, eluted second) as solids. Example 66: ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.13 (s, 1H), 4.60 (d, J = 13.4 Hz, 1H), 4.28 (d, J = 13.4 Hz, 1H), 4.24 – 4.18 (m, 3H), 3.82 – 3.74 (m, 1H), 3.70 (s, 3H), 3.54 – 3.50 (m, 1H), 3.47 – 3.43 (m, 1H), 3.33 – 3.33 (m, 1H), 3.05 – 2.84 (m, 3H), 2.65 – 2.53 (m, 3H), 2.26 – 2.19 (m, 2H), 2.10 – 2.03 (m, 1H), 1.73 – 1.66 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 567.3 (M+H)⁺. Example 67: ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.14 (s, 1H), 4.59 (d, J = 13.3 Hz, 1H), 4.28 (d, J = 13.4 Hz, 1H), 4.25 – 4.20 (m, 3H), 3.79 – 3.76 (m, 1H), 3.70 (s, 3H), 3.55 – 3.50 (m, 2H), 3.34 – 3.33 (m, 1H), 3.04 – 2.85 (m, 3H), 2.65 – 2.57 (m, 3H), 2.28 – 2.21 (m, 2H), 2.10 – 2.03 (m, 1H), 1.72 – 1.67 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 567.3 (M+H)⁺. Example 68 Ethyl (2S,5R,R_a)-5-((4-(3-amino-3-oxopropyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate Example 69 Ethyl (2S,5R,S_a)-5-((4-(3-amino-3-oxopropyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-(3-amino-3-oxopropyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a solution of 3-(3-(((3R,6S)-1-(tert-butoxycarbonyl)-6-(ethoxycarbonyl)piperidin- 3-yl)amino)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-4-yl)propanoic acid (60 mg, 0.086 mmol) in DCM (1 mL) were added HATU (100 mg, 0.258 mmol), DIEA (56 mg, 0.43 mmol) and NH₄Cl (12 mg, 0.172 mmol). The mixture was stirred at RT for 2 hrs. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0–10% MeOH in DCM) to afford the title compound (30 mg) as a solid. LC-MS (ESI) (m/z): 696.4 (M+H)⁺. Step 2: Ethyl (2S,5R,R_a)-5-((4-(3-amino-3-oxopropyl)-13-hydroxy-11-(trifluoromethyl)- 5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2- carboxylate and ethyl (2S,5R,S_a)-5-((4-(3-amino-3-oxopropyl)-13-hydroxy-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-(3-amino-3-oxopropyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (28 mg, 0.04 mmol) in DCM (1 mL) was added HCl/1,4-dioxane (1 mL, 4M) at RT and the mixture was stirred at RT for 1 hr. The mixture was concentrated to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 25–90% MeCN in H₂O with 0.1% NH₄HCO₃) to give Example 68 (2.1 mg, eluted first) and Example 69 (1.8 mg, eluted second) as solids. Example 68: ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.14 (s, 1H), 4.63 – 4.53 (m, 3H), 4.29 (d, J = 13.5 Hz, 1H), 4.27 – 4.20 (m, 3H), 3.82 – 3.75 (m, 1H), 3.63 – 3.55 (m, 2H), 2.98 – 2.81 (m, 3H), 2.69 – 2.59 (m, 1H), 2.54 – 2.44 (m, 2H), 2.32 – 2.19 (m, 2H), 2.12 – 2.03 (m, 1H), 1.74 – 1.69 (m, 3H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m/z: 552.4 (M+H)⁺. Example 69: ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.13 (s, 1H), 4.60 – 4.57 (m, 3H), 4.28 (d, J = 13.5 Hz, 1H), 4.26 – 4.20 (m, 3H), 3.80 – 3.75 (m, 1H), 3.59 – 3.53 (m, 2H), 2.97 – 2.85 (m, 3H), 2.64 – 2.57 (m, 1H), 2.52 – 2.45 (m, 2H), 2.30 – 2.21 (m, 2H), 2.11 – 2.03 (m, 1H), 1.73 – 1.68 (m, 3H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m/z: 552.4 (M+H)⁺. Example 70 3-(3-(((3R,6S,R_a)-6-(ethoxycarbonyl)piperidin-3-yl)amino)-13-hydroxy-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-4-yl)propanoic acid Example 71 3-(3-(((3R,6S,S_a)-6-(ethoxycarbonyl)piperidin-3-yl)amino)-13-hydroxy-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-4-yl)propanoic acid

