Macrocyclic compounds as inhibitors of nlrp3 activity and therapeutic uses thereof

Abstract

This application discloses novel macrocyclic compounds of formula (I) and their analogues, methods for their preparation, pharmaceutical compositions comprising such compounds, and their use as drugs for treating and regulating cytokines (such as IL-1β and IL-18) and regulating NLRP. 3 or suppress NLRP 3 Its therapeutic uses are related to diseases or conditions involving the activation of components involved in the inflammatory process.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to International Patent Application No. PCT / CN2023 / 135591, filed November 30, 2023, and International Patent Application No. PCT / CN2024 / 085202, filed April 1, 2024; the disclosures of the above two applications are hereby incorporated herein by reference in their entirety.

[0003] open field

[0004] This application relates to macrocyclic pyridazine compounds and their analogues as cytokines (such as IL-1β and IL-18) or NLRP3 regulators, as well as their preparation methods and therapeutic uses.

[0005] Disclosure Background

[0006] Nucleotide-binding oligomerization domain-like receptors (or NOD-like receptors, NLRs) are a class of pattern recognition receptors (PRRs) that act as intracellular sensors, responsible for recognizing pathogen-associated molecular patterns (PAMPs) and damage- or danger-associated molecular patterns (DAMPs). NLRP3 can be activated by a wide variety of stimuli. Increasing evidence suggests that NLRs play a crucial role in the innate immune response to infection and cellular damage. Among the many NOD-like receptors, nucleotide-binding oligomerization domain-rich, leucine-rich repeat-sequence-containing protein 3 (NLRP3) has been well-established to form inflammasomes; this process involves the oligomerization of NLRP3, which in turn recruits adaptor proteins—apoptosis-associated speckle-like proteins (ASCs) containing caspase activation and recruitment domains—and effector zymogens—pro-caspase-1. The formation of the NLRP3 inflammasome activates caspase-1, which in turn catalyzes proteolytic reactions, releasing pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 [Nat. Rev. Immunol. 2013,13(6):397-411]. Activation of the NLRP3 inflammasome also leads to the lysis of Gasdermin D (GSDMD), which in turn triggers pyroptosis; this is a rapid and pro-inflammatory form of cell death, which occurs through the formation of membrane pores by GSDMD lysis.

[0007] Studies have shown that dysregulated activation of the NLRP3 inflammasome is involved in the pathogenesis of various human diseases. Most notably, gain-of-function mutations in the NLRP3 gene can lead to inherited diseases such as cryoprene-associated periodic syndrome (CAPS). Furthermore, abnormal activation of the NLRP3 inflammasome can exacerbate various chronic human diseases, including neurodegenerative diseases (such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease), metabolic diseases (such as atherosclerosis and type 2 diabetes), and inflammatory diseases (such as acute gout attacks and osteoarthritis). Recent research has also reported the role of NLRP3 in cancer development and progression [Nat. Immunol. 2021, 22(5):550-559].

[0008] Several biologics targeting the NLRP3 / IL-1β innate immune pathway have been approved for marketing. These include Anakinra (a recombinant IL-1 receptor antagonist), Canakinumab (a humanized monoclonal antibody targeting IL-1β), and Rilonacept (a soluble decoy receptor that simultaneously binds to IL-1β and IL-1α and blocks their interaction with cell surface receptors). Results from the CANTOS study showed that treatment with Canakinumab significantly reduced the likelihood of recurrent cardiovascular events, strongly demonstrating the clear clinical benefit of treating inflammation in high-risk cardiovascular patients. Furthermore, targeting and inhibiting NLRP3 activation with small molecule drugs is also a viable strategy; CRID3 (also known as MCC950) is a typical example. Researchers have confirmed through cryo-electron microscopy (Cryo-EM) or X-ray crystallography that CRID3 can directly bind to the full-length NLRP3 protein, while a certain analogue can bind to the NACHT domain of the NLRP3 protein [Nature 2022; 604:184-189; J. Mol. Biol. 2021, 433(24);167309]. Compared to using biologics to target IL-1β, using specific small molecule inhibitors to target NLRP3 has potential advantages: first, specific NLRP3 inhibitors can preserve the normal function of other inflammasomes that produce IL-1β; second, the half-life of small molecule drugs is generally much shorter than that of biologics (e.g., Canakinumab has a half-life of up to 28 days in humans). This latter advantage allows for rapid discontinuation of the drug when necessary (e.g., in the event of infection), thus providing greater flexibility for clinical treatment.

[0009] CRID3 (CP-456,773) was discovered by Pfizer researchers in the late 1990s, when its target was still unclear [US Patent No. 6,166,064; J. Pharmacol. Exp. Ther. 2001, 299:187-197]. Its clinical trials were subsequently halted, presumably due to safety concerns. Since its biological target was identified as NLRP3 in 2015 [Nat. Med. 2015, 21:248–255], several NLRP3 inhibitors, primarily distributed in the peripheral nervous system, have entered clinical trials. However, CRID3 and its derivatives have proven to have extremely weak brain penetration, far below the generally accepted standards for brain penetration in this field. Although a few NLRP3 inhibitors in early clinical trials claim central nervous system (CNS) penetration, the CNS penetration of these allegedly CNS-penetrating NLRP3 inhibitors has not been independently verified. Therefore, there is still an urgent need to develop NLRP3 inhibitors with CNS penetration, high specificity, and high safety to advance their clinical development and application.

[0010] Inhibiting the NLRP3 / IL-1β innate immune pathway with small molecule modulators may be an effective and feasible approach for treating and preventing a variety of diseases [Nat. Rev. Drug Discov. 2018, 18(5):1141-1160;Pharmacol. Rev. 2021, 73:968-1000]. These diseases include, but are not limited to: genetic disorders (such as cryoprene-associated periodic syndrome, CAPS), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, and traumatic brain injury), metabolic diseases (such as atherosclerosis and type 2 diabetes), inflammatory diseases (such as acute gout attacks and osteoarthritis), cancer, and other related human diseases. NLRP3 inhibitors may have potential efficacy in treating inflammatory bowel disease (IBD, including Crohn's disease and ulcerative colitis) [Front Immunol. 2019, 10:276]. In such applications, gut-specific NLRP3 inhibitors may be more advantageous than systemic NLRP3 inhibitors. Therefore, NLRP3 inhibitors confined to the gut are expected to demonstrate practical application value in the treatment of human diseases.

[0011] Various pyridazine derivatives or analogs have been disclosed as NLRP3 inhibitors. See, for example: WO2020 / 234715, WO2021 / 193897, WO2022 / 135567, WO2022 / 166890, WO2022 / 216971, US Patent Nos. 11,319,319, 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, Applications for NLRP3 inhibitors based on pyridazines and related structures, WO2024 / 169858, WO2024 / 169895, WO2024 / 188994, WO2024 / 193541, WO2024 / 193699, WO2024 / 193703, WO2024 / 213552, WO2024 / 217442, WO2024 / 218100, and WO2024 / 218188, indicate that most of these compounds exhibit properties suitable for use as peripherally restricted NLRP3 inhibitors. A few applications involving NLRP3 inhibitors with central nervous system (CNS) penetration appear to have various deficiencies. To date, among the NLRP3 inhibitors currently in human clinical trials with publicly disclosed structures, none claim to possess CNS penetration capabilities, and none have demonstrated good brain penetration after replication in non-clinical species models. Therefore, there is an urgent need to develop NLRP3 inhibitors with CNS penetration capabilities. None of the aforementioned applications have demonstrated NLRP3 inhibitors with proven intestinal restriction (i.e., functioning only within the gut).

[0012] Therefore, it remains necessary to develop novel compounds with potent central nervous system (CNS) penetration or distribution characteristics limited to the intestines, and which also possess suitable pharmacokinetic, safety, and physicochemical properties, as NLRP3 inhibitors for the treatment of various diseases and conditions.

[0013] Overview of Public Content

[0014] This disclosure aims to meet the above-mentioned needs by providing macrocyclic pyridazine compounds and their derivatives as NLRP3 inhibitors, particularly NLRP3 inhibitors that are confined to the intestine or can penetrate the central nervous system.

[0015] In one aspect, this disclosure provides a compound having the structure of formula (I):

[0016]

[0017] Or its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein:

[0018] X is NR 4 S, O or CR 5 R 6 ;

[0019] Y is CR 5 R 6 OR key;

[0020] Z is N or CR 7 ;

[0021] Ring A is a 4-7 membered heterocyclic group, C 6-10 Aryl, 5-6 heteroaryl, or 4-7 carbocyclic, each optionally independently selected from R 1 One to three groups are substituted; however, when A is C... 6-10 When aryl or 5-6 heteroaryl, R 1 It is not an oxygen group (=O).

[0022] W 1 W 3 and W 5 Each independently selected from CR 5 R 6 O, S and NR 4 And W 2 W 4 and W 6 Each is independently selected from key, CR 5 R 6 O, S and NR 4 But the premise is W 1W 2 W 3 W 4 W 5 and W 6 In this context, no two non-carbon atoms are directly connected, nor are they connected to the same carbon atom; or, where R... 5 With R 6 R 4 With R 5 、or R 4 With R 6 Additional 3-4 element helical rings or 5-7 element bridge rings can be formed;

[0023] m is 0, 1, 2, or 3; and

[0024] n is 0, 1, or 2

[0025] R 1 Each time it appears, it is independently selected from -H, C. 1-8 Alkyl, C 3-7 cycloalkyl, C 1-8 Alkyl-CO-, 4-7 membered heterocyclic groups, OR 8 CO2R 8 C(O)NR 8 R 9 Halogen, CN, NR 8 R 9 And oxygen group (=O); where, C 1-8 Alkyl, C 3-7 cycloalkyl, C 1-8 Each of the alkyl-CO- and 4-7 membered heterocyclic groups may optionally be replaced by 1-3 independently selected R 10 Substitution of groups;

[0026] R 2 It can be -OH, -OCHF2, -OCF3, -CHF2, -CF3, -CH2CF3, -OMe, -F, or -H;

[0027] R 3 Each time it appears, it is independently selected from -H, C. 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, halogens, -CN, -SF5, -NR 8 R 9 -OR 8 -SR 8 , aryl and heteroaryl; of which, C 3-6 cycloalkyl and C 1-6Each alkyl group may optionally be surrounded by 1-3 independently selected from halogens, oxo groups, and C. 1-4 The alkyl group is substituted; and wherein the aryl and heteroaryl groups are each optionally replaced by 1-3 groups independently selected from halogens and C. 1-4 Alkyl group substitution;

[0028] R 4 Each time it appears, it is independently selected from -H, C. 1-4 Alkyl, -C(O)-C 1-4 Alkyl and C 3-7 cycloalkyl; wherein, C 1-4 Alkyl and C 3-7 Each cycloalkyl group may optionally be independently selected from 1 to 3 R groups. 10 Substitution of groups;

[0029] R 5 and R 6 Each occurrence is independently selected from -H, halogen, -OR. 8 -NR 8 R 9 C 1-4 Alkyl, C 3-7 Cycloalkyl and 4-7 membered heterocyclic groups, wherein C 1-4 Alkyl, C 3-7 Each of the cycloalkyl and 4-7 membered heterocyclic groups may optionally be replaced by 1-3 independently selected R 10 Substitution of groups;

[0030] Or, R connected to the same atom 5 and R 6 Together they form = O;

[0031] Alternatively, R connected to the same or different atoms 5 and R 6 It can form a 3-6 membered carbon ring or heterocycle, which can optionally be divided by 1-3 R... 10 Group substitution;

[0032] R 7 Independently selected from H and C 1-8 Alkyl, C 3-7 Cycloalkyl, aryl, heteroaryl, halogen, -CN, -OR 8 -NR 8 R 9 -CO2R 11 and -C(O)N(R) 11 R 12 ); where C 1-4 Alkyl, C 3-7Each of the cycloalkyl, aryl, and heteroaryl groups may optionally be selected from 1 to 3 independently chosen from R 13 Substitution of groups;

[0033] Or, R 7 Can be used with R 4 R 5 or R 6 Together they form a 5-7 membered carbon ring or heterocycle, which can be optionally divided by 1-3 R atoms. 10 Group substitution;

[0034] R 8 and R 9 Independently selected from -H, -C(O)R 12 -C(O)N(R) 11 R 12 -C(=NR) 12 )N(R 11 R 12 C 1-6 Alkyl, C 3-7 cycloalkyl and aryl; wherein, C 1-6 Alkyl, C 3-7 Each of the cycloalkyl and aryl groups may optionally be selected from 1 to 3 independently chosen from R 10 The group is substituted, but when R 8 or R 9 When it is aryl, R 10 It cannot be =O;

[0035] Each occurrence of R 10 Each is independently selected from -H, -CO2R 11 -C(O)N(R) 11 )2、-CN、-OR 11 Halogen, C 1-6 Alkyl, cyclopropyl, aryl, =O, -SR 11 and -N(R) 11 R 12 );

[0036] Each occurrence of R 11 Each is independently selected from -H, -CO2R 12 -C(O)R 12 -C(O)NR 12 C(=NR 12 )N(R 12 )2、-C(=NR 12 )N(R 12 )2、-C(O)N(R 12 2. Aryl and C 1-6Alkyl groups, wherein each aryl group and C 1-6 The alkyl group may optionally be substituted with 1 to 3 groups independently selected from halogens, -OH and -NH2;

[0037] Each occurrence of R 12 Each is independently selected from -H, aryl, and C. 1-4 Alkyl groups, wherein each aryl group or C 1-4 The alkyl group may optionally be substituted with 1 to 3 groups independently selected from halogens, -OH and -NH2;

[0038] R 13 Each time it appears, it is independently selected from -H, halogen, -OH, -N(R) 12 )2、-NR 12 C(=NR 12 )N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 C(O)R 12 -NR 12 C(O)OR 12 -OC(O)N(R) 12 )2、-CO2R 12 -COR 12 -C(O)NR 12 C(=NR 12 )N(R 12 )2、-C(=NR 12 )N(R 12 )2、-C(O)N(R 12 2. Aryl and C 1-6 Alkyl; wherein the aryl and C 1-6 Each alkyl group may optionally be substituted with one to three independent groups selected from halogens, -OH and -NH2.

[0039] In another aspect, this disclosure provides a pharmaceutical composition comprising a compound of formula (I) according to any of the embodiments disclosed herein (or a stereoisomer, tautomer, isotope derivative thereof or a pharmaceutically acceptable salt thereof), and one or more pharmaceutically acceptable carriers.

[0040] On the other hand, this disclosure provides a method for treating or preventing a disease or condition that is responsive to inhibition of NLRP3 and is performed on a subject in need of such treatment; the method includes administering to the subject an effective amount of a compound of formula (I) according to any embodiment disclosed herein (or a stereoisomer, tautomer, isotopic derivative thereof or a pharmaceutically acceptable salt thereof).

[0041] On the other hand, this disclosure provides a method for treating or preventing a disease or condition in a subject that responds to NLRP3 inhibition, the method comprising administering to the subject in need an effective amount of a pharmaceutical composition comprising a compound of formula (I) according to any embodiment disclosed herein, or a stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof.

[0042] On the other hand, this disclosure provides the use of a compound of formula (I) according to any embodiment disclosed herein, or a stereoisomer, tautomer, isotope derivative or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease selected from neurodegenerative diseases, metabolic diseases, inflammatory syndromes, autoinflammatory diseases, cancer and genetic diseases.

[0043] In one embodiment, the diseases or conditions that the disclosed compounds can treat include neurodegenerative diseases, metabolic diseases, inflammatory syndromes, autoinflammatory diseases, cancer, or genetic diseases.

[0044] Other aspects and advantages will become clearer in the following detailed description, embodiments and claims.

[0045] Detailed description of this disclosure

[0046] This disclosure provides novel macrocyclic compounds and analogues as therapeutic agents for diseases or conditions related to the treatment and regulation of cytokines (such as IL-1β and IL-18), regulation of NLRP3, or inhibition of the activation of NLRP3 and its associated inflammatory process components.

[0047] In one aspect, this disclosure provides a compound having the structure of formula (I):

[0048]

[0049] Or its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein:

[0050] X is NR 4 S, O or CR 5 R 6 ;

[0051] Y is CR 5 R 6 OR key;

[0052] Z is N or CR 7 ;

[0053] Ring A is a 4-7 membered heterocyclic group, C 6-10Aryl, 5-6 heteroaryl, or 4-7 carbocyclic, each optionally independently selected from R 1 One to three groups are substituted; however, when A is C... 6-10 When aryl or 5-6 heteroaryl, R 1 It is not an oxygen group (=O).

[0054] W 1 W 3 and W 5 Each independently selected from CR 5 R 6 O, S and NR 4 And W 2 W 4 and W 6 Each is independently selected from key, CR 5 R 6 O, S and NR 4 But the condition is: in W 1 W 2 W 3 W 4 W 5 and W 6 In this context, no two non-carbon atoms are directly connected, nor are they connected to the same carbon atom; or, where R... 5 With R 6 R 4 With R 5 、or R 4 With R 6 Additional 3-4 element helical rings or 5-7 element bridge rings can be formed;

[0055] m is 0, 1, 2, or 3; and

[0056] n is 0, 1, or 2.

[0057] R 1 Each time it appears, it is independently selected from -H, C. 1-8 Alkyl, C 3-7 cycloalkyl, C 1-8 Alkyl-CO-, 4-7 membered heterocyclic groups, OR 8 CO2R 8 C(O)NR 8 R 9 Halogen, CN, NR 8 R 9 And oxygen group (=O); where, C 1-8 Alkyl, C 3-7 cycloalkyl, C 1-8Each of the alkyl-CO- and 4-7 membered heterocyclic groups may optionally be replaced by 1-3 independently selected R 10 Group substitution; R 2 It can be -OH, -OCHF2, -OCF3, -CHF2, -CF3, -CH2CF3, -OMe, -F, or -H;

[0058] R 3 Each time it appears, it is independently selected from -H, C. 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, halogens, -CN, -SF5, -NR 8 R 9 -OR 8 -SR 8 , aryl and heteroaryl; of which, C 3-6 cycloalkyl and C 1-6 Each of the alkyl groups may optionally be surrounded by 1-3 groups independently selected from halogens, oxo groups, and C. 1-4 The alkyl group is substituted; and each of the aryl and heteroaryl groups may optionally be replaced by 1-3 groups independently selected from halogens and C. 1-4 Alkyl group substitution;

[0059] R in various places 4 Independently selected from -H, C 1-4 Alkyl, -C(O)-C 1-4 Alkyl and C 3-7 cycloalkyl, wherein each C 1-4 Alkyl and C 3-7 The cycloalkyl group may optionally be composed of 1-3 independently selected R 10 Substitution of groups;

[0060] R in various places 5 and R 6 Independently selected from -H, halogen, -OR 8 -NR 8 R 9 C 1-4 Alkyl, C 3-7 Cycloalkyl and 4-7 membered heterocyclic groups, wherein each C 1-4 Alkyl, C 3-7 The cycloalkyl group and the 4-7 membered heterocyclic group may optionally be replaced by 1-3 independently selected R 10 Substitution of groups;

[0061] Or, R connected to the same atom 5 and R 6They can collectively form =O;

[0062] Alternatively, R connected to the same or different atoms 5 and R 6 It can form a 3-6 membered carbon ring or heterocycle, which can optionally be divided by 1-3 R... 10 Group substitution;

[0063] R 7 Independently selected from H and C 1-8 Alkyl, C 3-7 Cycloalkyl, aryl, heteroaryl, halogen, -CN, -OR 8 -NR 8 R 9 -CO2R 11 and -C(O)N(R) 11 R 12 ); where C 1-4 Alkyl, C 3-7 Cycloalkyl, aryl, and heteroaryl groups may each be optionally selected by 1 to 3 independently chosen from R 13 Substitution of groups;

[0064] Or, R 7 Can be used with R 4 R 5 or R 6 Together they form a 5-7 membered carbon ring or heterocycle, which can be optionally divided by 1-3 R atoms. 10 Group substitution;

[0065] R 8 and R 9 Independently selected from -H, -C(O)R12, -C(O)N(R) 11 R 12 -C(=NR) 12 )N(R 11 R 12 C 1-6 Alkyl, C 3-7 cycloalkyl and aryl; wherein, C 1-6 Alkyl, C 3-7 Each of the cycloalkyl and aryl groups may optionally be selected from 1 to 3 independently chosen from R 10 The group is substituted, but when R 8 or R 9 When it is aryl, R 10 Not equal to O.

[0066] R 10 Each time it appears, it is independently selected from -H, -CO2R. 11 -C(O)N(R)11 )2、-CN、-OR 11 Halogen, C 1-6 Alkyl, cyclopropyl, aryl, =O, -SR 11 and -N(R) 11 R 12 );

[0067] R 11 Each time it appears, it is independently selected from -H, -CO2R. 12 -C(O)R 12 -C(O)NR 12 C(=NR 12 )N(R 12 )2、-C(=NR 12 )N(R 12 )2、-C(O)N(R 12 2. Aryl and C 1-6 alkyl, wherein the aryl and C 1-6 Each of the alkyl groups may optionally be substituted by 1 to 3 groups independently selected from halogens, -OH and -NH2;

[0068] R 12 Each time it appears, it is independently selected from -H, aryl, and C. 1-4 alkyl, wherein the aryl or C 1-4 Each of the alkyl groups may optionally be substituted with 1 to 3 groups independently selected from halogens, -OH, and -NH2; and

[0069] R 13 Each time it appears, it is independently selected from -H, halogen, -OH, -N(R) 12 )2、-NR 12 C(=NR 12 )N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 C(O)R 12 -NR 12 C(O)OR 12 -OC(O)N(R) 12 )2、-CO2R 12 -COR 12 -C(O)NR 12 C(=NR 12 )N(R 12 )2、-C(=NR 12 )N(R 12 )2、-C(O)N(R 12 2. Aryl and C1-6 alkyl, wherein the aryl and C 1-6 Each of the alkyl groups may optionally be substituted with 1 to 3 groups independently selected from halogens, -OH and -NH2.

[0070] In some embodiments, this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein:

[0071] X is NR 4 S, O or CR 5 R 6 ;

[0072] Y is CR 5 R 6 OR key;

[0073] Z is N or CR 7 ;

[0074] Ring A is a 5-6 membered heterocyclic group, a 5-6 membered carbocyclic group, or a phenyl group, each of which can be independently selected from R. 1 One to three groups are substituted;

[0075] W 1 W 3 and W 5 Each independently for CR 5 R 6 O or S; and W 2 W 4 and W 6 Each independently forms a key, CR 5 R 6 O or S, but only if W 1 W 2 W 3 W 4 W 5 and W 6 Within a given element, no two non-carbon atoms may be directly connected to each other or connected to the same carbon atom.

[0076] m can be 0, 1, 2, or 3;

[0077] n is 0, 1, or 2;

[0078] i is either 1 or 2 independently each time it appears;

[0079] R 1 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6Alkyl-CO-, 4-6 membered heterocyclic groups, -OR 8 -CO2R 8 -C(O)NR 8 R 9 Halogen, -CN, -NR 8 R 9 , O group (=O), -C 1-6 Alkylene-(R 10 ) i -C 3-6 Cycloalkylene-(R 10 ) i -C(O)-C 1-6 Alkyl-(R) 10 ) i And -(4-6 heterocyclic subunit)-(R 10 ) i ;

[0080] R 2 It can be -OH, -OCHF2, -OCF3, -CHF2, -CF3, -CH2CF3, -OMe, -F, or -H;

[0081] R 3 Each time it appears, it is independently selected from -H, C. 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, halogens, -CN, -NR 8 R 9 -OR 8 -SR 8 , phenyl and 5-6 heteroaryl; wherein, the C 3-6 cycloalkyl, C 1-6 Alkyl, phenyl, and 5-6 heteroaryl groups may each optionally be surrounded by 1-3 independently selected halogens and C. 1-4 Alkyl group substitution;

[0082] R 4 Each time it appears, it is independently selected from -H, C. 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-6 cycloalkyl, -C 1-6 Alkylene-(R 10 ) i and -C 3-6 Cycloalkylene-(R 10 ) i ;

[0083] R 5 and R 6Each occurrence is independently selected from -H, halogen, or -OR. 8 -NR 8 R 9 C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, -C 1-6 Alkylene-(R 10 ) i -C 3-6 Cycloalkylene-(R 10 ) i -C(O)-C 1-6 Alkyl-(R) 10 ) i and -(4-6-membered heterocyclic subunit)-(R 10 ) i ;

[0084] Or, R 5 and R 6 They combine to form an oxygen group (=O);

[0085] R 7 Selected from -H, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 heteroaryl, -halogen, -CN, -OR 8 -NR 8 R 9 -CO2R 11 -C(O)N(R) 11 R 12 -C 1-6 Alkylene-(R 13 ) i and -C 3-6 Cycloalkylene-(R 13 ) i ;

[0086] R 8 Each time it appears, it is independently selected from -H, -C(O)R. 12 -C(O)N(R) 11 R 12 C 1-6 Alkyl, C 3-6 cycloalkyl, phenyl, -C 1-6 Alkylene-(R 10 ) i -C 3-6 Cycloalkylene-(R 10 ) i and -phenylene-(R 10 ) i ;

[0087] R 9 Each time it appears, it is independently selected from -H, C. 1-4 Alkyl and C 3-6 cycloalkyl;

[0088] R 10 Each occurrence is independently selected from -H, -CN, halogen, and C. 1-4 Alkyl, cyclopropyl, phenyl, =O, -OR 11 -SR 11 -CO2R 11 -C(O)N(R) 11 )2 and -N(R 11 R 12 );

[0089] R 11 Each time it appears, it is independently selected from -H, -CO2R. 12 -C(O)R 12 -C(O)NR 12 C(=NR 12 )N(R 12 )2、-C(=NR 12 )N(R 12 )2、-C(O)N(R 12 2. Phenyl and C 1-6 Alkyl groups, including phenyl and C 1-6 Each alkyl group may optionally be substituted with one to three independent groups selected from halogens, -OH and -NH2;

[0090] R 12 Each time it appears, it is independently selected from -H, aryl, and C. 1-4 alkyl, wherein the aryl or C 1-4 Each of the alkyl groups is optionally substituted by 1-3 groups independently selected from halogens, -OH, and -NH2; and

[0091] R 13 Each time it appears, it is independently selected from -H, halogen, -OH, -N(R) 12 )2、-NR 12 C(=NR 12 )N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 C(O)R 12 -NR 12 C(O)OR 12 -OC(O)N(R) 12 )2、-CO2R12 -C(O)R 12 -C(O)NR 12 C(=NR 12 )N(R 12 )2、-C(=NR 12 )N(R 12 )2、-C(O)N(R 12 2. Aryl and C 1-6 alkyl, wherein the aryl and C 1-6 Each of the alkyl groups is optionally substituted by 1-3 groups independently selected from halogens, OH and NH2.

[0092] In some embodiments, this disclosure provides a compound of formula (I), or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein:

[0093] X is NR 4 S, O or CR 5 R 6 ;

[0094] Y is CR 5 R 6 OR key;

[0095] Z is CR 7 ;

[0096] m can be 0, 1, 2, or 3;

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

[0098] A is a 5-6 membered heterocyclic group;

[0099] W 1 For CR 5 R 6 Or O;

[0100] W 2 For O, S, CR 5 R 6 OR key;

[0101] W 3 For CR 5 R 6 Or O;

[0102] W 4 For CR 5 R 6 OR key;

[0103] W 5 For CR 5 R6 、O or S;

[0104] W 6 For CR 5 R 6 Or key; but only if it is in W 1 W 2 W 3 W 4 W 5 and W 6 In this system, no two non-carbon atoms may be directly connected to each other, nor may they be connected to the same carbon atom.

[0105] R 1 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl-CO-, 4-6 membered heterocyclic groups, -OR 8 -CO2R 8 -CONR 8 R 9 Halogen, -CN, -NR 8 R 9 Oxygenation (=O), -C 1-6 Alkylene-CN, -C 1-6 Alkylene halogen, -C 1-6 alkylene-cyclopropyl, -C 1-6 alkylene-phenyl, -C 1-6 Alkylene-OR 11 -C 1-6 Alkylene-SR 11 -C 1-6 Alkylene-CO2R 11 -C 1-6 Alkylene-C(O)N(R) 11 )2、-C 1-6 Alkylene-N(R) 11 R 12 -OC(O)R 12 -OC(O)N(R) 11 R 12 -OC (=NR) 12 )N(R 11 R 12 -OC 3-6 Cycloalkyl, -O-phenyl, -OC 1-6 Alkylene-CN, -OC 1-6 Alkylene-halogen, -OC 1-6 alkylene-cyclopropyl, -OC 1-6 alkylene-phenyl, -OC 1-6Alkylene-OR 11 -OC 1-6 Alkylene-SR 11 -OC 1-6 Alkylene-CO2R 11 -OC 1-6 Alkylene-C(O)N(R) 11 )2、-OC 1-6 Alkylene-N(R) 11 R 12 -C(O)OC 1-6 Alkylene-CN, -C(O)OC 1-6 Alkylene-halogen, -C(O)OC 1-6 alkylene-cyclopropyl, -C(O)OC 1-6 alkylene-phenyl, -C(O)OC 1-6 Alkylene-OR 11 -C(O)OC 1-6 Alkylene-SR 11 , -C(O)OC 1-6 Alkylene-CO2R 11 , -C(O)OC 1-6 Alkylene-C(O)N(R) 11 )2, -C(O)OC 1-6 Alkylene-N(R) 11 R 12 );

[0106] R 2 It can be -OH, -OCHF2, -OCF3, -CHF2, -CF3, -CH2CF3, -OMe, -F, or -H;

[0107] R 3 Each time it appears, it is independently selected from H and C. 3-6 cycloalkyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl halogens, CN, and halogens;

[0108] R 4 Each time it appears, it is independently selected from H and C. 1-4 Alkyl groups and -C(O)-C 1-4 alkyl;

[0109] R 5 Each occurrence is independently selected from H, halogen, and -OR. 8 -NR 8 R 9 and C 1-4 alkyl;

[0110] R 6 Each time it appears, it is independently selected from H and C. 1-4 alkyl;

[0111] R 7 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 heteroaryl, halogen, -CN, -OR 8 -NR 8 R 9 -CO2R 11 -CON(R) 11 R 12 -C 1-6 Alkylene halogen, -C 1-6 alkylene -OH, -C 1-6 Alkylene-N(R) 12 )2、-C 1-6 Alkylene-NR 12 C(=NR 12 )N(R 12 )2、-C 1-6 Alkylene-NR 12 C(O)N(R 12 )2、-C 1-6 Alkylene-NR 12 C(O)R 12 -C 1-6 Alkylene-NR 12 C(O)OR 12 -C 1-6 Alkylene-OC(O)N(R) 12 )2、-C 1-6 Alkylene-CO2R 12 -C 1-6 Alkylene-C(O)R 12 -C 1-6 Alkylene-C(O)N(R) 12 )2、-C 1-6 Alkylene-CO2R 12 -C 1-6 Alkylene-C(O)R 12 -C 1-6 Alkylene-C(O)NR 12 C(=NR 12 )N(R 12 )2、-C 1-6 Alkylene-C(=NR) 12 )N(R 12 )2、-C 1-6 Alkylene-C(O)N(R) 12)2、-C 1-6 alkylene-phenyl, -OC(O)R 12 -OC(O)N(R) 11 R 12 -OC (=NR) 12 )N(R 11 R 12 -OC 3-6 Cycloalkyl, -O-phenyl, -OC 1-6 Alkylene -OH, -OC 1-6 Alkylene-CO2R 11 -OC 1-6 Alkylene-C(O)N(R) 11 )2、-OC 1-6 Alkylene-CN, -OC 1-6 Alkylene-SR 11 -OC 1-6 Alkylene-C(O)N(R) 11 R 12 ) and -OC 1-6 Alkylene-C(O)N(R) 11 )2;

[0112] Each occurrence of R 8 Each is an independent H or C 1-4 alkyl;

[0113] Each occurrence of R 9 Each is an independent H or C 1-4 alkyl;

[0114] Each occurrence of R 10 Independently selected from H, -CN, halogens, C 1-4 Alkyl, cyclopropyl, phenyl, =O, -OR 11 -SR 11 -CO2R 11 -CON(R) 11 )2 and -N(R 11 R 12 );

[0115] Each occurrence of R 11 Independently selected from -H, -CO2R 12 -COR 12 -C(O)N(R) 12 )2 and C 1-6 Alkyl, wherein C 1-6 The alkyl group may optionally be substituted by 1-3 groups independently selected from halogens, OH and NH2;

[0116] R 12 Each time it appears, it is independently selected from H, aryl, and C. 1-4 Alkyl groups, wherein each aryl group or C 1-4 The alkyl group is optionally substituted with 1-3 groups independently selected from halogens, OH and NH2.

[0117] In some embodiments, this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein:

[0118] X is NR 4 S or O;

[0119] Y is CR 5 R 6 OR key;

[0120] Z is CR 7 ;

[0121] m is 0, 1, or 2;

[0122] n is 0 or 1;

[0123] A is a six-membered heterocyclic group;

[0124] W 1 For CR 5 R 6 Or O;

[0125] W 2 For O, S or CR 5 R 6 ;

[0126] W 3 For CR 5 R 6 Or O;

[0127] W 4 For CR 5 R 6 OR key;

[0128] W 5 For CR 5 R 6 、O or S;

[0129] W 6 For CR 5 R 6 Or chemical bonds; but the premise is: in W 1 W 2 W 3 W 4W 5 and W 6 In this process, no two non-carbon atoms may be directly connected to each other, nor may they be connected to the same carbon atom.

[0130] R 1 Each occurrence is independently selected from -H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl-CO-, 4-6 membered heterocyclic groups, -OR 8 -CO2R 8 -CONR 8 R 9 Halogen, -CN, -NR 8 R 9 Oxygenation (=O), -C 1-6 Alkylene-OR 10 -C 1-6 Alkylene -OC(O)NH2, -C 1-6 Alkylene-C(O)OR 11 -C(O)OR 11 and -C(O)OC 1-6 Alkylene-OR 10 ;

[0131] R 2 It can be -OH, -OCHF2, -OCF3, -OMe, -F, or -H;

[0132] R 3 Each time it appears, it is independently selected from H and C. 3-6 cycloalkyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl halogens, -CN, and halogens;

[0133] R 4 Each time it appears, it is independently selected from H and C. 1-4 Alkyl groups and -C(O)-C 1-4 alkyl;

[0134] R 5 Each occurrence is independently H or C. 1-4 alkyl;

[0135] R 6 Each occurrence is independently H or C. 1-4 alkyl;

[0136] R 7 Selected from -H, -CN, C 1-6 Alkyl, -OR8 -NR 8 R 9 -O-CO2R 11 -CON(R) 11 R 12 -C 1-6 alkylene -OH, -C 1-6 Alkylene-N(R) 12 )2、-C 1-6 Alkylene-NR 12 C(=NR 12 )N(R 12 )2、-C 1-6 Alkylene-NR 12 C(O)N(R 12 )2、-C 1-6 Alkylene-NR 12 C(O)R 12 -C 1-6 Alkylene-NR 12 C(O)OR 12 -C 1-6 Alkylene-OC(O)N(R) 12 )2、-C 1-6 Alkylene-CO2R 12 -C 1-6 Alkylene-C(O)R 12 -C 1-6 Alkylene-C(O)N(R) 12 )2、-OC(O)R 12 -OC(O)N(R) 11 R 12 -OC 1-6 Alkylene -OH, -OC 1-6 Alkylene-CO2R 11 -OC 1-6 Alkylene-C(O)N(R) 11 )2、-OC 1-6 Alkylene-CN, -OC 1-6 Alkylene-SR 11 -OC 1-6 Alkylene-C(O)N(R) 11 R 12 ) and -OC 1-6 Alkylene-C(O)N(R) 11 )2;

[0137] R 8 It is independently H or C each time it appears. 1-4 alkyl;

[0138] R 9 It is independently H or C each time it appears. 1-4 alkyl;

[0139] R 10 Each occurrence is independently selected from H, -CN, halogen, C. 1-4 Alkyl, cyclopropyl, phenyl, =O, -OR 11 -SR 11 -CO2R 11 -CON(R) 11 )2 and -N(R 11 R 12 );

[0140] R 11 Each time it appears, it is independently selected from -H, -CO2R. 12 -C(O)R 12 -C(O)N(R) 12 )2 and C 1-6 Alkyl, wherein C 1-6 The alkyl group may optionally be substituted with 1-3 groups independently selected from halogens, -OH, and -NH2; and

[0141] R 12 Each time it appears, it is independently selected from -H, aryl, and C. 1-4 alkyl, wherein the aryl or C 1-4 Each of the alkyl groups may optionally be substituted with 1 to 3 groups independently selected from halogens, -OH and -NH2.

[0142] In some embodiments, this disclosure provides a compound of formula (I), or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein:

[0143] X is NR 4 ;

[0144] Y is CR 5 R 6 OR key;

[0145] Z is CR 7 ;

[0146] m is 0, 1, or 2;

[0147] n is 0 or 1;

[0148] A is piperidinyl;

[0149] W 1 For CR 5 R 6 Or O;

[0150] W 2 For O, CR 5 R 6 OR key;

[0151] W 3 For CR 5 R 6 Or O;

[0152] W 4 For CR 5 R 6 OR key;

[0153] W 5 For CR 5 R 6 Or O;

[0154] W 6 For CR 5 R 6 Or key; but only if it is in W 1 W 2 W 3 W 4 W 5 and W 6 There is no situation where two non-carbon atoms are directly connected to each other or connected to the same carbon atom;

[0155] R 1 Each time it appears, it is independently selected from H and C. 1-4 Alkyl, -OR 8 -CO2R 8 -CONR 8 R 9 Halogen, -CN, -NR 8 R 9 -C 1-4 alkylene -OH, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -OC(O)NH2, -C 1-6 Alkylene -C(O)OH, -C 1-6 Alkylene-C(O)OC 1-6 Alkyl, -C(O)OH, -C(O)OC 1-6 Alkyl groups and -C(O)OC 1-6 alkylene-OH;

[0156] R 2 It can be -OH, -OCHF2, -OCF3, -OMe, or -F;

[0157] R 3 Each time it appears, it is independently selected from H and C. 3-6 cycloalkyl, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -OC 1-2 Halogenated alkyl groups;

[0158] R 4 Each occurrence is independently selected from H and -C(O)-C. 1-2 alkyl;

[0159] R 5 It is independently H or C each time it appears. 1-2 alkyl;

[0160] R 6 It is independently H or C each time it appears. 1-2 alkyl;

[0161] R 7 Selected from -H, -CN, C 1-6 Alkyl, -CON(R) 11 R 12 -C 1-4 alkylene -OH, -C 1-4 Alkylene-N(R) 12 )2、-C 1-4 Alkylene-NR 12 C(O)N(R 12 )2、-C 1-4 Alkylene-NR 12 C(O)R 12 -C 1-4 Alkylene-NR 12 C(O)OR 12 -C 1-4 Alkylene-OC(O)N(R) 12 )2、-C 1-6 Alkylene-CO2R 12 -C 1-6 Alkylene-C(O)R 12 and -C 1-4 Alkylene-C(O)N(R) 12 )2;

[0162] Each R 8 Independently H or C 1-4 alkyl;

[0163] Each R 9 Independently H or C 1-4 alkyl;

[0164] Each R11 Independently H or C 1-4 Alkyl; and

[0165] Each R 12 Independently H or C 1-4 alkyl.