Step 1: 3-(3-(((3R,6S)-1-(tert-butoxycarbonyl)-6-(ethoxycarbonyl)piperidin-3-yl)amino)- 13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-4-yl)propanoic acid To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-(3-methoxy-3-oxopropyl)-13- (methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (90 mg, 0.127 mmol) in THF/water (2 mL, v/v= 3/1) was added LiOH.H₂O (6 mg, 0.14 mmol) at 0 °C and the mixture was stirred at 0 °C for 4 hrs. The mixture was acidified with 1N aq. HCl to pH~4 and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness to give the title compound (60 mg) as a solid. LC-MS (ESI) m/z: 697.4 (M+H)⁺. Step 2: 3-(3-(((3R,6S,R_a)-6-(ethoxycarbonyl)piperidin-3-yl)amino)-13-hydroxy-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-4-yl)propanoic acid and 3-(3-(((3R,6S,S_a)-6-(ethoxycarbonyl)piperidin-3-yl)amino)-13-hydroxy-11- (trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-4-yl)propanoic acid To a solution of 3-(3-(((3R,6S)-1-(tert-butoxycarbonyl)-6-(ethoxycarbonyl)piperidin- 3-yl)amino)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6- c]pyridazin-4-yl)propanoic acid (30 mg, 0.046 mmol) in DCM (1 mL) was added HCl/1,4- dioxane (1 mL, 4 M) at RT and the mixture was stirred at RT for 1 hr. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 25–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give Example 70 (1.8 mg, eluted first) and Example 71 (1.6 mg, eluted second) as solids. Example 70: ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.14 (s, 1H), 4.59 (d, J = 13.3 Hz, 1H), 4.38 – 4.26 (m, 4H), 4.01 – 3.92 (m, 1H), 3.82 – 3.72 (m, 2H), 3.28 – 3.24 (m, 1H), 2.98 – 2.83 (m, 4H), 2.52 – 2.38 (m, 3H), 2.32 – 2.24 (m, 1H), 2.11 – 2.03 (m, 1H), 1.93 – 1.82 (m, 2H), 1.79 – 1.67 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m/z: 553.3 (M+H)⁺. Example 71: ¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 7.13 (s, 1H), 4.58 (d, J = 13.3 Hz, 1H), 4.42 – 4.36 (m, 1H), 4.34 – 4.25 (m, 3H), 4.03 – 3.97 (m, 1H), 3.79 – 3.69 (m, 2H), 3.28 – 3.23 (m, 1H), 2.97 – 2.84 (m, 4H), 2.53 – 2.33 (m, 3H), 2.29 – 2.22 (m, 1H), 2.11 – 2.03 (m, 1H), 1.94 – 1.83 (m, 2H), 1.77 – 1.64 (m, 2H), 1.33 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m/z: 553.3 (M+H)⁺. Example 72 Ethyl (2S,5R,R_a)-5-((4-carbamoyl-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate Example 73 Ethyl (2S,5R,S_a)-5-((4-carbamoyl-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-carbamoyl-13-(methoxymethoxy)-11- (trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a mixture of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-cyano-13-(methoxymethoxy)-11- (trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (100 mg, 0.15 mmol) in DMSO (2 mL) were added K₂CO₃ (104 mg, 0.75 mmol) and H₂O2 (170 mg, 1.5 mmol, 30% wt. in H₂O) at RT and the mixture was stirred at RT for 1 hr. The mixture was quenched with saturated aq. Na₂S₂O₃ 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 give the title compound (70 mg) as an oil. LC-MS (ESI) m/z: 684.3 (M+H)⁺. Step 2: Ethyl (2S,5R,R_a)-5-((4-carbamoyl-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate & Ethyl (2S,5R,S_a)-5-((4-carbamoyl-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9- tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-carbamoyl-13-(methoxymethoxy)- 11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxonino[5,6-c]pyridazin-3- yl)amino)piperidine-1,2-dicarboxylate (50 mg, 0.07 mmol) in DCM (2 mL) was added TFA (1 mL) and the mixture was stirred at RT for 1 hr. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (WELCH ultimate XB-C18 250*21.2 mm, 0–95% MeCN in H₂O with 0.1% NH₄HCO₃) to give Example 72 (8 mg, eluted first) and Example 73 (7 mg, eluted second) as solids. Example 72: ¹H NMR (400 MHz, CD₃OD) δ 6.81 (s, 1H), 6.79 (s, 1H), 4.58 (d, J = 13.4 Hz, 1H), 4.24 – 4.18 (m, 4H), 3.77 (d, J = 10.5 Hz, 1H), 3.50 – 3.47 (m, 1H), 3.44 – 3.40 (m, 1H), 3.34 – 3.33 (m, 1H), 2.94 – 2.89 (m, 1H), 2.57 (dd, J = 12.2, 10.3 Hz, 1H), 2.22 – 2.08 (m, 3H), 1.98 – 1.89 (m, 1H), 1.69 – 1.61 (m, 3H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 540.2 (M+H)⁺. Example 73: ¹H NMR (400 MHz, CD₃OD) δ 6.82 (s, 1H), 6.79 (s, 1H), 4.58 (d, J = 13.5 Hz, 1H), 4.24 – 4.18 (m, 4H), 3.77 (d, J = 10.2 Hz, 1H), 3.47 – 3.41 (m, 2H), 3.36 – 3.31 (m, 1H), 2.95 – 2.91 (m, 1H), 2.57 – 2.52 (m, 1H), 2.23 – 2.09 (m, 3H), 1.97 – 1.88 (m, 1H), 1.69 – 1.62 (m, 3H), 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m/z): 540.2 (M+H)⁺. The examples listed in Table 3 were prepared following the methods and protocols outlined below from appropriate starting materials. Table 3. Examples prepared using methods previously discussed

Error! Reference source not found.4 below listed conditions for the resolution of epimeric pairs of compounds in Table 3 above. As a convention, the smaller examples numbers in each pair eluted first on the column. Table 4. Conditions for resolution of epimers

BIOLOGICAL ASSAY EXAMPLES 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 interested in systemic (peripheral) or tissue directed such as CNS or gut targeted inhibitors, compounds intended for these applications should also have adequate exposure in the targeted tissues. 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 10⁵ cells/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 hr at 37°C, 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°C, 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 IC₅₀ data is fitted to a non-liner regression equation (log inhibitor vs. response – Variable slope four parameters The resulting IC₅₀ or geomean of IC₅₀’s from THP-1 cells were shown in Table 5. Data which is above ≥3000 nM is listed as +, <3000 and ≥1000 nM is listed as ++, data which is <1000 and ≥300 nM is listed as +++, data which is <300 and ≥50 nM is listed as ++++, data which is <50 and ≥15 nM is listed as +++++, data which is <15 nM is listed as ++++++. These results showed that the compounds of this disclosure showed potent inhibition of IL-1β formation in THP-1 cells. Table 5. Inhibition of IL-1β in THP-1 cells

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.

Claims

CLAIMS What is claimed is: 1. A compound having the structure of Formula I:

or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X is NR⁴, S, O, or CR⁵R⁶; Y is CR⁵R⁶ or a bond; Z is N or CR⁷; Ring A is 4-7 membered heterocyclyl, C_6-10 aryl, 5-6 membered heteroaryl, or 4-7 membered carbocyclyl, each optionally substituted with one to three groups independently selected from R¹, except that R¹ is not oxo (=O) when A is C_6-10 aryl or 5-6 membered heteroaryl; W¹, W³, and W⁵ are each independently selected from CR⁵R⁶, O, S, and NR⁴; and W², W⁴, and W⁶ are each independently selected from a bond, CR⁵R⁶, O, S, and NR⁴, with the proviso that no two non-carbon atoms are connected directly nor to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; alternatively, wherein R⁵ and R⁶, R⁴ and R⁵, or R⁴ and R⁶ can form additional 3-4 membered spiro or 5-7 membered bridged rings; m is 0, 1, 2, 3; and n is 0, 1, 2 R¹ at each occurrence is independently selected from -H, C_1-8alkyl, C_3-7 cycloalkyl, C_1-8alkyl-CO-, 4-7 membered heterocyclyl, OR⁸, CO₂R⁸, C(O)NR⁸R⁹, halo, CN, NR⁸R⁹, and oxo (=O), wherein each of C_1-8alkyl, C_3-7cycloalkyl, C_1-8alkyl-CO-, and 4-7 membered heterocyclyl is optionally substituted with 1-3 groups independently selected from R¹⁰; R² is -OH, -OCHF₂, -OCF₃, -CHF₂, -CF₃, -CH₂CF₃, -OMe, -F, or -H; R³ at each occurrence is independently selected from -H, C_3-6cycloalkyl, C_1-6alkyl, C_1- 6haloalkyl, -O-C_1-6haloalkyl, halo, -CN, -SF₅, -NR⁸R⁹, -OR⁸, -SR⁸, aryl, and heteroaryl, wherein C_3-6cycloalkyl and C_1-6alkyl are each optionally substituted with 1-3 groups independently selected from halo, oxo, and C_1-4alkyl; and wherein aryl and