[0166] In some embodiments, this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein:

[0167] X = NH;

[0168] Y = key;

[0169] Z = CR 7 ;

[0170] A = ;

[0171] W 1 = CH2 or O;

[0172] W 2 = O, CH22 or bond;

[0173] W 3 = CH2 or O;

[0174] W 4 = CH2 or bond;

[0175] W 5 = CH2 or O;

[0176] W 6 = CH2 or bond; but only if, in W 1 W 2 W 3 W 4 W 5 and W 6 In this system, no two non-carbon atoms may be directly connected to each other, nor may they be connected to the same carbon atom.

[0177] m = 0, 1, or 2;

[0178] n = 0 or 1;

[0179] R 1= H, CH3, -CH2OH, -CH2CH2OH, -CH2OC(O)NH2, -CH2CH2C(O)OH, -CH2CH2C(O)OCH3, -CH2CH2C(O)OCH2CH3, -CH2CH2C(O)O- i Pr, -CH2CH2C(O)OBu t , -CH2CH2CH2C(O)OH, -CH2CH2CH2C(O)OCH3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O- i Pr, -C(O)OCH2CH2OH, or -C(O)OCH2CH2CH2OH;

[0180] R 2 = OH or F;

[0181] R 3 = -CF3, -OCH3, -OCHF2, -OCF3 or cyclopropyl; and

[0182] R 7 = 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.

[0183] In some embodiments, this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, having a structure selected from formula (Ia):

[0184] ,

[0185] Where A, X, Z, m, n, R 1 R 2 R 3 R 5 R 6 and W 1 To W 6 The definition is the same as in any of the foregoing embodiments of Formula I. In some embodiments, this disclosure provides a compound of Formula I, or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, having a structure selected from Formula (Ib):

[0186] ,

[0187] Where A, X, m, n, R 1 R 2 R 3 R 5 R 6 R 7 and W 1 To W 6 As defined in any of the foregoing embodiments of Formula I.

[0188] In some embodiments, this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, having a structure selected from formula (Ic):

[0189] ,

[0190] Where X, m, n, R 1 R 2 R 3 R 5 R 6 R 7 and W 1 To W 6 As defined in any of the foregoing embodiments of Formula I.

[0191] In some embodiments, this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, the structure of which is selected from formula (Id):

[0192] .

[0193] Where X, m, n, R 1 R 2 R 3 R 5 R 6 R 7 and W 1 To W 6 As defined in any of the foregoing embodiments of Formula I.

[0194] In some embodiments, this disclosure provides a compound of formula (I), or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, having formula (Ie):

[0195] ,

[0196] Where A, X, Z, m, n, R 1 R 2 R 3 and W1 To W 6 The definition is the same as in any of the foregoing embodiments of Formula I.

[0197] In some embodiments, this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, having a structure selected from formula (If):

[0198] ,

[0199] Where A, X, m, n, R 1 R 2 R 3 R 7 and W 1 To W 6 The definition is the same as in any of the foregoing embodiments of Formula I.

[0200] In some embodiments, this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, the structure of which is selected from formula (Ig):

[0201] ,

[0202] Where A, X, m, n, R 1 R 3 R 7 and W 1 To W 6 The definition is the same as in any of the foregoing embodiments of Formula I.

[0203] In some embodiments, this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, the structure of which is selected from formula (Ih):

[0204] .

[0205] Where X, m, n, R 1 R 3 R 7 and W 1 To W 6 As defined in any of the foregoing embodiments of Formula I.

[0206] In some embodiments, this disclosure provides a compound of formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) (according to any of the foregoing embodiments disclosed), or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof; wherein, W 1 W 3 and W 5 Each is CH2; and W 2 W 4 and W 6 Each is independently CH2 or a bond.

[0207] In some embodiments, this disclosure provides a compound conforming to formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) (as described in any of the foregoing disclosed embodiments), or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof; wherein, W 1 W 2 W 3 and W 5 Each is CH2; and W 4 and W 6 Each is a key.

[0208] In some embodiments, this disclosure provides a compound conforming to formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) (as described in any of the foregoing disclosed embodiments), or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof; wherein, W 1 W 2 W 3 W 4 and W 5 Each is CH2; and W 6 For key.

[0209] In some embodiments, this disclosure provides a compound of formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) conforming to any of the foregoing disclosed embodiments, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein W 1 W 2 W 3 W 4 W 5 and W 6 Each is CH2.

[0210] In some embodiments, this disclosure provides a compound of formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) conforming to any of the foregoing disclosed embodiments, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein W 1 W 3 W 5 and W 6 Each is CH2; W 2 It is O; and W 4 It can be CH2 or a single bond.

[0211] In some embodiments, this disclosure provides a compound conforming to formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) (according to any of the foregoing disclosed embodiments), or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof; wherein, W 1 W 2 W 5 and W 6 Each is CH2; W 3 It is O; and W 4 It is CH2 or a bond.

[0212] In some embodiments, this disclosure provides a compound conforming to formula I, (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) (according to any of the foregoing disclosed embodiments), or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof; wherein, W 1 For O; W 2 W 3 and W 5 Each is CH2; W 4 It is O; and W 6 It is CH2 or a bond.

[0213] In some embodiments, this disclosure provides a compound of Formula I, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof; wherein the compound is selected from the compounds listed in List 1.

[0214] List 1

[0215] 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 47a, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, , , , , , , , , , , , , , , , , , , , , , , .

[0216] In one embodiment, this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds listed in Table 5, which have an IC50 value of less than 1000 nM in inhibiting IL-1β production in THP-1 cells (List 2).

[0217] In some embodiments, preferably, this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds listed in Table 5, which have an IC50 value of less than 300 nM in inhibiting IL-1β production in THP-1 cells (List 3).

[0218] In some embodiments (and sometimes more preferably), this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof; wherein the compound is selected from the compounds listed in Table 5 that have an IC50 value of less than 50 nM in inhibiting IL-1β formation in THP-1 cells (List 4).

[0219] In some embodiments (and sometimes even more preferably), this disclosure provides a compound of formula I, or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof; wherein the compound is selected from the compounds listed in Table 5 that have an IC50 value of less than 15 nM in inhibiting IL-1β formation in THP-1 cells (List 5).

[0220] In another aspect, this 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, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0221] On the other hand, this disclosure provides a method for treating or preventing a disease or condition in a subject that responds to NLRP3 inhibition, the method comprising administering to the subject in need 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, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.

[0222] In another aspect, this disclosure provides a method for treating or preventing a disease or condition in a subject that responds to NLRP3 inhibition, the method comprising administering to a subject in need 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, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject, the method comprising administering to a subject in need 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, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof; wherein the disease or condition is a neurodegenerative disease, a metabolic disease, an inflammatory syndrome, an autoinflammatory disease, cancer, or a genetic disease.

[0224] In some embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject with such need, the method 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, tautomer, isotope derivative, or pharmaceutically acceptable salt thereof; wherein the disease or condition is a neurodegenerative disease, a metabolic disease, an inflammatory syndrome, an autoinflammatory disease, cancer, or a genetic disease.

[0225] In some embodiments, in this disclosure, the neurodegenerative disease is Parkinson's disease or Alzheimer's disease; the metabolic disease is type 2 diabetes or atherosclerosis; the inflammatory disease is an acute gout attack, 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, or pancreatic cancer; and the hereditary disease is cryoprene-associated periodic syndrome.

[0226] On the other hand, this disclosure provides for the use of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) according to any embodiment disclosed herein, or stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for treating diseases or conditions selected from neurodegenerative diseases, metabolic diseases, inflammatory syndromes, autoinflammatory diseases, cancer, and genetic diseases.

[0227] In one embodiment, in certain parts of this disclosure, the neurodegenerative disease is Parkinson's disease or Alzheimer's disease.

[0228] In one embodiment, in certain parts of this disclosure, the metabolic disease is type 2 diabetes or atherosclerosis.

[0229] In one embodiment, in certain parts of this disclosure, the inflammatory disease is a gout attack, osteoarthritis, ulcerative colitis, or Crohn's disease.

[0230] In one embodiment, in certain portions of this disclosure, the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis.

[0231] In one embodiment, in certain portions of this disclosure, cancer is lung cancer, breast cancer, prostate cancer, skin cancer, colorectal cancer, and pancreatic cancer.

[0232] In one embodiment, in certain portions of this disclosure, the hereditary disease is cold pyridine-associated periodic syndrome.

[0233] In one aspect, this disclosure provides compounds having the structure of formula (I):

[0234]

[0235] Or its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0236] X is NR 4 S, O or CR 5 R 6 ;

[0237] Y is CR 5 R 6 OR key;

[0238] Z is N or CR 7 ;

[0239] Ring A is a 4-7 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, or 4-7 membered carbocyclic, each group may be independently selected from R 1 One to three groups are substituted, but when A is C 6-10 When aryl or 5-6 heteroaryl, R 1 Not an oxygen group (=O);

[0240] W 1 W 3 and W 5 Each independently selected from CR 5 R 6 O, S and NR 4 And W 2 W 4 and W 6 Each is independently selected from key, CR 5 R 6 O, S and NR 4 But the premise is: in W 1 W 2 W 3 W 4 W 5 and W 6 In this configuration, no two non-carbon atoms can be directly bonded or bonded to the same carbon atom, with the sole exception of an SS bond; or, where R 5 With R 6 R 4 With R 5 、or R 4 With R 6 Additional 3-4 element spiral rings or 5-7 element bridge rings can be formed.

[0241] R 1 Each time it appears, it is independently selected from H and C. 1-5 Alkyl, C 3-7 cycloalkyl, C 1-4 Alkyl-CO, 4-7 membered heterocyclic groups, OR 8 CO2R 8 CONR 8 R 9 Halogen, CN, NR 8 R9 And oxygen group (=O); where, C 1-5 Alkyl, C 3-7 cycloalkyl, C 1-4 The alkyl-CO and 4-7 membered heterocyclic groups may each be optionally replaced by 1-3 independently selected R groups. 10 Substitution of groups;

[0242] R 2 It can be OH, OCHF2, OCF3, CHF2, CF3, CF3CH2, OMe, F, or H;

[0243] R 3 Each time it appears, it is independently selected from H and C. 3-6 cycloalkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, O-halogenated C 1-4 Alkyl, halogen, CN, SF5, NR 8 R 9 OR 8 SR 8 , aryl and heteroaryl; of which, C 3-6 cycloalkyl and C 1-4 Each alkyl group may optionally be surrounded by 1-3 independently selected from halogens, oxo groups, and C. 1-3 The alkyl group is substituted; and wherein the aryl and heteroaryl groups are each optionally replaced by 1-3 groups independently selected from halogens and C. 1-3 Alkyl group substitution;

[0244] Each R 4 Independently selected from H and C 1-4 Alkyl and C 3-7 cycloalkyl, wherein each C 1-4 Alkyl and C 3-7 The cycloalkyl group may optionally be composed of 1-3 independently selected R 10 Substitution of groups;

[0245] R 5 and R 6 Independently selected from H, halogen, OR 8 NR 8 R 9 C 1-4 Alkyl, C 3-7 Cycloalkyl and 4-7 membered heterocyclic groups, wherein each C 1-4 Alkyl, C 3-7 The cycloalkyl and 4-7 membered heterocyclic groups may optionally be replaced by 1-3 independently selected from R 10 Substitution of groups;

[0246] Or, R connected to the same atom 5 and R 6 Together they form = O;

[0247] Alternatively, R connected to the same or different atoms 5 and R 6 It can form a 3-6 membered carbon ring or heterocycle, which can be optionally divided by 1-3 R atoms. 10 Group substitution;

[0248] R 7 Independently selected from H and C 1-4 Alkyl, C 3-7 cycloalkyl, aryl, heteroaryl, halogen, CN, OR 8 NR 8 R 9 CO2R 11 and CON(R) 11 R 12 ); where C 1-4 Alkyl, C 3-7 Each of the cycloalkyl, aryl, and heteroaryl groups may be optionally composed of 1 to 3 independently selected from R 11 Substitution of groups;

[0249] Or, R 7 Can be used with R 4 R 5 or R 6 Together they form a 5-7 membered carbon ring or heterocycle, which can be optionally divided by 1-3 R atoms. 10 Group substitution;

[0250] R 8 and R 9 Independently selected from H, COR 12 C(O)N(R) 11 R 12 ), C(=NR) 12 )N(R 11 R 12 C 1-4 Alkyl, C 3-7 cycloalkyl and aryl; wherein, C 1-4 Alkyl, C 3-7 Each of the cycloalkyl and aryl groups may optionally be selected from 1 to 3 independently chosen from R 10 The group is substituted, but when R 8 or R 9 When it is aryl, R 10 It cannot be =O;

[0251] R 10Each occurrence is independently selected from H and CO2R. 11 CON(R) 11 2. CN, OR 11 Halogen, C 1-4 Alkyl, cyclopropyl, aryl, =O, SR 11 and N(R) 11 R 12 );

[0252] R 11 Each time it appears, it is independently selected from H, halogen, OH, N(R) 12 2. NR 12 C(=NR 12 )N(R 12 2. NR 12 C(=O)N(R 12 2. NR 12 C(=O)R 12 NR 12 C(=O)OR 12 OC(=O)N(R) 12 2. CO2R 12 COR 12 C(O)NR 12 C(=NR 12 )N(R 12 2. C(=NR) 12 )N(R 12 )2 C(=O)N(R) 12 2. Aryl and C 1-6 Alkyl; wherein the aryl and C 1-6 Each alkyl group may optionally be substituted with 1-3 groups independently selected from halogens, OH and NH2;

[0253] R 12 Each time it appears, it is independently selected from H, aryl, and C. 1-4 Alkyl; wherein the aryl or C 1-4 Each alkyl group may optionally be substituted with 1-3 groups independently selected from halogens, OH and NH2;

[0254] m is 0, 1, 2, or 3; and

[0255] n is 0, 1, or 2.

[0256] In some embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof have formula (Ia):

[0257] ,

[0258] Among them, all m, n, A, X, Z, R 1 R 2 R 3 R 5 R 6 and W 1 To W 6 All groups are as defined in formula (I).

[0259] In some embodiments, a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof has formula (Ib):

[0260] ,

[0261] Among them, all m, n, A, X, R 1 R 2 R 3 R 5 R 6 R 7 and W 1 To W 6 All functional groups are as shown in formula (I).

[0262] In some embodiments, a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof has formula (Ic):

[0263] ,

[0264] Where m, n, X, R 1 R 2 R 3 R 5 R 6 R 7 and W 1 To W 6 All functional groups are as shown in formula (I). In some embodiments, the compound of formula (I), its stereoisomer, or its pharmaceutically acceptable salt has formula (Id):

[0265] ,

[0266] Where m, n, X, R 1 R 3 R 5 R 6 R 7 and W 1 To W 6 All functional groups are as shown in formula (I).

[0267] In some embodiments, a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof has formula (Ie):

[0268] ,

[0269] Where m, n, A, X, Z, R 1 R 2 R 3 and W 1 To W 6 The definitions of the groups are as shown in formula (I).

[0270] In some embodiments, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt has formula (If):

[0271] ,

[0272] Among them, all m, n, A, X, R 1 R 2 R 3 R 7 and W 1 To W 6 All groups are as defined in formula (I).

[0273] In some embodiments, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt has formula (Ig):

[0274] ,

[0275] Where m, n, A, X, R 1 R 3 R 7 and W 1 To W 6 All groups are as defined in formula (I).

[0276] In some embodiments, a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof has formula (Ih):

[0277] ,

[0278] Among them, all m, n, X, R 1 R 3 R 7 and W 1 To W 6 All functional groups are as defined in formula (I).

[0279] In some embodiments, in compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (Ih), their stereoisomers, or pharmaceutically acceptable salts thereof, W 1 W 3 and W 5 Each is CH2; and W 2 W 4 and W 6 Each is independently CH2 or a bond.

[0280] In some embodiments, in compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (Ih), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein W 1 W 2 W 3 and W 5 Each is CH2; and W 4 and W 6 Each is a key.

[0281] In some embodiments, in compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (Ih), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein W 1 W 2 W 3 W 4 and W 5 Each is CH2; and W 6 For key.

[0282] In one embodiment, in compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (Ih), or their stereoisomers or pharmaceutically acceptable salts, wherein W 1 W 2 W 3 W 4 W 5 and W 6 Both are CH2.

[0283] In some embodiments, in compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (Ih), or their stereoisomers or pharmaceutically acceptable salts, wherein W 1 W 3 W 5 and W 6 Both are CH2; W 2 For O; W4 For key.

[0284] In one embodiment, in compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), and (Ih), or their stereoisomers or pharmaceutically acceptable salts, wherein W 1 W 2 W 5 and W 6 Both are CH2; W 3 For O; W 4 For key.

[0285] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih) according to any of the disclosed embodiments, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0286] In some embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject that responds to NLRP3 inhibition, the method comprising administering to the subject in need an effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih) according to any of the disclosed embodiments, its stereoisomers, or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, this disclosure provides a method for treating or preventing a disease or condition in a subject that responds to NLRP3 inhibition, the method comprising administering to the subject in need a pharmaceutical composition comprising an effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih) according to any of the disclosed embodiments, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0288] In one embodiment, this disclosure provides the use of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih) (according to any embodiment disclosed herein) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder associated with NLRP3 activity in a subject requiring treatment.

[0289] In some embodiments, this disclosure provides pharmaceutical compositions using compounds comprising (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih) (according to any embodiment disclosed herein) or stereoisomers thereof or pharmaceutically acceptable salts thereof for treating diseases or disorders related to NLRP3 activity in subjects requiring treatment.

[0290] In one embodiment, this disclosure provides a medicament for treating a disease or condition associated with NLRP3 activity in a subject requiring treatment, using a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (Ig), or (Ih), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any embodiment disclosed herein.

[0291] In some embodiments, the diseases or conditions associated with NLRP3 activity are neurodegenerative diseases, metabolic diseases, inflammatory syndromes, autoinflammatory diseases, cancer, or genetic diseases.

[0292] In some embodiments, the disease or condition is a neurodegenerative disease selected from Parkinson's disease or Alzheimer's disease.

[0293] In some embodiments, the disease or condition is a metabolic disease selected from type 2 diabetes or atherosclerosis.

[0294] In some embodiments, the disease or condition is an inflammatory disease selected from gout attacks, osteoarthritis, ulcerative colitis, and Crohn's disease.

[0295] In some embodiments, the disease or condition is an autoinflammatory disease selected from multiple sclerosis or rheumatoid arthritis.

[0296] In one embodiment, the disease or condition is cancer, specifically lung cancer.

[0297] In some embodiments, the disease or condition is a hereditary disease, namely cold pyridine-associated periodic syndrome.

[0298] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art.

[0299] The term "alkyl" refers to a branched or unbranched monovalent aliphatic hydrocarbon group derived from an alkane containing 1 to 12 carbon atoms by removing a hydrogen atom. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms. In some embodiments (sometimes preferred), the alkyl group contains 1 to 6 carbon atoms; and in some embodiments (sometimes more preferred), the alkyl group contains 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl, and their isomers. The alkyl group may be substituted or unsubstituted.

[0300] The term "alkenyl" refers to any monovalent aliphatic hydrocarbon group derived from an alkene containing 2 to 12 carbon atoms, formed by removing a hydrogen atom. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 8 carbon atoms. In some embodiments (sometimes preferred), the alkenyl group contains 2 to 6 carbon atoms; and in some embodiments (sometimes more preferred), the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to: vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, etc., and their isomers. The alkenyl group may be substituted or unsubstituted.