heteroaryl are each optionally substituted with 1-3 groups independently selected from halo and C_1-4alkyl; R⁴ at each occurrence is independently selected from -H, C_1-4 alkyl, -C(O)-C_1-4 alkyl, and C_3-7 cycloalkyl, wherein each of C_1-4 alkyl and C_3-7 cycloalkyl is optionally substituted with 1-3 groups independently selected from R¹⁰; R⁵ and R⁶ at each occurrence are independently selected from -H, halo, -OR⁸, -NR⁸R⁹, C_1-4 alkyl, C_3-7 cycloalkyl, and 4-7 membered heterocyclyl, wherein each of C_1-4 alkyl, C_3-7 cycloalkyl, and 4-7 membered heterocyclyl is optionally substituted with 1-3 groups independently selected from R¹⁰; or alternatively, R⁵ and R⁶ connected to the same atom taken together form =O; or alternatively, R⁵ and R⁶ connected to the same or different atoms can form a 3-6 membered carbocyclic or heterocyclyl ring optionally substituted with 1-3 groups of R¹⁰; R⁷ is independently selected from H, C_1-8 alkyl, C_3-7 cycloalkyl, aryl, heteroaryl, halo, -CN, -OR⁸, -NR⁸R⁹, -CO₂R¹¹, and -C(O)N(R¹¹R¹²), wherein each of C_1-4 alkyl, C_3-7 cycloalkyl, aryl, and heteroaryl is optionally substituted with 1-3 groups independently selected from R¹³; or alternatively, R⁷ and R⁴ or R⁵ or R⁶ can form a 5-7 membered carbocyclic or heterocyclyl ring optionally substituted with 1-3 groups of R¹⁰; R⁸ and R⁹ are independently selected from -H, -C(O)R¹², -C(O)N(R¹¹R¹²), - C(=NR¹²)N(R¹¹R¹²), C_1-6 alkyl, C_3-7 cycloalkyl, and aryl, wherein each of C_1-6 alkyl, C_3-7 cycloalkyl, and aryl is optionally substituted with 1-3 groups independently selected from R¹⁰, except that R¹⁰ is not =O when R⁸ or R⁹ is aryl; R¹⁰ at each occurrence is independently selected from -H, -CO₂R¹¹, -C(O)N(R¹¹)₂, - CN, -OR¹¹, halo, C_1-6 alkyl, cyclopropyl, aryl, =O, -SR¹¹, and -N(R¹¹R¹²); R¹¹ at each occurrence is independently selected from -H, -CO₂R¹², -C(O)R¹², - C(O)NR¹²C(=NR¹²)N(R¹²)₂, -C(=NR¹²)N(R¹²)₂, -C(O)N(R¹²)₂, aryl, and C_1-6 alkyl, wherein each of the aryl and C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂; R¹² at each occurrence is independently selected from -H, aryl, and C_1-4 alkyl, wherein each of the aryl or C_1-4 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂; and R¹³ at each occurrence is independently selected from -H, halo, -OH, -N(R¹²)₂, - NR¹²C(=NR¹²)N(R¹²)₂, -NR¹²C(O)N(R¹²)₂, -NR¹²C(O)R¹², -NR¹²C(O)OR¹², -OC(O)N(R¹²)₂, -CO₂R¹², -COR¹², -C(O)NR¹²C(=NR¹²)N(R¹²)₂, -C(=NR¹²)N(R¹²)₂, -C(O)N(R¹²)₂, aryl, and C_1-6 alkyl, wherein each of the aryl and C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂. 2. The compound according to Claim 1, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X is NR⁴, S, O, or CR⁵R⁶; Y is CR⁵R⁶ or a bond; Z is N or CR⁷; Ring A is 5-6 membered heterocyclyl, 5-6 membered carbocyclyl, or phenyl, each optionally substituted with one to three groups independently selected from R¹; W¹, W³, and W⁵ are each independently CR⁵R⁶, O, or S; and W², W⁴, and W⁶ are each independently a bond, CR⁵R⁶, O, or S, with the proviso that no two non-carbon atoms are connected directly with each other or to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; m is 0, 1,