[0301] The term "alkynyl" refers to a monovalent aliphatic hydrocarbon group derived from an alkyne containing 2 to 12 carbon atoms by removing a hydrogen atom. In some embodiments, the alkynyl group contains 2 to 10 carbon atoms. In some embodiments, the alkynyl group contains 2 to 8 carbon atoms. In some embodiments (sometimes preferred), the alkynyl group contains 2 to 6 carbon atoms; and in some embodiments (sometimes more preferred), the alkynyl group contains 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to: ethynyl, propynyl, butynyl, isobutynyl, pentyynyl, hexynyl, heptyynyl, octyynyl, nonynyl, decanynyl, undecanynyl, dodecanynyl, etc., and their isomers. The alkynyl group can be substituted or unsubstituted.

[0302] The term "cycloalkyl" refers to any monovalent group formed by removing a hydrogen atom from a cycloalkane. In some embodiments, the cycloalkyl group contains 3 to 10 carbon atoms. In some embodiments, the cycloalkyl group contains 3 to 8 carbon atoms. In some embodiments (sometimes preferred), the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. The cycloalkyl group may be substituted or unsubstituted.

[0303] The term "heterocyclic group" refers to a monocyclic or polycyclic non-aromatic carbocyclic group containing at least one heteroatom (N, O, and / or S) in its ring. At least one ring in the heterocyclic group's ring system is non-aromatic, and its saturation can be arbitrary. The heteroatom can be located on a non-aromatic or aromatic ring of the heterocyclic group. The heterocyclic group can contain 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, the heterocyclic group is preferably a 3-, 4-, 5-, 6-, or 7-membered monocyclic group; sometimes, the heterocyclic group is preferably an 8-, 9-, or 10-membered bicyclic group. Examples of heterocyclic groups include, but are not limited to: azirrolyl, acridine, carbazolyl, cyclophosphinyl, dioxolane, imidazolinyl, imidazoalkyl, morpholinyl, ethylene oxide, oxacycloheptyl, oxacyclobutyl, piperidinyl, piperazinyl, pyrazolinyl, pyrazolyl, 1,3-dioxenyl, 1,3-dioxanecycloyl, 1,4-dioxenyl, 1,4-dioxanecycloyl, 1,3-oxothiohexanecycloyl, and 1,4-oxothiohexanecycloyl. 2H-1,3-dioxolane, 1,3-dithiopentanyl, isoxazolinyl, isoxazolinyl, oxazolinyl, oxazolinyl, oxazolidinone, thiazolinyl, 1,3-oxothiopentanyl, dihydroindolyl, isodihydroindolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolyl, and tetrahydroquinolinyl.

[0304] The term "alkylene" refers to a saturated, straight-chain or branched divalent aliphatic hydrocarbon group derived from a parent alkane formed by removing two hydrogen atoms, the parent alkane containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 carbon atoms); sometimes preferably containing 1 to 8 carbon atoms, sometimes more preferably containing 1 to 6 carbon atoms, and sometimes even more preferably containing 1 to 4 carbon atoms. Non-limiting examples of alkylene include, but are not limited to: methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. The alkylene can be substituted or unsubstituted.

[0305] The term "alkenyl" refers to an alkylene group as defined above, containing 2 to 12 carbon atoms, having at least two carbon atoms and at least one carbon-carbon double bond; preferably C. 2-10 alkenyl, more preferably C 2-8 alkenyl, sometimes more preferably C 2-6alkenyl, sometimes even more preferably C 2-4 Alkenyl group. Non-limiting examples of alkenyl groups include, but are not limited to: -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, etc. The alkenyl group may be substituted or unsubstituted.

[0306] In this disclosure, the terms “alkyl” and “alkylene,” “alkenyl” and “alkenylene,” “aryl” and “arylene,” “cycloalkyl” and “cycloalkylene,” or similar terms, are sometimes used interchangeably. Therefore, the interpretation of these terms should be based on the context and should be in accordance with the manner understood by one of ordinary skill in the art.

[0307] The term "aryl" refers to a fully carbon monocyclic or polycyclic fused ring group comprising 6 to 14 atoms (a "fused" ring system is one in which each ring shares a pair of adjacent carbon atoms with another ring in the system), and having a fully conjugated π-electron system. Preferably, the aryl group comprises 6 to 10 atoms, such as phenyl and naphthyl; most preferably, phenyl. The aryl group can be substituted or unsubstituted.

[0308] The term "heteroaryl" refers to an aryl system comprising 5 to 14 atoms, wherein the ring atoms include 1 to 4 heteroatoms selected from O, S, and N. Preferably, the heteroaryl comprises 5 to 10 atoms (e.g., 5, 6, 7, 8, 9, and 10 atoms); more preferably, it comprises 5 or 6 atoms, such as: furanyl, thiopheneyl, phthalazinyl, pyrroleyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, thiazolyl, pyridinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoyindolyl, benzothiopheneyl, etc. The heteroaryl can be fused with the ring of an aryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is a heteroaryl. The heteroaryl group can be substituted or unsubstituted.

[0309] The term "alkoxy" refers to a group in the form of -O- (alkyl), such as methoxy, ethoxy, propoxy, butoxy, etc.

[0310] The term "cycloalkoxy" refers to -O- (cycloalkyl); for example, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc.

[0311] The term "bond" refers to a covalent bond represented by the symbol "-".

[0312] The term "hydroxyl group" refers to the -OH group.

[0313] The term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, or iodine atoms.

[0314] The term "amino" refers to the -NH2 group.

[0315] The term "alkylthio" refers to alkyl-S-.

[0316] The term "alkylamino" refers to "alkyl-NH-", and sometimes also to dialkylamino (-NRaRb), wherein the two alkyl groups (Ra and Rb) may be the same or different. Preferably, the alkyl group is a C1-C6 alkyl group; more preferably, it is a C1-C4 alkyl group. Examples of alkylamino groups include, but are not limited to: CH3-NH-, -N(CH3)2, -N(CH2CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -NH-Bu t -N(CH3)(Bu t ) wait.

[0317] The term "cyano" refers to the -CN group.

[0318] The term "halogenated alkyl" refers to an alkyl group that is substituted with one or more halogen atoms, wherein the halogen atoms may be the same or different.

[0319] The term "nitro" refers to the -NO2 group.

[0320] The term "oxo group" refers to the =O group.

[0321] The term "carboxyl group" refers to the -C(O)OH group.

[0322] The term "alkoxycarbonyl" refers to the -C(O)O(alkyl) group.

[0323] The term "alkyl carbonyl" refers to a -C(O)-alkyl group.

[0324] The terms “optional” or “optionally” mean that the event or situation described below may occur, but is not required to occur; and the description covers all possibilities in which the event or situation may or may not occur. For example, “optionally alkyl-substituted heterocyclic group” means that an alkyl group may be present, but is not required to be present; the description covers both cases where the heterocyclic group is alkyl-substituted and cases where the heterocyclic group is not alkyl-substituted.

[0325] The term "substituted" means that one or more hydrogen atoms in the group—preferably up to five, more preferably one to three hydrogen atoms—are independently substituted by the corresponding number of substituents. Those skilled in the art can determine the feasibility of such substitution experimentally or theoretically without excessive effort. For example, an amino or hydroxyl group containing free hydrogen atoms may result in an unstable structure when combined with a carbon atom containing an unsaturated bond (such as an alkene bond).

[0326] As used herein, the term "covalent bonding principle" refers to the fundamental rules and principles governing the formation of covalent bonds in organic compounds, namely those rules and principles commonly understood by those skilled in the art. For example, a carbon atom is a tetravalent atom and can only form four covalent bonds (such as four single bonds, or one double bond plus two single bonds, etc.); an oxygen atom is a divalent atom and can only form two covalent bonds (two single bonds in the "-O-" structure and one double bond in the "=O" structure).

[0327] In some embodiments, when alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or similar groups (or portions thereof) are substituted, the substituents may be substituted at any available connection point; and the substituents may be one or more, sometimes preferably one to five, and sometimes more preferably one to three, these substituents being independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 alkylthio, C1-C6 alkamino, di(C1-C6 alkyl)amino, thiol, hydroxyl, nitro, cyano, amino, C3-C6 cycloalkyl, 5 to 10 membered heterocyclic groups, C6-C 10 Aryl, 5- to 10-membered heteroaryl, C3-C6 cycloalkoxy, C1-C6 cycloalkylthio, 5- to 10-membered heterocyclic thio, and oxo. In some embodiments (sometimes preferred), the substituent is independently selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, di(C1-C6 alkyl)amino, thiol, hydroxy, nitro, cyano, amino, and oxo. In some embodiments (sometimes more preferred), the substituent is independently selected from C1-C4 alkyl, halogen, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylamino, di(C1-C4 alkyl)amino, thiol, hydroxy, nitro, cyano, and amino. As will be understood by those skilled in the art, the oxo group (=O) cannot be used as a substituent for aryl or heteroaryl groups, nor can it substitute for an unsaturated carbon atom in any other group.

[0328] The representation of carbon atoms or ring atoms in substituents (such as alkyl, cycloalkyl, carbocyclic, aryl, heteroaryl, heterocyclic, or similar groups) may take different forms, but should be understood to have the same meaning as understood by those skilled in the art. For example, alkyl groups containing 1 to 6 carbon atoms may be represented as "C1-C6 alkyl", "C6 ... 1-6 Alkyl", C 1- "6alkyl" or similar form; other substituents can also be represented in a similar manner.

[0329] As used in this article, the term "isomer" refers to all types of isomerism that a compound may exhibit, depending on the specific context in which it is applied. These isomers may include stereoisomers, configurational isomers, geometric isomers, conformational isomers, or similar types.

[0330] The term "stereoisomer" refers to isomers that are structurally identical but differ in their spatial atomic arrangement; this difference may or may not originate from an asymmetric (chiral) center in the structure. The term encompasses enantiomers, diastereomers, transisomers, and mixtures thereof. The term "transisomer" specifically refers to a particular type of stereoisomer—a conformational stereoisomer—formed due to steric hindrance within the molecule, resulting in impeded or significantly slowed rotation of single bonds. Some transisomers can be isolated and purified in a stable form. For example, some compounds involved in this disclosure may exist under different conditions as mixtures of transisomers (e.g., equal-proportion mixtures or mixtures rich in a particular transisomer) or as purified transisomers. All such stereoisomers and mixtures thereof are included within the scope of this disclosure, whether the compound is presented in a chiral form or as a single isomer or a combination of multiple isomers.

[0331] This disclosure also covers cis / trans isomers (or Z / E isomers) resulting from different configurations of substituents on double bonds (especially C=C double bonds); such isomers are sometimes also referred to as geometric isomers.

[0332] The compounds disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that is in equilibrium and readily converts from one isomer to another. Non-limiting examples include keto-enol tautomers, imine-enamine tautomers, or similar forms.

[0333] In this specification and claims, the terms “comprise” (and any form of “comprise”, such as “comprise” and “comprises”), “have” (and any form of “have”, such as “have” and “has”), “includes” (and any form of “includes”, such as “includes” and “include”), or “contains” (and any form of “contains”, such as “contains” and “contain”) should be understood as inclusive or open-ended and do not exclude other elements or method steps not listed.

[0334] In this disclosure (especially in the context of the following claims), the terms “a,” “an,” “the,” and similar pronouns should be interpreted to cover both singular and plural forms, unless otherwise stated herein or the context clearly contradicts it.

[0335] If the plural form is used for compounds, salts and the like, it should be understood that it also covers a single compound, salt or the like.

[0336] As used herein, the term "and / or" refers to and covers any and all possible combinations of one or more of the listed items. When used in a list containing two or more items, the term "and / or" means that either item listed may be used alone, or any combination of two or more of the listed items may be used.

[0337] "Pharmaceutical composition" refers to a mixture of one or more compounds (or physiologically / pharmaceutically acceptable salts thereof) described in this disclosure with other chemical components such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to the body, thereby aiding in the absorption of the active ingredient and enabling it to exert its biological activity.

[0338] As used herein, the term "pharmaceutically acceptable" means compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for contact with patient tissues and do not have excessive toxicity, irritation, allergic reactions, or other problems or complications (i.e., have a reasonable benefit / risk ratio) and are effective for their intended use.

[0339] "Pharmaceutically acceptable salts" refer to salts of the compounds disclosed herein; such salts are safe and effective in mammalian use and possess the corresponding biological activity. These salts can be prepared during the final isolation and purification of the compounds, or they can be prepared alone by reacting a suitable nitrogen atom with a suitable acid. Pharmaceutically acceptable salts are well known in the art. See, for example, the literature by SM Berge et al. published in *J. Pharm. Sci.*, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids.

[0340] Acids commonly used to prepare pharmaceutically acceptable salts include inorganic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and thiocyanate) and organic acids (such as p-toluenesulfonic acid, salicylic acid, tartaric acid, hydrogen tartrate, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid) and related inorganic and organic acids. Preferred pharmaceutically acceptable salts include hydrochloride salts or hydrobromide salts.

[0341] Base addition salts can be prepared during the final separation and purification of compounds by reacting the carboxyl group with a suitable base (e.g., hydroxides, carbonates, or bicarbonates of metal cations, or ammonia, or organic primary, secondary, or tertiary amines). Pharmaceutically acceptable cations include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, and N-methylmorpholine.

[0342] Although the compounds (or their pharmaceutically acceptable salts) disclosed herein can be administered directly as raw material chemicals when used for treatment, the active ingredient can also be formulated into a pharmaceutical composition. Therefore, this disclosure further provides a pharmaceutical composition comprising any of the compounds disclosed herein (or their pharmaceutically acceptable salts), and one or more (preferably one to three) pharmaceutically acceptable carriers, diluents, or other excipients. The carriers, diluents, or other excipients must be "acceptable," meaning they should be compatible with other components in the formulation and harmless to the treated subject.

[0343] In the compounds disclosed herein, the atoms may exhibit their natural isotopic abundance; or one or more atoms may be artificially enriched to contain a specific isotope—an isotope with the same atomic number but a different atomic mass or mass number than that predominantly found in nature. For example, substitution with a heavier isotope (e.g., replacing hydrogen H with deuterium, i.e., ²H or D) can provide certain therapeutic advantages stemming from improved metabolic stability of the compound (e.g., prolonged half-life in vivo or reduced required dosage); therefore, such isotopic substitution may be preferred in certain specific situations. Furthermore, certain isotopically labeled compounds (e.g., those labeled with...) 3 H and 14 C-labeled compounds can be used for tissue distribution determination of compounds and / or substrates. Isotope-labeled compounds are typically prepared by following steps similar to those disclosed in the “Reaction Formulas” and / or “Examples” below, but replacing the corresponding isotope-labeling reagent with a non-isotope-labeling reagent. This invention is intended to cover all suitable isotope variants of the disclosed compounds.

[0344] Pharmaceutical formulations can be presented in unit dose form, each unit dose containing a predetermined amount of the active ingredient. Typically, the pharmaceutical compositions involved in this disclosure are administered at a frequency of once every 1 to 5 days, or approximately 1 to 5 times daily; alternatively, they can be administered via continuous infusion. Such administration methods can be used for the treatment of both chronic and acute diseases. The amount of active ingredient used to bind with the carrier material to prepare a single-dose formulation will vary depending on the condition being treated, the severity of the condition, the timing of administration, the route of administration, the excretion rate of the compound used, the duration of treatment, and factors such as the patient's age, sex, weight, and physical condition. Preferred unit-dose formulations refer to those containing a daily dose (or a sub-dose as described above), or a formulation containing an appropriate fraction of the active ingredient. Generally, treatment should begin with a low dose, i.e., a dose level far below the optimal dose of the compound. Subsequently, the dose should be gradually increased in small increments until optimal efficacy is achieved in the current specific circumstances. Overall, the administered concentration level of the compound is optimal for producing an effective therapeutic effect without causing significant harmful or adverse side effects.

[0345] When the compositions of this disclosure comprise a combination of one of the compounds of this disclosure with one or more (preferably one or two) additional therapeutic or preventative agents, the dose levels of the compound and the additional agents are generally between about 10% and 150% of their usual dose in a monotherapy regimen, more preferably between about 10% and 80%.

[0346] Pharmaceutical formulations are suitable for administration via any suitable route, such as oral (including buccal or sublingual), rectal, nasal, local (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intradermal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or intradermal injection or infusion). Such formulations can be prepared by any method known in the pharmaceutical field, such as by conjugating the active ingredient with a carrier or excipients. Oral or injectable administration is preferred.

[0347] Pharmaceutical formulations suitable for oral administration may be in the form of discrete units, such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or effervescent agents; or oil-in-water or water-in-oil emulsions.

[0348] For example, if administered orally in tablet or capsule form, the active pharmaceutical ingredient can be combined with an orally accessible, non-toxic, and pharmaceutically acceptable inert carrier (such as ethanol, glycerol, or water). Powder preparation involves pulverizing the compound to a suitable fineness and mixing it with a similarly pulverized pharmaceutical carrier (such as edible carbohydrates like starch or mannitol). Furthermore, flavoring agents, preservatives, dispersants, and colorants may be added to the formulation.

[0349] The capsules are prepared by first preparing a powder mixture as described above, and then filling it into pre-formed capsule shells. Before filling, gliding agents and lubricants, such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol, may be added to the powder mixture. Additionally, disintegrants or solubilizers (such as agar, calcium carbonate, or sodium carbonate) may be added to improve the bioavailability of the drug after oral ingestion.

[0350] In addition, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture as needed or necessary. Suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth, or sodium alginate), carboxymethyl cellulose, polyethylene glycol, etc. Lubricants used in this type of dosage form include sodium oleate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc. For example, the tablet manufacturing process typically includes: preparing a powder mixture, granulating or slugging, adding lubricants and disintegrants, and finally compressing into tablets. The powder mixture is prepared by mixing a suitably pulverized compound with the above-mentioned diluent or matrix; in addition, binders (such as carboxymethyl cellulose, alginate, gelatin, or polyvinylpyrrolidone), dissolution retarders (such as paraffin), absorption promoters (such as quaternary ammonium salts), and / or adsorbents (such as bentonite, kaolin, or dicalcium phosphate) may be selectively added. Powder mixtures can be processed by wet granulation: the mixture is moistened with a binder such as syrup, starch paste, gum arabic, or cellulose / polymer solution, and then extruded into granules through a sieve. Alternatively, the powder mixture can be directly fed into a tableting machine for compression, resulting in irregularly shaped slugs that are then broken into granules. To prevent granules from adhering to the tableting die during compression, stearic acid, stearates, talc, or mineral oil can be added for lubrication. The lubricated mixture is then compressed into tablets. The compounds disclosed herein can also be mixed with an inert carrier with good flowability and directly compressed into tablets without granulation or blistering. Furthermore, transparent or opaque protective coatings can be provided for the tablets; these coatings typically consist of a shellac sealing layer, a sugar or polymer coating layer, and a wax polishing layer. Colorants can be added to these coatings to differentiate unit dosages.

[0351] Oral liquid formulations such as solutions, syrups, and elixirs can be prepared in unit doses to ensure that a specific amount of the formulation contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an appropriately flavored aqueous solution; while elixirs require the use of a non-toxic carrier. In addition, solubilizers and emulsifiers (such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavoring agents (such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners), and similar excipients may be added.

[0352] Where appropriate, unit-dose formulations for oral administration can be processed using microencapsulation techniques. Such formulations can also be specially prepared to achieve sustained or controlled release of the drug; for example, this can be achieved by coating or embedding particulate drugs in polymers, waxes, or other similar matrices.

[0353] It should be understood that, in addition to the ingredients specifically mentioned above, such formulations may also contain other excipients commonly used in the art, depending on the specific type of formulation; for example, formulations suitable for oral administration may contain flavoring agents.

[0354] The terms “subject,” “patient,” or similar terms include humans and other mammals, including but not limited to cats, dogs, pigs, horses, sheep, goats, monkeys, chimpanzees, etc., preferably humans.

[0355] The terms “disease,” “symptom,” and “condition,” or similar terms used in this article, are generally used interchangeably.

[0356] The term "therapeutic effective amount" refers to the amount of a compound or composition that, when administered to a subject to treat a disease, is sufficient to achieve a therapeutic effect on that disease. "Therapeutic effective amount" can vary due to a variety of factors, including, but not limited to, the compound used, the disease and its severity, and the age, weight, or other factors of the subject being treated. When the term applies to a single active ingredient administered alone, it refers only to the amount of that ingredient itself. When the term applies to combination therapy, it refers to the total amount of all active ingredients required to produce a therapeutic effect, regardless of whether these ingredients are administered in combination, sequentially, or simultaneously.

[0357] The terms “treatment,” “under treatment,” “therapy,” or similar terms mean: (i) suppressing the disease, symptom, or condition, i.e., preventing its further development; and (ii) alleviating the disease, symptom, or condition, i.e., promoting the resolution of the disease, symptom, and / or condition. Furthermore, the compounds involved in this disclosure can also be used to exert a preventive effect, i.e., to prevent a disease, symptom, or condition from occurring in subjects who are susceptible to having the disease, symptom, and / or condition but have not yet been diagnosed with it.

[0358] When the term "about" is used to describe parameters such as pH, concentration, and temperature, it indicates that the parameter varies within ±10%, more preferably ±5%, and even more preferably ±2%. Those skilled in the art should understand that when a parameter is not a critical parameter, the given value is generally for illustrative purposes only and not to limit its value.

[0359] The following non-limiting synthetic schemes, preparation methods and processes, as well as examples, further illustrate certain aspects of this disclosure.

[0360] Compound preparation and biological assay

[0361] As will be appreciated by those skilled in the art, the methods for synthesizing the compounds listed herein are readily apparent to those of ordinary skill in the art. The synthetic chemical transformations and protecting group methodologies (including protection and deprotection) used to synthesize the compounds described herein are well-known in the art, including, for example, those described in R. Larock's *Comprehensive Organic Transformations* (VCH Publishers, 1989); TW Greene and PGM Wuts' *Protective Groups in Organic Synthesis* (2nd edition, John Wiley and Sons, 1991); L. Fieser and M. Fieser's *Fieser and Fieser's Reagents for Organic Synthesis* (John Wiley and Sons, 1994); and L. Paquette's *Encyclopedia of Reagents for Organic Synthesis* (John Wiley and Sons, 1995) and subsequent editions.

[0362] Abbreviations

[0363] The following abbreviations have the meanings shown:

[0364] AcOH = Acetic acid

[0365] AgOTf = Silver trifluoromethanesulfonate

[0366] AIBN = Azobisisobutyronitrile

[0367] Boc = tert-butyloxycarbonyl

[0368] BPO = Benzoyl peroxide

[0369] CyJohn Phos = (2-Biphenyl)dicyclohexylphosphine

[0370] 4CzPN-Bu = 3,4,5,6-tetrakis(3,6-ditert-butylcarbazole-9-yl)-1,2-dicyanophenyl

[0371] DCM = dichloromethane

[0372] DIEA or DIPEA = diisopropylethylamine

[0373] DMF = N,N - dimethylformamide

[0374] DMSO = dimethyl sulfoxide

[0375] dppfO2 = 1,1'-bis(diphenylphosphino)ferrocene dioxide

[0376] DTBMP = 2,6 - di - tert - butyl - 4 - methylpyridine

[0377] EtOH = ethanol

[0378] EtOAc = ethyl acetate

[0379] FA = formic acid

[0380] HBpin = pinacolborane

[0381] HCHO = formaldehyde

[0382] HPLC = high performance liquid chromatography

[0383] hr or h = hour

[0384] K2S2O8 = potassium persulfate

[0385] LC - MS = liquid chromatography – mass spectrometry

[0386] M = mol / L.

[0387] m - CPBA = m - chloroperoxybenzoic acid

[0388] Me = methyl

[0389] MeCN = acetonitrile

[0390] MeOH = methanol

[0391] MOMCl = chloromethyl methyl ether

[0392] MsCl = Methanesulfonyl chloride

[0393] NaBH3CN = Sodium cyanoborohydride

[0394] NaH = Sodium hydride

[0395] NMR = Nuclear Magnetic Resonance

[0396] NIS = N-iodosuccinimide

[0397] NOE = Nuclear Overhauser effect

[0398] NBS = N-bromosuccinimide

[0399] Pd(dppf)Cl2 = dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium

[0400] Pd(dtbpf)Cl2 = [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride

[0401] PE = Petroleum Ether

[0402] Pd(OAc)₂ = Palladium(II) acetate

[0403] POCl3 = Phosphorus oxychloride

[0404] Py = pyridine

[0405] RT = room temperature

[0406] Rt = Retention time

[0407] Ruphos = 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl

[0408] Ruphos Pd G3 = mesylate-(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0409] Sat. = saturated

[0410] SFC = Supercritical Fluid Chromatography

[0411] SPhos = 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0412] SPhos Pd G2 = Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2-amino-1,1'-biphenyl)]palladium(II)

[0413] TBAF = Tetrabutylammonium fluoride

[0414] TBSCl = tert-butyldimethylchlorosilane

[0415] TEA = Triethylamine

[0416] Tert-butyl XPhos = 2-Di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl

[0417] TFA = Trifluoroacetic acid

[0418] THF = Tetrahydrofuran

[0419] TLC = Thin-layer chromatography

[0420] TMAD = N,N,N',N'-Tetramethylazodicarbonamide

[0421] TMSCl = Trimethylchlorosilane

[0422] General conditions and procedures

[0423] In the following examples, all chemical reagents used were purchased commercially (such as Alfa, Acros, Sigma Aldrich, TCI, Shanghai Chemical Reagent Company, etc.) and used directly without further purification. Tetrahydrofuran (THF) was continuously refluxed with sodium and benzophenone and then freshly distilled under nitrogen protection; dichloromethane was continuously refluxed with calcium hydride (CaH2) and then freshly distilled under nitrogen protection.

[0424] Flash chromatography was performed on a Biotage Isolera One instrument, using columns packed with 200–300 mesh silica gel particles. Both analytical and preparative thin-layer chromatography (TLC) plates were HSGF 254 (0.15–0.2 mm thick, purchased from Shanghai Anbang Co., Ltd., China). Nuclear magnetic resonance (NMR) spectra were recorded using a Bruker AVANCE NEO 400 spectrometer (Bruker, Switzerland), with measurements taken at approximately 20–30 °C unless otherwise specified. The abbreviations used are as follows: s (singleton); d (doublet); t (triplet); q (quartet); m (multiplex); dd (doublet); dt (doublet); bs (broad peak). Chemical shift values ​​are expressed as low-field ppm (δ) values ​​relative to tetramethylsilane (TMS). Mass spectrometry (MS) determinations were performed in electrospray ionization (ESI) mode on an LCMS2020 mass spectrometer (Shimadzu Corporation, Japan). Compound purification was carried out using various methods as needed, including but not limited to preparative chromatography under acidic, neutral, or alkaline conditions using normal-phase or reversed-phase high-performance liquid chromatography (HPLC), rapid column chromatography, or preparative thin-layer chromatography plates.

[0425] Preparative HPLC: Unless otherwise specified, compounds were purified using a SHIMADZU LH-40 or FRC-40 instrument equipped with a YMC-Triart C18 column (5 μm, 120 Å, 250 x 20 mm) and one of the following solvent systems: H2O, MeCN, and H2O containing 0.1% FA; or H2O, MeOH, and H2O containing 0.1% FA; or H2O, MeCN, and H2O containing 0.1% NH4OH / NH4HCO3. Specific elution gradients were determined based on retention times obtained from analytical LC-MS; however, all elution gradients involving H2O with MeCN or MeOH were typically completed within a 20-minute run at a flow rate of 20 mL / min. Auto-blend mode was used to ensure that the FA concentration remained at 0.1% throughout the run. For purification using FA-containing eluents, the final product after lyophilization or drying is a complete or partial salt of formic acid (FA), as confirmed by NMR. The qualitative properties of these salts are described in the "Examples" section.

[0426] Analytical LC-MS: Analytical LC-MS was performed using a SHIMADZU LCMS2020 instrument equipped with a Shim-pack Scepter C18 column (3.0 x 33 mm, 3 μm). The column temperature was set to 40 °C. The solvent systems used were as follows: Solvent A: H2O containing 0.05% HCOOH; Solvent B: MeCN. All compounds were analyzed using the same elution gradient, i.e., the proportion of solvent B increased from 20% to 95% within a 3-minute run, at a flow rate of 1.2 mL / min.

[0427] Preparative chiral SFC separation: Using a Waters SFC 80 (Waters Corporation, USA) or Nexera UCPrep (Shimadzu Corporation, Japan) system, the stereoisomer mixture was separated on any of the following columns: ChiralPak AS-H (21.2 x 250 mm, 5 μm), ChiralPak IA (21.2 x 250 mm, 5 μm), ChiralPak AD-H (21.2 x 250 mm, 5 μm), or ChiralPak IC (21.2 x 250 mm, 5 μm); the eluent was a MeOH / CO2 system, an EtOH / CO2 system, or an isopropanol / CO2 system containing 0.05% diethylamine, the flow rate was 40 mL / min, and the column temperature was set to 40 °C.

[0428] Analytical chiral SFC separation: Using a Waters UPCC (Waters Corporation, USA) or UC (Shimadzu Corporation, Japan) system, analyze mixtures of stereoisomers or single enantiomers on any of the following columns: ChiralPak AS-H (4.6 x 100 mm, 3.5 μm), ChiralPak IA (4.6 x 100 mm, 3.5 μm), ChiralPak AD-H (4.6 x 100 mm, 3.5 μm), or ChiralPak IC (4.6 x 100 mm, 3.5 μm); use MeOH / CO2 system, EtOH / CO2 system, or isopropanol / CO2 system containing 0.05% diethylamine, at a flow rate of 1.8 mL / min, and at a column temperature of 40 °C.

[0429] Final preparation scheme for the target compound:

[0430] General Solution 1:

[0431] In General Scheme 1, compound II is prepared by deprotonating compound I under suitable base and solvent (e.g., LiHMDS, THF), followed by a substitution reaction with bromoacetate. Treating compound II with hydrazine hydrate, followed by treatment with a suitable oxidant (e.g., CuX2), yields compound IV. Chlorinating compound IV with POCl3, followed by a substitution reaction with a suitable substituted piperidine nucleophile (e.g., amine, thiol, alcohol, etc.), yields compound VI. Finally, deprotecting compound VI and functionalizing it under suitable conditions (e.g., alkylation, reductive amination, acylation, etc.) yields macrocyclic compound I.

[0432] General Solution 2

[0433] In general scheme 2, compound VIII is prepared under Suzuki coupling conditions (e.g., using Ruphos Pd G3, a base, and a solvent) at a suitable temperature. Compound VIII undergoes a ring-closure metathesis reaction catalyzed by a suitable catalyst (e.g., Grubbs catalysts I, II, III, or Hoveyda-Grubbs catalyst I) to yield compound IX. Compound IX is then hydrogenated under a suitable catalyst (e.g., Pd / C, Pd(OH)2, etc.) in an H2 atmosphere to generate compound X. Finally, compound X undergoes deprotection and functionalization modification under suitable conditions (e.g., alkylation, reductive amination, acylation, etc.) to yield macrocyclic compound II.

[0434] General Solution 3

[0435]

[0436] In general scheme 3, compound XIII is prepared from compound XI under Miyaura borylation conditions (e.g., bis(pinacol)diboron, Pd(dppf)Cl2, KOAc, solvent 1,4-dioxane); subsequently, a Suzuki coupling reaction is performed (e.g., Ruphos Pd G3, Na2CO3, solvent 1,4-dioxane / H2O). Deprotection of compound XIII and functionalization modification under suitable conditions (e.g., alkylation, reductive amination, acylation, etc.) yields macrocyclic compound III.

[0437] General Solution 4

[0438]

[0439] In general scheme 4, compound XV is prepared under Suzuki coupling conditions (e.g., Ruphos Pd G3, base, and solvent) at a suitable temperature. Deprotection of compound XV with a suitable reagent (e.g., TBAF for removing the TBS group) yields the diol compound XVI. Subsequently, one hydroxyl group in the diol compound XVI is converted to the corresponding halogroup or OMs / OTos group, and the intermediate is treated with a suitable base (e.g., NaH, AgOTf / dimethylpyridine) in a suitable solvent to obtain compound XVII. Finally, deprotection of compound XVII and functionalization modification using suitable conditions (e.g., alkylation, reductive amination, acylation, etc.) yields macrocyclic compound IV.

[0440] General Solution 5

[0441]

[0442] In general scheme 5, formula XVIII is reacted via a Minisci reaction (oxidant-induced or photo-induced, such as K2S2O8, AgNO3) to obtain formula XIX. Formula XIX is then deprotected and functionalized under suitable conditions (e.g., alkylation, acylation, or substitution with other electrophilic agents) to obtain formula XXI. Formula XXI is then deprotected and functionalized under suitable conditions (e.g., alkylation, reductive amination, acylation) to finally obtain macrocyclic V.

[0443] General Solution 6

[0444]

[0445] In general scheme 6, deprotection of formula XXIII (prepared according to the general scheme above) yields formula XVIII. Treatment of formula XVIII with a chlorinating agent (such as POCl3, SOCl2, etc.) or Tf2O yields formula XXIV. Formula XXV can be prepared using suitable reagents via transition metal-catalyzed cross-coupling reactions (such as Suzuki reactions, Stille reactions, etc.) or SnAr reactions (reactions with nucleophiles). Deprotection of formula XXV and (if necessary) functionalization modifications under suitable conditions (such as alkylation, reductive amination, acylation, etc.) yield macrocyclic compound VI.

[0446] Preparation of intermediates examples

[0447] Intermediate 1

[0448] (R)-3-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloropyridazine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0449]

[0450] Step 1: tert-Butyldimethyl(pent-4-yn-1-oxy)silane

[0451] Imidazole (12.1 g, 178 mmol) was added to a solution of pentyl-4-yn-1-ol (10 g, 118 mmol) dissolved in dichloromethane (DCM, 100 mL), followed by the addition of TBSCl (21.5 g, 142.6 mmol) in portions at 0 °C. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with DCM, washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–3% EtOAc) to give the target product (18 g) as an oil. 1 H 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).

[0452] Step 2: 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-3,6-dichloropyridazine

[0453] To a solution of 3,6-dichloro-1,2,4,5-tetraazine (6 g, 39.7 mmol) dissolved in toluene (50 mL), tert-butyldimethyl(pentane-4-yn-1-oxy)silane (11.8 g, 59.6 mmol) was added at room temperature, and the mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. The mixture was then concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–10% ethyl acetate) to give the target compound (11 g) as a solid. 1 HNMR (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).

[0454] Step 3: (R)-3-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloropyridazine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0455] To a solution of 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-3,6-dichloropyridazine (11 g, 34.2 mmol) in DMSO (100 mL), tert-butyl (R)-3-aminopiperidine-1-carboxylate (20.6 g, 102.7 mmol) and DIEA (13.2 g, 102.7 mmol) were added at room temperature; the mixture was then stirred at 150 °C for 8 h under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether / ethyl acetate 0–30%) to give the title compound (6 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ6.52 (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) + .

[0456] Intermediate 2

[0457] 1-(tert-butyl)-2-ethyl(2S,5R)-5-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloropyridazine-3-yl)amino)piperidine-1,2-dicarboxylic acid ester

[0458]

[0459] Step 1: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloropyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0460] To a solution of 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-3,6-dichloropyridazine (10 g, 31.1 mmol) in DMSO (100 mL) (11.1 g, 40.4 mmol), 1-(tert-butyl)-2-ethyl(2S,5R)-5-aminopiperidine-1,2-dicarboxylate (prepared according to the method for intermediate 3 of WO2020216766) (11.1 g, 40.4 mmol) and NaF (2.6 g, 62.2 mmol) were added at room temperature. The mixture was stirred at 130 °C for 48 hours under a nitrogen atmosphere. The mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAc. The filtrate was washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: PE containing 0–35% EtOAc) to give the title compound (3.5 g) in solid form. 1 H 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 = 6.0Hz, 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) + .

[0461] Intermediate 3

[0462] 5-Methoxy-7-(methoxymethoxy)benzo[c][1,2]oxaborazole-1(3H)-ol

[0463]

[0464] Step 1: Methyl 2-bromo-5-methoxy-3-(methoxymethoxy)benzoate

[0465] DIPEA (8.2 g, 63.6 mmol) was added to a solution of methyl 2-bromo-3-hydroxy-5-methoxybenzoate (prepared according to the method in Synlett (2022), 33(11), 1087-1091) (5.5 g, 21 mmol) in dichloromethane (DCM) (60 mL), followed by the dropwise addition of MOMCl (3.4 g, 42 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h, followed by quenching with water and extraction twice with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether / ethyl acetate, 0–30%) to give the title compound (5 g) as a solid. 1 H NMR (400MHz, 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) + .

[0466] Step 2: Methyl 5-methoxy-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoate

[0467] To a solution of methyl 2-bromo-5-methoxy-3-(methoxymethoxy)benzoate (1.8 g, 5.92 mmol) dissolved in 20 mL of 1,4-dioxane, 4,4,5,5-tetramethyl-1,3,2-dioxoboropentane (1.1 g, 8.59 mmol), triethylamine (TEA, 1.8 g, 17.8 mmol), SPhos (487 mg, 1.18 mmol), and Pd(MeCN)₂Cl₂ (153 mg, 0.591 mmol) were added sequentially under nitrogen protection and at room temperature. The mixture was degassed three times with nitrogen, and then stirred overnight at 60 °C under nitrogen atmosphere. After the reaction was complete, the mixture was diluted with ethyl acetate; the organic layer was separated, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether / ethyl acetate, gradient 0–15%) to give the target product (1.5 g) in solid form. 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) + .

[0468] Step 3: 5-Methoxy-7-(methoxymethoxy)benzo[c][1,2]oxoborhecopene-1(3H)-ol

[0469] To a solution of methyl 5-methoxy-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoate (6 g, 17.0 mmol) dissolved in THF (60 mL), LiBH4 (26 mL, 52.0 mmol, 2 M THF solution) was added dropwise at 0 °C; the mixture was then stirred overnight at room temperature under nitrogen protection. The reaction mixture was quenched with saturated aqueous NH4Cl solution at 0 °C and extracted three times with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the title compound (3.6 g) as a solid. 1 H 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) + .

[0470] Intermediate 4

[0471] 7-(methoxymethoxy)-5-(trifluoromethoxy)benzo[c][1,2]oxaborane-1(3H)-ol

[0472]

[0473] Step 1: 3-Hydroxy-5-(trifluoromethoxy)benzoic acid

[0474] Under a nitrogen atmosphere, at room temperature, 10.1 g (252 mmol) of NaOH, 1.16 g (1.26 mmol) of Pd₂(dba)₃, and 1.34 g (3.16 mmol) of tert-butylXPhos were added 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). The reaction mixture was degassed three times with nitrogen and stirred at 100 °C for 3 h. The mixture was then diluted with water and washed twice with ethyl acetate. The aqueous layer was acidified to pH approximately 2 with 2 N hydrochloric acid and extracted three times with DCM / MeOH (v / v = 5 / 1). The organic layers were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (12 g) as a solid. LC-MS (ESI) (m / z): 220.8 (MH)-.