2, or 3; n is 0, 1, or 2; i at each occurrence is independently 1 or 2; R¹ at each occurrence is independently selected from H, C_1-6alkyl, C_3-6cycloalkyl, C_1- ₆alkyl-CO-, 4-6 membered heterocyclyl, -OR⁸, -CO₂R⁸, -C(O)NR⁸R⁹, halo, -CN, -NR⁸R⁹, oxo (=O), -C_1-6alkylene-(R¹⁰)_i, -C_3-6cycloalkylene-(R¹⁰)_i, -C(O)-C_1-6alkyl-(R¹⁰)_i, and -(4-6 membered heterocyclylene)-(R¹⁰)_i; R² is -OH, -OCHF₂, -OCF₃, -CHF₂, -CF₃, -CH₂CF₃, -OMe, -F, or -H; R³ at each occurrence is independently selected from -H, C_3-6cycloalkyl, C_1-6alkyl, C_1- ₆haloalkyl, -O-C_1-6haloalkyl, halo, -CN, -NR⁸R⁹, -OR⁸, -SR⁸, phenyl, and 5-6 membered heteroaryl, wherein the C_3-6cycloalkyl, C_1-6alkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted with 1-3 groups independently selected from halo and C_1-4alkyl; R⁴ at each occurrence is independently selected from -H, C_1-6 alkyl, -C(O)-C_1-6alkyl, C_3-6cycloalkyl, -C_1-6alkylene-(R¹⁰)_i, and -C_3-6cycloalkylene-(R¹⁰)_i; R⁵ and R⁶ at each occurrence are independently selected from -H, halo, -OR⁸, -NR⁸R⁹, C_1-4 alkyl, C_3-6cycloalkyl, 4-6 membered heterocyclyl, -C_1-6alkylene-(R¹⁰)_i, -C_3- ₆cycloalkylene-(R¹⁰)_i, -C(O)-C_1-6alkyl-(R¹⁰)_i, and -(4-6 membered heterocyclylene)-(R¹⁰)_i; or alternatively, R⁵ and R⁶ taken together form oxo (=O); R⁷ is selected from -H, C_1-6 alkyl, C_3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, - halo, -CN, -OR⁸, -NR⁸R⁹, -CO₂R¹¹, -C(O)N(R¹¹R¹²), -C_1-6alkylene-(R¹³)_i, and -C_3- ₆cycloalkylene-(R¹³)_i; R⁸ at each occurrence is independently selected from -H, -C(O)R¹², -C(O)N(R¹¹R¹²), C_1-6 alkyl, C_3-6 cycloalkyl, phenyl, -C_1-6alkylene-(R¹⁰)_i, -C_3-6cycloalkylene-(R¹⁰)_i and - phenylene-(R¹⁰)_i; R⁹ at each occurrence is independently selected from -H, C_1-4 alkyl, and C_3-6 cycloalkyl; R¹⁰ at each occurrence is independently selected from -H, -CN, halo, C_1-4 alkyl, cyclopropyl, phenyl, =O, -OR¹¹, -SR¹¹, -CO₂R¹¹, -C(O)N(R¹¹)₂, and -N(R¹¹R¹²); R¹¹ at each occurrence is independently selected from -H, -CO₂R¹², -C(O)R¹², - C(O)NR¹²C(=NR¹²)N(R¹²)₂, -C(=NR¹²)N(R¹²)₂, -C(O)N(R¹²)₂, phenyl, and C_1-6 alkyl, wherein each of phenyl and C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂; R¹² at each occurrence is independently selected from -H, aryl, and C_1-4 alkyl, wherein each of the aryl or C_1-4 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂; and R¹³ at each occurrence is independently selected from -H, halo, -OH, -N(R¹²)₂, - NR¹²C(=NR¹²)N(R¹²)₂, -NR¹²C(O)N(R¹²)₂, -NR¹²C(O)R¹², -NR¹²C(O)OR¹², -OC(O)N(R¹²)₂, -CO₂R¹², -C(O)R¹², -C(O)NR¹²C(=NR¹²)N(R¹²)₂, -C(=NR¹²)N(R¹²)₂, -C(O)N(R¹²)₂, aryl, and C_1-6 alkyl, wherein each of the aryl and C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, OH, and NH₂.

3. The compound according to Claim 1, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X is NR⁴, S, O, or CR⁵R⁶; Y is CR⁵R⁶ or a bond; Z is CR⁷; m is 0, 1, 2, or 3; n is 0, 1, or 2; A is 5-6 membered heterocyclyl; W¹ is CR⁵R⁶ or O; W² is O, S, CR⁵R⁶, or bond; W³ is CR⁵R⁶ or O; W⁴ is CR⁵R⁶ or bond; W⁵ is CR⁵R⁶, O, or S; W⁶ is CR⁵R⁶ or bond; with the proviso that no two non-carbon atoms are connected directly with each other or to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; R¹ at each occurrence is independently selected from H, C_1-6 alkyl, C_3-6cycloalkyl, C_1- ₆alkyl-CO-, 4-6 membered heterocyclyl, -OR⁸, -CO₂R⁸, -CONR⁸R⁹, halo, -CN, -NR⁸R⁹, oxo (=O), -C_1-6alkylene-CN, -C_1-6alkylene-halo, -C_1-6alkylene-cyclopropyl, -C_1-6alkylene-phenyl, -C_1-6alkylene-OR¹¹, -C_1-6alkylene-SR¹¹, -C_1-6alkylene-CO₂R¹¹, -C_1-6alkylene-C(O)N(R¹¹)₂, - C_1-6alkylene-N(R¹¹R¹²), -OC(O)R¹², -OC(O)N(R¹¹R¹²), -O-C(=NR¹²)N(R¹¹R¹²), -O-C_3- ₆cycloalkyl, -O-phenyl, -O-C_1-6alkylene-CN, -O-C_1-6alkylene-halo, -O-C_1-6alkylene- cyclopropyl, -O-C_1-6alkylene-phenyl, -O-C_1-6alkylene-OR¹¹, -O-C_1-6alkylene-SR¹¹, -O-C_1- ₆alkylene-CO₂R¹¹, -O-C_1-6alkylene-C(O)N(R¹¹)₂, -O-C_1-6alkylene-N(R¹¹R¹²), -C(O)O-C_1- ₆alkylene-CN, -C(O)O-C_1-6alkylene-halo, -C(O)O-C_1-6alkylene-cyclopropyl, -C(O)O-C_1- ₆alkylene-phenyl, -C(O)O-C_1-6alkylene-OR¹¹, -C(O)O-C_1-6alkylene-SR¹¹, -C(O)O-C_1- ₆alkylene-CO₂R¹¹, -C(O)O-C_1-6alkylene-C(O)N(R¹¹)₂, -C(O)O-C_1-6alkylene-N(R¹¹R¹²); R² is -OH, -OCHF₂, -OCF₃, -CHF₂, -CF₃, -CH₂CF₃, -OMe, -F, or -H; R³ at each occurrence is independently selected from H, C_3-6cycloalkyl, C_1-4alkyl, C_1- ₄haloalkyl, -O-C_1-4haloalkyl, CN, and halo; R⁴ at each occurrence is independently selected from H, C_1-4 alkyl, and -C(O)-C_1-4 alkyl; R⁵ at each occurrence is independently selected from H, halo, -OR⁸, -NR⁸R⁹, and C_1-4 alkyl; R⁶ at each occurrence is independently selected from H and C_1-4 alkyl; R⁷ is selected from H, C_1-6 alkyl, C_3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, - halo, -CN, -OR⁸, -NR⁸R⁹, -CO₂R¹¹, -CON(R¹¹R¹²), -C_1-6alkylene-halo, -C_1-6alkylene-OH, - C_1-6alkylene-N(R¹²)₂, -C_1-6alkylene-NR¹²C(=NR¹²)N(R¹²)₂, -C_1-6alkylene-NR¹²C(O)N(R¹²)₂, -C_1-6alkylene-NR¹²C(O)R¹², -C_1-6alkylene-NR¹²C(O)OR¹², -C_1-6alkylene-OC(O)N(R¹²)₂, -C_1- ₆alkylene-CO₂R¹², -C_1-6alkylene-C(O)R¹², -C_1-6alkylene-C(O)N(R¹²)₂, -C_1-6alkylene-CO₂R¹², -C_1-6alkylene-C(O)R¹², -C_1-6alkylene-C(O)NR¹²C(=NR¹²)N(R¹²)₂, -C_1-6alkylene- C(=NR¹²)N(R¹²)₂, -C_1-6alkylene-C(O)N(R¹²)₂, -C_1-6alkylene-phenyl, -OC(O)R¹², - OC(O)N(R¹¹R¹²), -O-C(=NR¹²)N(R¹¹R¹²), -O-C_3-6cycloalkyl, -O-phenyl, -O-C_1-6alkylene- OH, -O-C_1-6alkylene-CO₂R¹¹, -O-C_1-6alkylene-C(O)N(R¹¹)₂, -O-C_1-6alkylene-CN, -O-C_1- ₆alkylene-SR¹¹, -O-C_1-6alkylene-C(O)N(R¹¹R¹²), and -O-C_1-6alkylene-C(O)N(R¹¹)₂; R⁸ at each occurrence is independently H or C_1-4 alkyl; R⁹ at each occurrence is independently H or C_1-4 alkyl; R¹⁰ at each occurrence is independently selected from H, -CN, halo, C_1-4 alkyl, cyclopropyl, phenyl, =O, -OR¹¹, -SR¹¹, -CO₂R¹¹, -CON(R¹¹)₂, and -N(R¹¹R¹²); R¹¹ at each occurrence is independently selected from -H, -CO₂R¹², -COR¹², - C(O)N(R¹²)₂, and C_1-6 alkyl, wherein C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, OH, and NH₂; and R¹² at each occurrence is independently selected from H, aryl, and C_1-4 alkyl, wherein each of the aryl or C_1-4 alkyl is optionally substituted with 1-3 groups independently selected from halo, OH, and NH₂. 4. The compound according to Claim 1, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X is NR⁴, S, or O; Y is CR⁵R⁶ or a bond; Z is CR⁷; m is 0, 1, or 2; n is 0 or 1; A is 6 membered heterocyclyl; W¹ is CR⁵R⁶ or O; W² is O, S, or CR⁵R⁶; W³ is CR⁵R⁶ or O; W⁴ is CR⁵R⁶ or bond; W⁵ is CR⁵R⁶, O, or S; W⁶ is CR⁵R⁶ or bond; with the proviso that no two non-carbon atoms are connected directly with each other or to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; R¹ at each occurrence is independently selected from -H, C_1-6 alkyl, C_3-6cycloalkyl, C_1-6alkyl-CO-,