[0475] Step 2: Methyl 3-hydroxy-5-(trifluoromethoxy)benzoate

[0476] TMSCl (9.34 mL, 108 mmol) was added to a methanol (240 mL) suspension of 3-hydroxy-5-(trifluoromethoxy)benzoic acid (12 g, 54.1 mmol), and the mixture was stirred overnight at 70 °C. The mixture was concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–10% ethyl acetate) to give the title compound (11 g) as a solid. 1 H 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).

[0477] Step 3: Methyl 2-bromo-3-hydroxy-5-(trifluoromethoxy)benzoate

[0478] NBS (4.22 g, 23.7 mmol) was added fractionally at 0 °C to a mixture of CCl4 (112 mL) and water (16.8 mL) containing methyl 3-hydroxy-5-(trifluoromethoxy)benzoate (5.6 g, 23.7 mmol). The mixture was then stirred at room temperature under a nitrogen atmosphere for 16 hours. After the reaction, the aqueous phase was extracted twice with dichloromethane (DCM). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–30% ethyl acetate) to give the title compound (3.2 g) as a solid; its regiochemical structure was confirmed by NOE and HMBC. 1 H NMR (400MHz, 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).

[0479] Step 4: Methyl 2-bromo-3-(methoxymethoxy)-5-(trifluoromethoxy)benzoate

[0480] DIPEA (4.3 g, 33.3 mmol) was added to a solution of methyl 2-bromo-3-hydroxy-5-(trifluoromethoxy)benzoate (3.5 g, 11.1 mmol) in dichloromethane (40 mL), followed by the dropwise addition of MOMCl (1.34 g, 16.7 mmol) at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether / ethyl acetate, 0–30%) to give the title compound (3.3 g) as a solid. 1 H 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) + .

[0481] Step 5: Methyl 3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5-(trifluoromethoxy)benzoate

[0482] Under a nitrogen atmosphere and at room temperature, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxoboropentan) (2.8 g, 11.0 mmol), KOAc (1.6 g, 16.3 mmol), and Pd(dppf)Cl2 (409 mg, 0.559 mmol) were added sequentially to a solution of methyl 2-bromo-3-(methoxymethoxy)-5-(trifluoromethoxy)benzoate (2 g, 5.59 mmol) in 1,4-dioxane (20 mL), and Pd(dppf)Cl2 (409 mg, 0.559 mmol). The mixture was degassed three times with nitrogen, and then stirred at 120 °C for 2 hours under a nitrogen atmosphere. The mixture was filtered, the filtrate was diluted with EtOAc, washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel; eluent: PE containing 0–50% EtOAc) to give the title compound (1.1 g) in solid form. 1 H 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) + .

[0483] Step 6: 7-(methoxymethoxy)-5-(trifluoromethoxy)benzo[c][1,2]oxoborhecopene-1(3H)-ol

[0484] The compound in this title is prepared according to the method and procedure described in step 3 of intermediate 3, and is in solid form. 1 HNMR (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) + .

[0485] Intermediate 5

[0486] 3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5-(trifluoromethyl)benzylacetate

[0487]

[0488] Step 1: 2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclohexane

[0489] To a mixture of 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (prepared according to the procedure of Example 20, WO2023178099) dissolved in 1,4-dioxane (100 mL) (5 g, 14.4 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxoboropentane (9.25 g, 72.2 mmol), triethylamine (TEA) (10 mL, 72.2 mmol), CyJohn Phos (0.51 g, 1.5 mmol), and Pd(OAc)₂ (0.32 g, 1.5 mmol) were added sequentially under a N₂ atmosphere; the mixture was then degassed three times with N₂ and stirred overnight at 95 °C under a N₂ atmosphere. The mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with ethyl acetate (EtOAc). The filtrate was washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: petroleum ether (PE) containing 0–10% EtOAc) to give the title compound (2.2 g) as a solid. 1 H 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).

[0490] Step 2: 2-(2-(bromomethyl)-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclohexane

[0491] NBS (0.68 g, 3.8 mmol) and AIBN (0.06 g, 0.35 mmol) were added to a CCl4 (24 mL) solution of 2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboropentane (1.2 g, 3.5 mmol). The resulting mixture was stirred at 80 °C for 5 hours under a nitrogen atmosphere. The mixture was then diluted with EtOAc, washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: PE containing 0–5% EtOAc) to give the title compound (1.1 g) as a solid. 1 H 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).

[0492] Step 3: Ethyl 3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5-(trifluoromethyl)benzoate

[0493] To a mixture of DMSO (4 mL) containing 2-(2-(bromomethyl)-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboropentan (200 mg, 0.471 mmol), KOAc (92.3 mg, 0.941 mmol) was added at room temperature, followed by stirring at 30 °C for 2 hours. The reaction mixture was diluted with EtOAc, washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: PE containing 0–20% EtOAc) to give the target product (80 mg) as an oil. 1 H 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).

[0494] Intermediate 6

[0495] 5-(difluoromethoxy)-7-(methoxymethoxy)benzo[c][1,2]oxoborhecopene-1(3H)-ol

[0496]

[0497] Step 1: Methyl 3-(benzyloxy)-5-hydroxybenzoate

[0498] K₂CO₃ (41.1 g, 298 mmol) was added to a solution of methyl 3,5-dihydroxybenzoate (50 g, 298 mmol) dissolved in DMF (500 mL), followed by dropwise addition of BnBr (40.7 g, 238 mmol) at 0 °C. The mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc, washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: 0–40% EtOAc in PE) to give the target product (35 g) as an oil. LC-MS (ESI) (m / z): 259 (M+H) + .

[0499] Step 2: Methyl 5-(benzyloxy)-2-bromo-3-hydroxybenzoate

[0500] NBS (21.7 g, 122 mmol) was added fractionally to a solution of methyl 3-(benzyloxy)-5-hydroxybenzoate (30 g, 116 mmol) in dichloromethane (300 mL) at 0 °C, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted twice with dichloromethane. The combined organic phases were washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–40% ethyl acetate) to give the target product (18 g) in an oily form. 1 H NMR (400 MHz, DMSO-d6) δ10.62 (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) + .

[0501] Step 3: Methyl 5-(benzyloxy)-2-bromo-3-(methoxymethoxy)benzoate

[0502] DIPEA (20.7 g, 160 mmol) was added to a solution of methyl 2-bromo-3-hydroxy-5-methoxybenzoate (18 g, 53.4 mmol) in dichloromethane (180 mL), followed by the dropwise addition of MOMCl (6.4 g, 80.1 mmol) at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted twice with dichloromethane. The combined organic phases were washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–20% ethyl acetate) to give the title compound (12 g) as a solid. 1 H 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).

[0503] Step 4: Methyl 5-(benzyloxy)-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoate

[0504] To a mixture of 1,4-dioxane (50 mL) containing methyl 5-(benzyloxy)-2-bromo-3-(methoxymethoxy)benzoate (5 g, 13.1 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxoboropentane (3.4 g, 26.2 mmol), triethylamine (TEA, 4.0 g, 39.3 mmol), S-Phos (539 mg, 2.6 mmol), and Pd(MeCN)₂Cl₂ (340 mg, 1.3 mmol) were added sequentially under nitrogen protection and at room temperature. The mixture was degassed three times with nitrogen, and then stirred overnight at 60 °C under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–40% ethyl acetate) to give the title compound (3.7 g) in solid form. 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).

[0505] Step 5: Methyl 5-hydroxy-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3-dioxolane-2-yl)benzoate

[0506] To a solution of methyl 5-(benzyloxy)-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzoate (3.7 g, 8.6 mmol) dissolved in methanol (40 mL), Pd / C (400 mg, 10% wt.) was added under a nitrogen atmosphere, followed by the introduction of hydrogen gas through a hydrogen balloon at room temperature and stirring overnight. The mixture was filtered, and the filtrate was concentrated to dryness to give the target product (2.4 g) as an oil. LC / MS (ESI) m / z: 339.2 (M+H) + .

[0507] Step 6: Methyl 5-(difluoromethoxy)-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzoate

[0508] Sodium dichlorofluoroacetate (1.82 g, 11.8 mmol) was added to a mixture of methyl 5-hydroxy-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzoate (2 g, 5.9 mmol) and Cs₂CO₃ (5.78 g, 17.7 mmol) in DMF (20 mL) at room temperature. The mixture was degassed three times under nitrogen, followed by stirring at 80 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with ice water, and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–20% ethyl acetate) to give the title compound (700 mg, 31% yield) as a 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).

[0509] Step 7: 5-(difluoromethoxy)-7-(methoxymethoxy)benzo[c][1,2]oxoboron-1(3H)-ol

[0510] The preparation method and operating procedure of the title compound are the same as those described in step 3 of intermediate 3, and the resulting product is in solid form. 1 H NMR (400 MHz, CDCl3) δ 6.76 (s, 1H), 6.75 (s, 1H), 6.55 (t, J = 73.5Hz, 1H), 5.25 (s, 2H), 5.03 (s, 2H), 3.57 (s, 3H). LC-MS (ESI) (m / z): 261 (M+H) + .

[0511] Intermediate 7

[0512] (R)-11-methoxy-3-(piperidin-3-ylamino)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-13-ol trifluoroacetate

[0513]

[0514] Step 1: tert-butyl(3R)-3-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-(2-(hydroxymethyl)-4-methoxy-6-(methoxymethoxy)phenyl)pyridazine-3-yl)amino)piperidine-1-carboxylate

[0515] To a mixed solution of 1,4-dioxane (80 mL) and water (8 mL) containing 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), 5-methoxy-7-(methoxymethoxy)benzo[c][1,2]oxoboronidecyclopenten-1(3H)-ol (intermediate 3, 2.8 g, 12.5 mmol), K3PO4 (8 g, 37.7 mmol), and SPhos PdG2 (1.8 g, 2.50 mmol) were added under a nitrogen atmosphere and at room temperature. The mixture was degassed three times with nitrogen and then stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed successively with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, eluent: petroleum ether containing 0–70% ethyl acetate) to give the title compound (4.6 g) as a solid. LC-MS (ESI) (m / z): 647 (M+H) + .

[0516] Step 2: tert-butyl(3R)-3-((6-(2-(hydroxymethyl)-4-methoxy-6-(methoxymethoxy)phenyl)-5-(3-hydroxypropyl)pyridazine-3-yl)amino)piperidine-1-carboxylate

[0517] 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), TBAF (14.3 mL, 14.3 mmol, 1 M THF solution) was added at 0 °C, followed by stirring at 25 °C for 3 h. The reaction mixture was diluted with EtOAc, washed five times with saturated NH4Cl aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: DCM containing 0–6% MeOH) to give the title compound (3.1 g) as a solid. LC-MS (ESI) m / z: 533 (M+H) + .

[0518] Step 3: (3R)-3-((6-(2-(bromomethyl)-4-methoxy-6-(methoxymethoxy)phenyl)-5-(3-hydroxypropyl)pyridazine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0519] Under a nitrogen atmosphere and at -20 °C, carbon tetrabromide (CBr4, 468 mg, 1.41 mmol) and triphenylphosphine (PPh3, 296 mg, 1.13 mmol) were added to a solution of (3R)-3-((6-(2-(hydroxymethyl)-4-methoxy-6-(methoxymethoxy)phenyl)-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (500 mg, 0.940 mmol) dissolved in dichloromethane (DCM, 50 mL). The mixture was then degassed three times with nitrogen and stirred at 30 °C for 1 hour under a nitrogen atmosphere. The mixture was concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: DCM containing 0–7% MeOH) 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]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1-carboxylate

[0520] To a chloroform (25 mL) 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), DTBMP (263 mg, 1.28 mmol) and AgOTf (247 mg, 0.96 mmol) were added at 0 °C under a N2 atmosphere; the mixture was then degassed three times with N2 and stirred for 1 h at room temperature under a N2 atmosphere. The mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with dichloromethane (DCM). The filtrate was concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, eluent: DCM containing 0–7% MeOH) to give the title compound (190 mg) as a solid. LC-MS (ESI) m / z: 515 (M+H) + .

[0521] Step 5: (R)-11-methoxy-3-(piperidin-3-ylamino)-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered ring[5,6-c]pyridazine-13-ol TFA salt

[0522] TFA (1 mL) was added to a solution of tert-butyl(R)-3-((11-methoxy-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanonylcyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (190 mg, 0.370 mmol) dissolved in DCM (2 mL), and the mixture was stirred at 0 °C for 0.5 h. The mixture was concentrated to dryness under reduced pressure to give the target compound (120 mg) as an oil; this product was used directly in the next reaction without purification. LC-MS (ESI) m / z: 371 (M+H) + .

[0523] The intermediates listed in "Error! Reference source not found." are all prepared according to the method and procedure for synthesizing intermediate 7 from intermediate 4, intermediate 5 or intermediate 6.

[0524]

[0525] Intermediate 11

[0526] 5-(benzyloxy)-7-(methoxymethoxy)benzo[c][1,2]oxaborazole-1(3H)-ol

[0527]

[0528] To a solution of methyl 5-(benzyloxy)-3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)benzoate (intermediate 6 compound 5, 5 g, 11.7 mmol) dissolved in THF (50 mL), LiBH4 (8.8 mL, 35.1 mmol, THF solution concentration 4 M) was added dropwise at 0 °C. The mixture was then stirred overnight at room temperature under a N2 atmosphere. After the reaction was complete, the reaction was quenched with ice water and extracted twice with DCM. The combined organic phases were washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound (3.4 g) solid. This product 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) + .

[0529] Intermediate 12

[0530]

[0531] Step 1: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((6-chloro-5-(3-hydroxypropyl)pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0532] 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) dissolved in THF (50 mL), TBAF (18 mL, 18 mmol, 1 M THF solution) was added at 0 °C, followed by stirring at 30 °C for 3 hours. The reaction mixture was diluted with EtOAc, washed five times with saturated NH4Cl aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: DCM containing 0–5% MeOH) to give the title compound (3.1 g) as a solid. LC-MS (ESI) m / z: 443 (M+H) + .

[0533] Step 2: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-((benzyloxy)methyl)-6-chloro-5-(3-hydroxypropyl)pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0534] Under a nitrogen atmosphere, BPO (55 mg, 0.22 mmol), 4CzPN-Bu (1.4 mg, 0.001 mmol), and 4A molecular sieve (10 mg) were added 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). The reaction mixture was degassed three times with nitrogen and stirred for 16 hours at room temperature under 18W white LED illumination. The mixture was then diluted with EtOAc, washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: PE containing 0–50% EtOAc) to give the title compound (460 mg) as a solid. LC / MS (ESI) m / z: 563.3 (M+H) + .

[0535] Step 3: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-((benzyloxy)methyl)-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloropyridazine-3-yl)amino)piperidine-1,2-dicarboxylic acid ester

[0536] 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-dicarboxylic acid ester (460 mg, 0.82 mmol) dissolved in dichloromethane (DCM, 50 mL), imidazole (225 mg, 3.3 mmol) and TBSCl (247 mg, 1.6 mmol) were added at 0 °C. The mixture was stirred at room temperature (RT) under a nitrogen atmosphere for 2 h. The mixture was then diluted with ethyl acetate (EtOAc), washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether / ethyl acetate 100:0 to 60:40) to give the title compound (380 mg) as a solid. LC / MS (ESI) m / z: 677.4 (M+H) + . Example

[0537] Example 1

[0538] (R)-10-cyclopropyl-3-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrobenzo[7,8]cyclooctano[1,2-c]pyridazine-12-ol carboxylate (partial)

[0539]

[0540] Step 1: (E)-6-(3-bromo-5-methoxyphenyl)hex-5-enoic acid

[0541] Under a nitrogen atmosphere and at room temperature, potassium tert-butoxide (31.3 g, 0.279 mol) was added to a solution of (4-carboxybutyl)triphenylphosphine bromide (49.5 g, 0.111 mol) in THF (500 mL), and the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 3-bromo-5-methoxybenzaldehyde (20 g, 93 mmol) in THF (300 mL) was added to the mixture, and the resulting mixture was stirred overnight at room temperature. The mixture was acidified with 1 N hydrochloric acid aqueous solution at 0 °C and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–40% ethyl acetate) to give the title compound (19 g) as a solid. LC-MS (ESI) (m / z): 299 / 301 (M+H) + .

[0542] Step 2: 6-(3-bromo-5-methoxyphenyl)hexanoic acid

[0543] PtO2 (1 g, 8.1 mmol) was added to a solution of (E)-6-(3-bromo-5-methoxyphenyl)hex-5-enoic acid (19 g, 63.5 mmol) in ethyl acetate (200 mL); the mixture was then degassed three times with nitrogen and stirred for 1 hour at room temperature under hydrogen balloon protection. 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) + .

[0544] Step 3: 2-Bromo-4-methoxy-7,8,9,10-tetrahydrobenzo[8]cycloene-5(6H)-one

[0545] 6-(3-bromo-5-methoxyphenyl)hexanoic acid (10 g, 0.66 mmol) was dissolved in Eaton reagent (100 mL) and stirred overnight at room temperature. The mixture was poured into a saturated aqueous solution of sodium bicarbonate at 0 °C and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–20% ethyl acetate) to give the title compound (1.05 g) in an oil. 1 H 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) + .

[0546] Step 4: ethyl acetate 2-(2-bromo-4-methoxy-5-oxo-5,6,7,8,9,10-hexahydrobenzo[8]cyclooctene-6-yl)

[0547] HMPA (0.60 mL, 3.44 mmol) was added to a THF (8 mL) solution containing 750 mg, 2.65 mmol of 2-bromo-4-methoxy-7,8,9,10-tetrahydrobenzo[8]cyclooctene-5(6H)-one (8 mL), followed by the dropwise addition of LiHMDS (1.99 mL, 3.97 mmol, 2 M THF solution) at 0 °C, and the mixture was stirred for 30 min at 0 °C under N2 atmosphere. Ethyl bromoacetate (663 mg, 3.97 mmol) was then added, and the mixture was stirred for 16 h at room temperature under N2 atmosphere. The mixture was quenched with ice water and extracted twice with EtOAc. The organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: PE containing 0–10% EtOAc) to obtain the target product (600 mg) in an oily form. LC-MS (ESI) (m / z): 369 / 371 (M+H) + .

[0548] Step 5: 10-Bromo-12-methoxy-4,4a,5,6,7,8-hexahydrobenzo[7,8]cyclooctano[1,2-c]pyridazine-3(2H)-one

[0549] A solution of hydrazine hydrate (5 mL, 85% wt.) was added to a solution of ethyl acetate (500 mg, 1.35 mmol) of 2-(2-bromo-4-methoxy-5-oxo-5,6,7,8,9,10-hexahydrobenzo[8]cyclooctene-6-yl) in EtOH (500 mg, 1.35 mmol), and the mixture was stirred at 80 °C for 5 hours. The mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound (250 mg) as a solid. LC-MS (ESI) (m / z): 337 / 339 (M+H) + .

[0550] Step 6: 10-Bromo-12-methoxy-5,6,7,8-tetrahydrobenzo[7,8]cyclooctyl[1,2-c]pyridazine-3(2H)-one

[0551] Copper chloride (199 mg, 1.48 mmol) was added to a MeCN (3 mL) solution of 10-bromo-12-methoxy-4,4a,5,6,7,8-hexahydrobenzo[7,8]cyclooctyl[1,2-c]pyridazine-3(2H)-one (250 mg, 0.74 mmol). The mixture was stirred at 80 °C for 2 h. The mixture was then diluted with water and extracted twice with EtOAc. The organic layers were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; DCM containing 0–5% MeOH) to give the title compound (150 mg) as a solid. LC-MS (ESI) (m / z): 335 / 337 (M+H) + .