4-6 membered heterocyclyl, -OR⁸, -CO₂R⁸, -CONR⁸R⁹, halo, -CN, -NR⁸R⁹, oxo (=O), -C_1-6alkylene-OR¹⁰, -C_1-6alkylene-OC(O)NH₂, -C_1-6alkylene-C(O)OR¹¹, - C(O)OR¹¹, and -C(O)O-C_1-6alkylene-OR¹⁰; R² is -OH, -OCHF₂, -OCF₃, -OMe, -F, or -H; R³ at each occurrence is independently selected from H, C_3-6cycloalkyl, C_1-4alkyl, C_1- ₄haloalkyl, -O-C_1-4haloalkyl, -CN, and halo; R⁴ at each occurrence is independently selected from H, C_1-4 alkyl, and -C(O)-C_1-4 alkyl; R⁵ at each occurrence is independently H or C_1-4 alkyl; R⁶ at each occurrence is independently H or C_1-4 alkyl; R⁷ is selected from -H, -CN, C_1-6 alkyl, -OR⁸, -NR⁸R⁹, -O-CO₂R¹¹, -CON(R¹¹R¹²), - C_1-6alkylene-OH, -C_1-6alkylene-N(R¹²)₂, -C_1-6alkylene-NR¹²C(=NR¹²)N(R¹²)₂, -C_1-6alkylene- NR¹²C(O)N(R¹²)₂, -C_1-6alkylene-NR¹²C(O)R¹², -C_1-6alkylene-NR¹²C(O)OR¹², -C_1-6alkylene- OC(O)N(R¹²)₂, -C_1-6alkylene-CO₂R¹², -C_1-6alkylene-C(O)R¹², -C_1-6alkylene-C(O)N(R¹²)₂, - OC(O)R¹², -OC(O)N(R¹¹R¹²), -O-C_1-6alkylene-OH, -O-C_1-6alkylene-CO₂R¹¹, -O-C_1- ₆alkylene-C(O)N(R¹¹)₂, -O-C_1-6alkylene-CN, -O-C_1-6alkylene-SR¹¹, -O-C_1-6alkylene- C(O)N(R¹¹R¹²), and -O-C_1-6alkylene-C(O)N(R¹¹)₂; R⁸ at each occurrence is independently H or C_1-4 alkyl; R⁹ at each occurrence is independently H or C_1-4 alkyl; R¹⁰ at each occurrence is independently selected from H, -CN, halo, C_1-4 alkyl, cyclopropyl, phenyl, =O, -OR¹¹, -SR¹¹, -CO₂R¹¹, -CON(R¹¹)₂, and -N(R¹¹R¹²); R¹¹ at each occurrence is independently selected from -H, -CO₂R¹², -C(O)R¹², - C(O)N(R¹²)₂, and C_1-6 alkyl, wherein C_1-6 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂; and R¹² at each occurrence is independently selected from -H, aryl, and C_1-4 alkyl, wherein each of the aryl or C_1-4 alkyl is optionally substituted with 1-3 groups independently selected from halo, -OH, and -NH₂.

5. The compound according to Claim 1, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X is NR⁴; Y is CR⁵R⁶ or a bond; Z is CR⁷; m is 0, 1, or 2; n is 0 or 1; A is piperidinyl; W¹ is CR⁵R⁶ or O; W² is O, CR⁵R⁶, or bond; W³ is CR⁵R⁶ or O; W⁴ is CR⁵R⁶ or bond; W⁵ is CR⁵R⁶ or O; W⁶ is CR⁵R⁶ or bond; with the proviso that no two non-carbon atoms are connected directly with each other or to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; R¹ at each occurrence is independently selected from H, C_1-4 alkyl, -OR⁸, -CO₂R⁸, - CONR⁸R⁹, halo, -CN, -NR⁸R⁹, -C_1-4alkylene-OH, -C_1-4alkylene-O-C_1-4alkyl, -C_1-4alkylene- OC(O)NH₂, -C_1-6alkylene-C(O)OH, -C_1-6alkylene-C(O)O-C_1-6alkyl, -C(O)OH, -C(O)O-C_1- ₆alkyl, and -C(O)O-C_1-6alkylene-OH; R² is -OH, -OCHF₂, -OCF₃, -OMe, or -F; R³ at each occurrence is independently selected from H, C_3-6cycloalkyl, C_1-2alkyl, C_1- ₂haloalkyl, and -O-C_1-2haloalkyl; R⁴ at each occurrence is independently selected from H and -C(O)-C_1-2 alkyl; R⁵ at each occurrence is independently H or C_1-2 alkyl; R⁶ at each occurrence is independently H or C_1-2 alkyl; R⁷ is selected from -H, -CN, C_1-6 alkyl, -CON(R¹¹R¹²), -C_1-4alkylene-OH, -C_1- 4alkylene-N(R¹²)₂, -C_1-4alkylene-NR¹²C(O)N(R¹²)₂, -C_1-4alkylene-NR¹²C(O)R¹², -C_1- 4alkylene-NR¹²C(O)OR¹², -C_1-4alkylene-OC(O)N(R¹²)₂, -C_1-6alkylene-CO₂R¹², -C_1-6alkylene- C(O)R¹², and -C_1-4alkylene-C(O)N(R¹²)₂; R⁸ at each occurrence is independently H or C_1-4 alkyl; R⁹ at each occurrence is independently H or C_1-4 alkyl; R¹¹ at each occurrence is independently H or C_1-4 alkyl; and R¹² at each occurrence is independently H or C_1-4 alkyl.