[0552] Step 7: 10-Bromo-3-chloro-12-methoxy-5,6,7,8-tetrahydrobenzo[7,8]cyclooctyl[1,2-c]pyridazine

[0553] 150 mg (0.45 mmol) of 10-bromo-12-methoxy-5,6,7,8-tetrahydrobenzo[7,8]cyclooctyl[1,2-c]pyridazine-3(2H)-one was dissolved in POCl3 (4 mL) and stirred at 100 °C for 1 hour. The mixture was concentrated to dryness. The residue was diluted with ice water and extracted twice with EtOAc. The organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (130 mg) as an oil; this product was used directly in the next reaction without purification. LC-MS (ESI) (m / z): 353 / 355 (M+H) + .

[0554] Step 9: tert-butyl(R)-3-((10-bromo-12-methoxy-5,6,7,8-tetrahydrobenzo[7,8]cyclooctano[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate

[0555] Cesium fluoride (84 mg, 0.55 mmol) was added to a mixture of 130 mg, 0.37 mmol of 10-bromo-3-chloro-12-methoxy-5,6,7,8-tetrahydrobenzo[7,8]cyclooctano[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), and the mixture was stirred overnight at 120 °C. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: DCM containing 0–5% MeOH) to give the title compound (110 mg) as a solid. LC-MS (ESI) (m / z): 517 / 519 (M+H) + .

[0556] Step 10: tert-butyl(R)-3-((10-cyclopropyl-12-methoxy-5,6,7,8-tetrahydrobenzo-[7,8]cyclooctano[1,2-c]pyridazine-3-yl)amino)piperidine-1-carboxylate

[0557] Under a nitrogen atmosphere, K3PO4 (158 mg, 0.74 mmol), tricyclohexylphosphine (12 mg, 0.04 mmol), and palladium acetate (4 mg, 0.02 mmol) were added sequentially to a mixture of tert-butyl(R)-3-((10-bromo-12-methoxy-5,6,7,8-tetrahydrobenzo-[7,8]cyclooctano[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). The mixture was degassed three times with nitrogen and then stirred overnight at 80 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel; eluent: DCM containing 0–5% MeOH) to give the title compound (80 mg) as a solid. LC-MS (ESI) (m / z): 479.3 (M+H) + .

[0558] Step 11: (R)-10-cyclopropyl-3-(piperidin-3-ylamino)-5,6,7,8-tetrahydrobenzo[7,8]cyclooctyl[1,2-c]pyridazine-12-ol

[0559] To a solution of tert-butyl(R)-3-((10-cyclopropyl-12-methoxy-5,6,7,8-tetrahydrobenzo[7,8]cyclooctyl[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (80 mg, 0.17 mmol) dissolved in dichloromethane (DCM, 1 mL), boron tribromide (42 mg, 0.17 mmol) was added at -78 °C under a nitrogen atmosphere, followed by stirring of the mixture at room temperature for 30 min. The mixture was quenched at 0 °C with a saturated aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the crude title compound (50 mg) as a solid. LC-MS (ESI) (m / z): 365 (M+H) + .

[0560] Step 12: (R)-10-cyclopropyl-3-((1-methylpiperidin-3-yl)amino)-5,6,7,8-tetrahydrobenzo[7,8]cyclooctyl[1,2-c]pyridazine-12-ol

[0561] Sodium cyanoborohydride (17 mg, 0.27 mmol) was added to a mixture of (R)-10-cyclopropyl-3-(piperidin-3-ylamino)-5,6,7,8-tetrahydrobenzo[7,8]cyclooctyl[1,2-c]pyridazine-12-ol (50 mg, 0.137 mmol) dissolved in methanol (MeOH, 1 mL) and 37% aqueous formaldehyde solution (0.3 mL) at 0 °C. The mixture was stirred at room temperature for 30 min. The mixture was then quenched with ice water. The mixture was purified by preparative HPLC (YMC-Actus Triart C18250*20 mm, mobile phase: a mixture of aqueous solution containing 0.1% formic acid and acetonitrile, gradient: 20–95% acetonitrile) to give the title compound (3.9 mg) as a solid. 1 H 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) + .

[0562] Example 2

[0563] 9-Cyclopropyl-3-(((R)-1-methylpiperidin-3-yl)amino)-6,7-dihydro-5H-benzo[6,7]cycloheptano[1,2-c]pyridazine-11-ol carboxylate (partial)

[0564]

[0565] The title compound was prepared using (3-carboxypropyl)triphenylphosphine bromide as the starting material, following the synthesis method and steps described in Example 1. 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) + .

[0566] Example 3

[0567] (R)-3-((1-methylpiperidin-3-yl)amino)-10-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[7,8]cyclooctyl[1,2-c]pyridazine-12-ol carboxylate (partial)

[0568]

[0569] Step 1: tert-butyl(R)-3-((6-chloro-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1-carboxylate

[0570] TBAF (8.08 g, 261.5 mmol) was added to a THF (60 mL) 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), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed successively with saturated aqueous NH4Cl solution and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, PE containing 0–80% EtOAc) 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

[0571] 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), Dess-Martin reagent (11.4 g, 27.0 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 4 h. The mixture was quenched with a saturated aqueous solution of NaHCO3 and filtered. The filtrate was extracted three times with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, PE containing 0–40% EtOAc) to give the title compound (2.6 g) as an oil. LC-MS (ESI) m / z: 369.4 (M+H) + .

[0572] Step 3: (R)-3-((5-(but-3-yn-1-yl)-6-chloropyridazine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0573] To a solution of (R)-3-((6-chloro-5-(3-oxopropyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (2.6 g, 7.05 mmol) dissolved in methanol (30 mL), K₂CO₃ (1.95 g, 14.1 mmol) and (1-diazo-2-oxopropyl)phosphonate dimethyl ester (1.62 g, 8.46 mmol) were added at 0 °C; the mixture was then stirred at room temperature for 3 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–35% ethyl acetate) 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) + .

[0574] Step 4: tert-butyl(R)-3-((5-(but-3-en-1-yl)-6-chloropyridazine-3-yl)amino)piperidine-1-carboxylate

[0575] 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 ethyl acetate (15 mL), Lindlar Pd catalyst (0.17 g, 0.411 mmol) was added at 0 °C. The mixture was then degassed three times with N2 and stirred at 0 °C under hydrogen balloon protection for 2 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C18 column, mobile phase: 0–55% acetonitrile / water solution containing 0.1% formic acid) to give the title compound (1.1 g) in an oily form. 1 H 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) + .

[0576] Step 5: (3R)-3-((6-(2-allyl-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-(but-3-en-1-yl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0577] To a mixture containing tert-butyl (R)-3-((5-(but-3-en-1-yl)-6-chloropyridazin-3-yl)amino)piperidin-1-carboxylate (900 mg, 2.46 mmol) and 1,4-dioxane (10 mL) of 2-(2-allyl-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboropentane (1.19 g, 3.20 mmol) and water (2 mL), Na₂CO₃ (0.78 g, 7.38 mmol), RuPhos (0.114 g, 0.246 mmol), and RuPhos Pd G₃ (0.206 g, 0.246 mmol) were added sequentially under a N₂ atmosphere; the mixture was then subjected to three N₂ treatments. The mixture was degassed and stirred at 120 °C for 5 hours under N2 atmosphere. The reaction mixture was filtered through a diatomaceous earth filter, and the filter cake was washed with EtOAc. The filtrate was washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: PE containing 0–40% EtOAc) to give the title compound (0.26 g) as a solid. LC-MS (ESI) m / z: 577.4 (M+H) + .

[0578] Step 6: (R,Z)-3-((12-(methoxymethoxy)-10-(trifluoromethyl)-5,6-dihydrobenzo[7,8]cyclooctyl[1,2-c]pyridazine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0579] Under a nitrogen atmosphere, Grubbs II catalyst (17.7 mg, 0.021 mmol) was added to a toluene (100 mL) solution of (3R)-3-((6-(2-allyl-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-(but-3-en-1-yl)pyridazin-3-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (100 mg, 0.174 mmol) at 0 °C. The mixture was stirred at 100 °C for 6 hours. The mixture was then concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (C18 column, mobile phase: aqueous solution containing 0.1% formic acid and acetonitrile, gradient 0–40%) to give the title compound (15 mg) as a solid. LC-MS (ESI) m / z: 535.2 (M+H) + .

[0580] Step 7: (R)-3-((12-(methoxymethoxy)-10-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[7,8]cyclooctyl[1,2-c]pyridazine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0581] Pd / C (3 mg, 10% wt.) was added to a solution of (R,Z)-3-((12-(methoxymethoxy)-10-(trifluoromethyl)-5,6-dihydrobenzo[7,8]cyclooctyl[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (15 mg, 0.028 mmol) dissolved in MeOH (2 mL) under a nitrogen atmosphere, followed by stirring of the mixture at room temperature for 1 hour under hydrogen balloon protection. 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) + .

[0582] Step 8: (R)-3-(piperidin-3-ylamino)-10-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[7,8]cyclooctyl[1,2-c]pyridazine-12-ol

[0583] To a solution of (R)-3-((12-(methoxymethoxy)-10-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[7,8]cyclooctyl[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (12 mg, 0.022 mmol) dissolved in 0.5 mL of 1,4-dioxane, a solution of HCl / 1,4-dioxane (0.5 mL, 4 M) was added, and the mixture was stirred at room temperature for 20 min. The mixture was adjusted to alkaline with saturated aqueous NaHCO3 solution and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (7 mg) as a solid. LC-MS (ESI) (m / z): 393.2 (M+H) + .

[0584] Step 9: (R)-3-((1-methylpiperidin-3-yl)amino)-10-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[7,8]cyclooctano[1,2-c]pyridazine-12-ol

[0585] To a mixture of (R)-3-(piperidin-3-ylamino)-10-(trifluoromethyl)-5,6,7,8-tetrahydrobenzo[7,8]cyclooctano[1,2-c]pyridazine-12-ol (7 mg, 0.018 mmol) dissolved in MeOH (1 mL) and 37% aqueous formaldehyde solution (0.2 mL), AcOH (2.2 mg, 0.036 mmol) and NaBH3CN (3.4 mg, 0.054 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 20 min. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250*20 mm, mobile phase: 10–95% MeCN / H2O system containing 0.1% FA) to finally obtain the title compound (2 mg) 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) + .

[0586] Example 4

[0587] (R)-3-((1-methylpiperidin-3-yl)amino)-12-(trifluoromethyl)-5,6,7,8,9,10-hexahydrobenzo[9,10]cyclodecane[1,2-c]pyridazine-14-ol carboxylate (partial)

[0588]

[0589] Step 1: 3,6-Dichloro-4-(pentan-4-yn-1-yl)pyridazine

[0590] Under a nitrogen atmosphere, hepta-1,6-diyne (9.16 g, 99.4 mmol) was added to a toluene (50 mL) solution of 3,6-dichloro-1,2,4,5-tetraazine (5 g, 33.1 mmol) at 25 °C. The mixture was stirred at 100 °C for 4 hours. Subsequently, the mixture was concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–20% ethyl acetate) to give the target product (5.5 g) as an oil. 1 H NMR (400 MHz, CDCl3) δ7.41 (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).

[0591] Step 2: (R)-3-((6-chloro-5-(pent-4-yn-1-yl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0592] CsF (7.81 g, 51.4 mmol) was added to a mixture of 3,6-dichloro-4-(pentan-4-yn-1-yl)pyridazine (5.5 g, 25.7 mmol) and (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (7.71 g, 38.6 mmol) in DMSO (60 mL). The mixture was stirred overnight at 120 °C. The mixture was then diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed successively with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–50% ethyl acetate) to give the target compound (4.2 g) as a solid. LC-MS (ESI) (m / z): 379 (M+H) + .

[0593] Step 3: (R)-3-((6-chloro-5-(pent-4-en-1-yl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0594] A mixture of tetrahydrofuran (8 mL) and ethyl acetate (8 mL) containing 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) was added to a solution at 0 °C with 0.15 g (0.37 mmol) of Lindra catalyst. The mixture was then degassed three times under a nitrogen atmosphere and stirred at 0 °C under hydrogen balloon protection for 2 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Pack ODS-AQ / S-5um / 12 nm 250*20mm; mobile phase: water containing 0–55% acetonitrile and 0.1% formic acid) to give the target compound (1.1 g) in an oily form. 1 H NMR (400MHz, 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).

[0595] Step 4: 2-(methoxymethoxy)-1-nitro-4-(trifluoromethyl)benzene

[0596] DIPEA (37.4 g, 289.7 mmol) was added to a solution of 2-nitro-5-(trifluoromethyl)phenol (20 g, 96.6 mmol) in dichloromethane (DCM, 200 mL), followed by dropwise addition of MOMCl (11.7 g, 144.8 mmol) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–20% ethyl acetate) to give the target product (21 g) in an oily form. 1 H 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).

[0597] Step 5: 2-(methoxymethoxy)-4-(trifluoromethyl)aniline

[0598] Pd / C (0.9 g, 10 wt%) was added to a methanol (MeOH, 200 mL) solution of 2-(methoxymethoxy)-1-nitro-4-(trifluoromethyl)benzene (21 g, 83.6 mmol) under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature by passing hydrogen through a hydrogen balloon. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give the target product (17.5 g) as an oil. LC-MS (ESI) m / z: 222.3 (M+H) + .

[0599] Step 6: 2-Iodo-6-(methoxymethoxy)-4-(trifluoromethyl)aniline

[0600] NIS (16.1 g, 71.2 mmol) was added to a solution of 2-(methoxymethoxy)-4-(trifluoromethyl)aniline (17.5 g, 79.1 mmol) dissolved in AcOH (180 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water, neutralized with saturated sodium bicarbonate solution, and extracted three times with EtOAc. The combined organic layers were washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel; eluent: PE containing 0–10% EtOAc) to give the title compound as a solid (19 g). 1 H 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) + .

[0601] Step 7: 2-Allyl-6-(methoxymethoxy)-4-(trifluoromethyl)aniline

[0602] To a solution of 2-iodo-6-(methoxymethoxy)-4-(trifluoromethyl)aniline (8 g, 23 mmol) dissolved in toluene (60 mL), allyl tributyltin (11.4 g, 34.6 mmol) and Pd(PPh3)4 (2.66 g, 2.30 mmol) were added at room temperature under a nitrogen atmosphere. The mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was then diluted with water and extracted twice with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel, eluent: petroleum ether containing 0–35% ethyl acetate) to give the target compound (5.6 g) as an oil. 1 H 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) + .

[0603] Step 8: 3-Allyl-2-iodo-5-(trifluoromethyl)phenol

[0604] To a solution of 2-allyl-6-(methoxymethoxy)-4-(trifluoromethyl)aniline (5.5 g, 21.05 mmol) dissolved in MeCN (30 mL), concentrated HCl (60 mL) was added at 0 °C, and the mixture was stirred at 0 °C for 10 min. Then, a solution of NaNO2 (0.69 g, 10.0 mmol) dissolved in water (20 mL) was added dropwise to the mixture at 0 °C, and stirring was continued at 0 °C for 1 h. Next, a solution of KI (6.99 g, 42.1 mmol) dissolved in water (40 mL) was added dropwise at 0 °C, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed successively with saturated aqueous Na2S2O3 solution and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: PE containing 0–15% EtOAc) to obtain the target product (4.3 g) in an oily state. 1 H NMR (400MHz, 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 (MH)-.

[0605] Step 9: 1-Allyl-2-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzene

[0606] DIPEA (5.07 g, 39.3 mmol) was added to a solution of 3-allyl-2-iodo-5-(trifluoromethyl)phenol (4.3 g, 13.1 mmol) dissolved in dichloromethane (DCM, 40 mL), followed by dropwise addition of MOMCl (1.59 g, 19.7 mmol) at 0 °C. The resulting mixture was stirred at room temperature (RT) for 2 h under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (EtOAc), washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether / EtOAc, v / v 100:0 to 90:10) 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).

[0607] Step 10: 2-(2-Allyl-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-Tetramethyl-1,3,2-dioxoboronylcyclohexane

[0608] To a THF (40 mL) solution of 1-allyl-2-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzene (4.6 g, 12.4 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxoboropentane (3.17 g, 24.8 mmol), CuI (0.24 g, 1.24 mmol), and NaH (0.74 g, 18.6 mmol, 60% mineral oil dispersion) were added sequentially at 0 °C under a N2 atmosphere. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water and extracted twice with EtOAc. The combined organic layers were washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel; eluent: PE containing 0–8% EtOAc) to give the title compound (4 g) in solid form. 1 H 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).

[0609] 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

[0610] To a mixture of tert-butyl(R)-3-((6-chloro-5-(pent-4-en-1-yl)pyridazin-3-yl)amino)piperidin-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-dioxoboropentane (0.74 g, 1.99 mmol) in 1,4-dioxane (5 mL) and water (1 mL), Na₂CO₃ (0.49 g, 4.59 mmol), RuPhos (71.4 mg, 0.15 mmol), and RuPhos Pd G₃ (0.128 g, 0.153 mmol) were sequentially added under a N₂ atmosphere; the mixture was then degassed three times with N₂. The reaction mixture was stirred at 120 °C for 4 hours under an atmospheric atmosphere. The reaction mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAc. The filtrate was washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by rapid chromatography (silica gel; eluent: PE containing 0–40% EtOAc) to give the title compound as a solid (0.48 g). LC-MS (ESI) m / z: 591.7 (M+H) + .

[0611] Step 12: tert-butyl(R,Z)-3-((14-(methoxymethoxy)-12-(trifluoromethyl)-5,6,7,10-tetrahydrobenzo[9,10]cyclodecyl[1,2-c]pyridazine-3-yl)amino)piperidine-1-carboxylate

[0612] Hoveyda-Grubbs II catalyst (31.8 mg, 0.051 mmol) was added 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) dissolved in toluene (200 mL) under a nitrogen atmosphere. The mixture was degassed three times with nitrogen and then stirred at 100 °C for 6 h under a nitrogen atmosphere. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Pack ODS-AQ / S-5um / 12 nm 250*20 mm, mobile phase: 0–40% acetonitrile / water solution containing 0.1% formic acid) to give the title compound (38 mg) as an oil. LC-MS (ESI) m / z: 563.3 (M+H)+ .

[0613] Step 13: tert-butyl(R)-3-((14-(methoxymethoxy)-12-(trifluoromethyl)-5,6,7,8,9,10-hexahydrobenzo[9,10]cyclodecano[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate

[0614] Pd / C (7 mg, 10% wt.) was added to a solution of tert-butyl(R,Z)-3-((14-(methoxymethoxy)-12-(trifluoromethyl)-5,6,7,10-tetrahydrobenzo[9,10]cyclodecano[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (38 mg, 0.068 mmol) dissolved in MeOH (2 mL) under a nitrogen atmosphere. The mixture was then stirred with a hydrogen balloon at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated to dryness to give the target product (25 mg) as an oil. LC-MS (ESI) m / z: 565.3 (M+H) + .

[0615] Step 14: (R)-3-(piperidin-3-ylamino)-12-(trifluoromethyl)-5,6,7,8,9,10-hexahydrobenzo[9,10]cyclodecane[1,2-c]pyridazine-14-ol

[0616] To a solution of tert-butyl(R)-3-((14-(methoxymethoxy)-12-(trifluoromethyl)-5,6,7,8,9,10-hexahydrobenzo[9,10]cyclodecano[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (25 mg, 0.044 mmol) in 1,4-dioxane (0.5 mL), a solution of HCl / 1,4-dioxane (0.2 mL, 4 M) was added, and the mixture was stirred at room temperature for 20 min. The mixture was then alkalized with a saturated aqueous sodium bicarbonate solution and extracted twice with dichloromethane (DCM). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, 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) + .