6. The compound according to Claim 1, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X = NH; Y = a bond; Z = CR⁷; N A = ; W¹ = CH₂ or O; W² = O, CH₂, or bond; W³ = CH₂ or O; W⁴ = CH₂ or bond; W⁵ = CH₂ or O; W⁶ = CH₂ or bond; with the proviso that no two non-carbon atoms are connected directly with each other or to the same carbon atom among W¹, W², W³, W⁴, W⁵, and W⁶; m = 0, 1, or 2; n = 0 or 1; R¹ = H, CH₃, -CH₂OH, -CH₂CH₂OH, -CH₂OC(O)NH₂, -CH₂CH₂C(O)OH, - CH₂CH₂C(O)OCH₃, -CH₂CH₂C(O)OCH₂CH₃, -CH₂CH₂C(O)O-iPr, -CH₂CH₂C(O)OBu^t, - CH₂CH₂CH₂C(O)OH, -CH₂CH₂CH₂C(O)OCH₃, -C(O)OH, -C(O)OCH₃, -C(O)OCH₂CH₃, - C(O)O-iPr, -C(O)OCH₂CH₂OH, or -C(O)OCH₂CH₂CH₂OH; R² = OH or F; R³ = -CF₃, -OCH₃, -OCHF₂, -OCF₃, or cyclopropyl; and R⁷ = H, -CN, -CH₂OH, -CH₂NH₂, -CH₂OC(O)NH₂, -CH₂NHC(O)NH₂, - CH₂NHC(O)CH₃, -CH₂NHC(O)OCH₃, -CH₂CH₂C(O)OH, -CH₂CH₂C(O)OCH₃, - CH₂CH₂C(O)NH₂, or -C(O)NH₂.

7. The compound according to any one of claims 1 to 5, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, having a structure selected from formula (Ia) to formula (Id): ,

,

.

8. The compound according to any one of claims 1 to 6, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, having a formula (Ie) to formula (Ih):

,

, ,

.

9. The compound according to any one of claims 1 to 8, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹, W³, and W⁵ are each CH₂; and W², W⁴, and W⁶ are each independently CH₂ or a bond.

10. The compound according to any one of claims 1 to 8, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹, W², W³, and W⁵ are each CH₂; and W⁴ and W⁶ are each a bond.

11. The compound according to any one of claims 1 to 8, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹, W², W³, W⁴, and W⁵ are each CH₂; and W⁶ is a bond.

12. The compound according to any one of claims 1 to 8, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹, W², W³, W⁴, W⁵, and W⁶ are each CH₂.

13. The compound according to any one of claims 1 to 8, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹, W³, W⁵, and W⁶ are each CH_2; W² is O; and W⁴ is CH₂ or a bond.

14. The compound according to any one of claims 1 to 8, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹, W², W⁵, and W⁶ are each CH_2; W³ is O; and W⁴ is CH₂ or a bond.

15. The compound according to any one of claims 1 to 8, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein W¹ is O; W², W³, and W⁵ are each CH₂; W⁴ is O; and W⁶ is CH₂ or a bond.

16. The compound according to Claim 1, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds of List 1, List 2, List 3, List 4, or List 5.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

18. 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 of any one of claims 1 to 16 or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 17.

19. A method for treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 16 or a stereoisomer, a tautomer, or an isotopic derivative, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 17, wherein the disease or condition is a neurodegenerative disorder, a metabolic ailment, an inflammatory syndrome, an autoinflammatory disease, cancer, or a hereditary disease.

20. The method of Claim 19, 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, osteoarthritis, ulcerative colitis, or Crohn’s disease; the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis; the cancer is lung cancer, breast cancer, prostate cancer, skin cancer, colorectal cancer, and pancreatic cancer; and the hereditary disease is cryopyrin-associated periodic syndrome.

21. Use of a compound according to any one of Claims 1 to 16, or a stereoisomer, a tautomer, or an isotopic derivative, a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a disease or condition selected from neurodegenerative disorders, metabolic ailments, inflammatory syndromes, autoinflammatory diseases, cancers, and hereditary diseases.