[0617] Step 15: (R)-3-((1-methylpiperidin-3-yl)amino)-12-(trifluoromethyl)-5,6,7,8,9,10-hexahydrobenzo[9,10]cyclodecane[1,2-c]pyridazine-14-ol

[0618] To a mixture of (R)-3-(piperidin-3-ylamino)-12-(trifluoromethyl)-5,6,7,8,9,10-hexahydrobenzo[9,10]cyclodecane[1,2-c]pyridazine-14-ol (13 mg, 0.031 mmol) and 37% aqueous solution… To a solution of MeOH (1 mL) containing HCHO (0.2 mL), AcOH (3.8 mg, 0.062 mmol) and NaBH3CN (5.8 mg, 0.09 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 20 min. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250*20mm column; mobile phase: H2O / MeCN system containing 0.1% FA, gradient 5–95%) to finally obtain the title compound (7 mg) solid. 1 H NMR (400MHz, 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) + .

[0619] Example 5

[0620] (R)-3-((1-methylpiperidin-3-yl)amino)-11-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-benzo[8,9]cyclononano[1,2-c]pyridazine-13-ol

[0621]

[0622] Step 1: 2-Bromo-3-iodo-5-(trifluoromethyl)phenol

[0623] To a solution of 2-iodo-6-(methoxymethoxy)-4-(trifluoromethyl)aniline (19 g, 54.7 mmol, intermediate 8 of Example 4) dissolved in MeCN (80 mL), an aqueous solution of HBr (30 mL, 40% w / w) was added at 0 °C. The mixture was stirred at 0 °C for 20 min, followed by dropwise addition of a solution of NaNO2 dissolved in water (20 mL) (3.97 g, 57.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h, followed by dropwise addition of a solution of CuBr2 dissolved in MeCN (24.3 g, 109.4 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The mixture was extracted twice with DCM. The combined organic layers were washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel; eluent: PE containing 0–20% EtOAc) to give the title compound (17 g) as an oil. LC-MS (ESI) m / z: 365.0 (MH)-.

[0624] Step 2: 2-Bromo-1-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzene

[0625] DIPEA (17.9 g, 139 mmol) was added to a solution of 2-bromo-3-iodo-5-(trifluoromethyl)phenol dissolved in DCM (180 mL), followed by dropwise addition of MOMCl (5.6 g, 69.5 mmol) at 0 °C. The mixture was stirred at room temperature under N2 atmosphere for 3 hours. The mixture was diluted with EtOAc, washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–10% EtOAc) to give the target compound (16 g) in an oily form. 1 H 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).

[0626] Step 3: 4-(5-(2-bromo-3-(methoxymethoxy)-5-(trifluoromethyl)phenyl)pent-4-yn-1-yl)-3,6-dichloropyridazine

[0627] To a mixture of 3,6-dichloro-4-(pentan-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), TEA (15 mL), CuI (0.48 g, 2.51 mmol), and Pd(PPh3)4 (2.90 g, 2.511 mmol) were added sequentially at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. The mixture was then filtered; the filtrate was diluted with EtOAc, washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–30% EtOAc) to give the target compound (10 g) as a solid. 1 H 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

[0628] 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) dissolved in 1,4-dioxane (30 mL), a solution of HCl / 1,4-dioxane (8.5 mL, 4 M) was added at 0 °C. The mixture was stirred at room temperature for 3 hours. The mixture was then adjusted to alkaline with a saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a solid (7.2 g). LC-MS (ESI) (m / z): 452.9 (M+H) + .

[0629] Step 5: 4-(5-(2-bromo-3-methoxy-5-(trifluoromethyl)phenyl)pent-4-yn-1-yl)-3,6-dichloropyridazine

[0630] 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) dissolved in acetonitrile (70 mL), K₂CO₃ (6.48 g, 46.9 mmol) and MeI (3.03 g, 23.5 mmol) were added at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was then diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: petroleum ether containing 0–20% ethyl acetate) to give the title compound (6.5 g) as a solid. 1 H 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) + .

[0631] Step 6: (R)-3-((5-(5-(2-bromo-3-methoxy-5-(trifluoromethyl)phenyl)pent-4-yn-1-yl)-6-chloropyridazine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0632] 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), under a nitrogen atmosphere and at room temperature, tert-butyl (R)-3-aminopiperidine-1-carboxylic acid (5.22 g, 26.1 mmol) and KF (2.27 g, 39.1 mmol) were added. The mixture was stirred at 110 °C for 6 hours. The mixture was then diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: petroleum ether containing 0–45% ethyl acetate) to give the title compound (3.2 g, 39% yield) as a solid.1 H NMR (400MHz, 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) + .

[0633] Step 7: tert-butyl(R)-3-((5-(5-(2-bromo-3-methoxy-5-(trifluoromethyl)phenyl)pentyl)-6-chloropyridazine-3-yl)amino)piperidine-1-carboxylate

[0634] PtO2 (0.11 g, 0.50 mmol) was added 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) dissolved in MeOH (30 mL) under nitrogen protection. The mixture was then stirred at room temperature using a hydrogen balloon for 5 hours. The mixture was filtered, and the filtrate was concentrated to dryness to give the target product (2.4 g) as an oil. LC-MS (ESI) m / z: 637.4 (M+H) + .

[0635] Step 8: tert-butyl(R)-3-((6-chloro-5-(5-(3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5-(trifluoromethyl)phenyl)pentyl)pyridazine-3-yl)amino)piperidine-1-carboxylate

[0636] 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-dioxoboronylcyclopropane) (1.44 g, 5.66 mmol) in 1,4-dioxane (20 mL), KOAc (0.83 g, 8.49 mmol) and Pd(dppf)Cl2·DCM (0.23 g, 0.28 mmol) were added under N2 atmosphere; the mixture was then degassed three times with N2 and stirred at 100 °C for 2 hours under N2 atmosphere. The mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with EtOAc. The filtrate was washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, eluent: PE containing 0–40% EtOAc) to give the title compound (1.2 g) as a solid. LC-MS (ESI) m / z: 683.4 (M+H) + .

[0637] Step 9: (R)-3-((13-methoxy-11-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-benzo[8,9]cyclononano[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0638] To a mixed solution of 1,4-dioxane (20 mL) and water (4 mL) containing (R)-3-((6-chloro-5-(5-(3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-5-(trifluoromethyl)phenyl)pentyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 1.76 mmol), Na₂CO₃ (0.56 g, 5.27 mmol), RuPhos (0.08 g, 0.176 mmol), and RuPhos Pd G₃ (0.15 g, 0.176 mmol) were added sequentially under a nitrogen atmosphere. The mixture was then degassed three times with nitrogen, and the reaction mixture was stirred at 120 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was filtered through a diatomaceous earth filter, and the filter cake was washed with ethyl acetate. The filtrate was washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: petroleum ether containing 0–40% ethyl acetate) to give the title compound (0.15 g) as a solid. LC-MS (ESI) m / z: 521.4 (M+H) + .

[0639] Step 10: (R)-13-methoxy-N-(piperidin-3-yl)-11-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-benzo[8,9]cyclononano[1,2-c]pyridazine-3-amine

[0640] A solution of HCl / 1,4-dioxane (1 mL, 4 M) was added to a solution of tert-butyl(R)-3-((13-methoxy-11-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-benzo[8,9]cyclononano[1,2-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (150 mg, 0.288 mmol) dissolved in 2 mL of 1,4-dioxane, and the mixture was stirred at room temperature for 30 min. The mixture was then alkalized with a saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, 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]cyclonon[1,2-c]pyridazine-3-amine

[0641] To a mixture of (R)-13-methoxy-N-(piperidin-3-yl)-11-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-benzo[8,9]cyclonon[1,2-c]pyridazin-3-amine (100 mg, 0.24 mmol) dissolved in MeOH (2 mL) and 37% aqueous formaldehyde solution (0.2 mL), AcOH (28.9 mg, 0.48 mmol) and NaBH3CN (45.2 mg, 0.72 mmol) were added at 0 °C, followed by stirring at room temperature for 20 min. The mixture was diluted with water and extracted twice with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (80 mg) as an oil. LC-MS (ESI) (m / z): 435.3 (M+H) + .

[0642] Step 12: (R)-3-((1-methylpiperidin-3-yl)amino)-11-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-benzo[8,9]cyclonon[1,2-c]pyridazine-13-ol

[0643] BBr3 (184 mg, 0.736 mmol) was added to a solution of (R)-13-methoxy-N-(1-methylpiperidin-3-yl)-11-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-benzo[8,9]cyclonon[1,2-c]pyridazine-3-amine (80 mg, 0.184 mmol) dissolved in DCM (2 mL) at -78 °C. The mixture was stirred for 1 hour in the range of -78 °C to room temperature. The mixture was slowly quenched with a saturated aqueous sodium bicarbonate solution at 0 °C and extracted three times with dichloromethane. The combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250*20 mm, mobile phase: aqueous solution containing 0.1% ammonium bicarbonate with acetonitrile content of 5–95%) to obtain the title compound (7 mg) in solid form. 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) + .

[0644] Example 6

[0645] (R)-3-((1-methylpiperidin-3-yl)amino)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-13-ol

[0646]

[0647] Step 1: 1-(bromomethyl)-2-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzene

[0648] Under a nitrogen atmosphere, NBS (385 mg, 2.17 mmol) was added to a DCE (6 mL) mixture of 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (500 mg, 1.45 mmol) and AIBN (47 mg, 0.29 mmol), and the reaction mixture was stirred at 80 °C for 18 hours. The reaction mixture was diluted with EtOAc, washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by chromatography (silica gel; eluent: PE containing 0–5% EtOAc) to give the target product (550 mg) as an oil. 1 HNMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.20 (s, 1H), 5.30 (s, 2H), 4.67 (s,2H), 3.53 (s, 3H).

[0649] Step 2: tert-butyl(R)-3-((6-chloro-5-(3-((2-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzyl)oxy)propyl)pyridazine-3-yl)amino)piperidine-1-carboxylate

[0650] To a THF (6 mL) solution containing tert-butyl(R)-3-((6-chloro-5-(3-hydroxypropyl)pyridazin-3-yl)amino)piperidine-1-carboxylate (174 mg, 0.47 mmol), NaH (28 mg, 0.70 mmol, 60% mineral oil dispersion) was added at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 20 min. Subsequently, 1-(bromomethyl)-2-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzene (200 mg, 0.47 mmol) was added to the mixture at 0 °C, and the resulting mixture was stirred at 25 °C for 15 h. The mixture was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by chromatography (silica gel; eluent: DCM containing 0–4% MeOH) to give the title compound (146 mg) as a solid. LC-MS (ESI) m / z: 715 (M+1) + .

[0651] Step 3: (R)-3-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0652] To a mixture of (R)-3-((6-chloro-5-(3-((2-iodo-3-(methoxymethoxy)-5-(trifluoromethyl)benzyl)oxy)propyl)pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.19 mmol) dissolved in 1,4-dioxane (6 mL) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1,3,2-dioxoboropentane (64 mg, 0.25 mmol), KOAc (49 mg, 0.50 mmol) and Pd(dppf)Cl2 (12 mg, 0.017 mmol) were added sequentially under a N2 atmosphere. The mixture was degassed three times with N2 gas, followed by stirring at 100 °C for 2 hours under N2 atmosphere. Water (1 mL), K2CO3 (69 mg, 0.50 mmol), and RuPhos Pd G3 (14 mg, 0.017 mmol) were added sequentially to the mixture under N2 atmosphere, and the resulting mixture was stirred at 90 °C for 1 hour under N2 atmosphere. The mixture was diluted with EtOAc, washed sequentially with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: DCM containing 0–5% MeOH) to give the title compound (40 mg) as a solid. LC-MS (ESI) m / z: 553 (M+H) + .

[0653] Step 4: (R)-3-(piperidin-3-ylamino)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered ring[5,6-c]pyridazine-13-ol hydrochloride

[0654] Tert-butyl(R)-3-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanonequine[5,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (40 mg, 0.08 mmol) was dissolved in a mixture of DCM (1 mL) and HCl / 1,4-dioxane (1 mL, 4 M) and stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (45 mg) as a solid; this product was used directly in the next reaction 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]oxononane[5,6-c]pyridazine-13-ol

[0655] To a mixture of (R)-3-(piperidin-3-ylamino)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-13-ol (45 mg, 0.08 mmol) and paraformaldehyde (7.4 mg, 0.25 mmol) dissolved in MeOH (1 mL), AcOH (0.001 mL, 0.012 mmol) and NaBH3CN (11.5 mg, 0.18 mmol) were added under a nitrogen atmosphere at 0 °C, followed by stirring at 25 °C for 0.5 h. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250*20mm, mobile phase: aqueous solution containing 0.1% NH4HCO3 and MeCN, gradient 5–95%) to give the title compound (2 mg) solid. 1 H 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) + .

[0656] Example 7

[0657] (R)-3-(3-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidin-1-yl)methyl propionate

[0658]

[0659] Step 1: tert-butyl(R)-3-((4-((benzyloxy)methyl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazine-3-yl)amino)piperidine-1-carboxylate

[0660] To a mixture of tert-butyl(R)-3-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (80 mg, 0.018 mmol) in MeCN (4 mL) and water (4 mL), 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) were added sequentially at room temperature. The mixture was degassed three times with N₂ gas, followed by stirring at 60 °C for 12 hours under N₂ atmosphere. The mixture was cooled to room temperature, diluted with ice water, and extracted twice with EtOAc. The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: PE containing 0–90% EtOAc) to give the title compound (30 mg, 25% yield) in an oil. LC-MS (ESI) m / z: 673.5 (M+H) + .

[0661] Step 2: tert-butyl(R)-3-((4-(hydroxymethyl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-1-carboxylate

[0662] Pd / C (5 mg, 10% wt.) was added to a MeOH solution of tert-butyl(R)-3-((4-((benzyloxy)methyl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (30 mg, 0.045 mmol) under a nitrogen atmosphere, followed by stirring of the mixture at 35 °C under hydrogen balloon protection for 1 hour. 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) + .

[0663] Step 3: (R)-4-(hydroxymethyl)-3-(piperidin-3-ylamino)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-13-ol

[0664] Trifluoroacetic acid (TFA, 0.5 mL) was added to a solution of tert-butyl(R)-3-((4-(hydroxymethyl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (25 mg, 0.043 mmol) dissolved in dichloromethane (DCM, 1 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure to give the target compound as an oil (18 mg, 96% yield). LC-MS (ESI) (m / z): 439.1 (M+H) + .

[0665] Step 4: (R)-3-(3-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidin-1-yl)methyl propionate

[0666] To a solution of (R)-4-(hydroxymethyl)-3-(piperidin-3-ylamino)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-13-ol (18 mg, 0.041 mmol) dissolved in methanol (1 mL), Cs₂CO₃ (26.8 mg, 0.082 mmol) and methyl acrylate (5.3 mg, 0.062 mmol) were added at 0 °C. The mixture was stirred at room temperature for 30 min. The mixture was then filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*21 mm; mobile phase: a mixture of aqueous solution containing 0.1% NH₄OH and MeCN, gradient 20–95%), finally yielding the title compound as a solid (6 mg, 28% yield). 1 H 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) + .

[0667] Example 8

[0668] (R)-3-(3-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidin-1-yl)propionic acid, formate hemisalt

[0669]

[0670] Step 1: (R)-3-(3-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazin-3-yl)amino)piperidin-1-yl)propionic acid (formic acid fractional salt)

[0671] LiOH (1.6 mg, 0.04 mmol) was added to a mixed solution containing methyl (R)-3-(3-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazin-3-yl)amino)piperidin-1-yl)propionate (2 mg, 0.004 mmol) (composed of 0.6 mL THF, 0.3 mL MeOH, and 0.2 mL water), and stirred at room temperature for 30 min. The mixture was filtered, and the residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*21.2 mm; mobile phase: a mixture of aqueous solution containing 0.1% formic acid and MeCN, gradient 10–95%), finally yielding the title compound (1 mg, 51% yield) as a solid. 1 H NMR (400MHz, 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) + .

[0672] Example 9

[0673] (R)-3-(3-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidin-1-yl)methyl propionate (formate)

[0674]

[0675] Step 1: (R)-3-(3-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered ring[5,6-c]pyridazin-3-yl)amino)piperidin-1-yl)methyl propionate (formic acid fractional salt)

[0676] To a mixture of (R)-11-methoxy-3-(piperidin-3-ylamino)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-13-ol trifluoroacetate (intermediate 7, 60 mg, 0.124 mmol) and Cs₂CO₃ (160 mg, 0.48 mmol) in MeOH (2 mL), methyl acrylate (15.4 mg, 0.16 mmol) was added at 0 °C, followed by stirring at 25 °C for 20 min. The mixture was filtered, and the filtrate was purified by preparative HPLC (column: YMC-Actus Triart C18 250*21 mm; mobile phase: acetonitrile in an aqueous solution containing 0.1% formic acid, increased from 10% to 95%), to give the title compound (20 mg) as a solid. 1 H 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) + .

[0677] The examples listed in "Error! Reference source not found" are prepared according to the methods and procedures described in Synthesis Example 9 (synthesized from intermediate 7, intermediate 8, intermediate 9 or intermediate 10).

[0678] Table 2. Examples prepared using the preparation procedure of Example 9

[0679]

[0680]

[0681]

[0682] Example 20

[0683] (R)-3-(3-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidin-1-yl)propionic acid

[0684]

[0685] LiOH (2.8 mg, 0.066 mmol) was added to a mixture of MeOH (1 mL) and water (0.2 mL) containing methyl(R)-3-(3-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxononocyclo[5,6-c]pyridazin-3-yl)amino)piperidin-1-yl)propionate (15 mg, 0.033 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*21 mm; mobile phase: 20–95% MeCN / H2O solution containing 0.1% NH3·H2O) to give the title compound (9 mg) as a solid. 1 H 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)+ .

[0686] Example 21

[0687] (R)-11-methoxy-3-((1-methylpiperidin-3-yl)amino)-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazine-13-ol

[0688]

[0689] Step 1: (R)-11-methoxy-3-((1-methylpiperidin-3-yl)amino)-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered ring[5,6-c]pyridazine-13-ol

[0690] To a mixture of (R)-11-methoxy-3-(piperidin-3-ylamino)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-13-ol (intermediate 7, 10 mg, 0.027 mmol) and 37% aqueous formaldehyde solution (4.4 mg, 0.054 mmol) in methanol (1 mL), acetic acid (one drop) and sodium cyanoborohydride (NaBH3CN, 5 mg, 0.081 mmol) were added at 0 °C, followed by stirring of the mixture at room temperature for 30 min. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*20 mm; mobile phase: aqueous solution containing 0.1% NH4HCO3 and acetonitrile, gradient 5–95%), finally yielding the title compound (0.43 mg) solid. LC-MS (ESI) (m / z): 385(M+H)+.

[0691] Example 22

[0692] (R)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-13-ol

[0693]

[0694] Step 1: (R)-3-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidin-3-yl)amino)-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazine-13-ol

[0695] To a mixture of (R)-11-methoxy-3-(piperidin-3-ylamino)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-13-ol (intermediate 7, 20 mg, 0.054 mmol) dissolved in MeOH (1 mL), and 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (19 mg, 0.108 mmol), one drop of AcOH and 10 mg of NaBH3CN (0.162 mmol) were added at 0 °C, followed by stirring at room temperature for 30 min. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases 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)+.

[0696] Step 2: (R)-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-13-ol

[0697] 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]oxononacyclo[5,6-c]pyridazine-13-ol (15 mg, 0.028 mmol) dissolved in dichloromethane (DCM, 0.5 mL), trifluoroacetic acid (TFA, 0.5 mL) was added at 0 °C, followed by stirring at 25 °C for 1 hour. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*20 mm; mobile phase: aqueous solution containing 0.1% NH4HCO3 and acetonitrile, gradient 5–95%) 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) + .

[0698] Example 23

[0699] (2S,5R)-5-((4-cyano-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0700]

[0701] Step 1: 5-(3-(benzyloxy)propyl)-3,6-dichloropyridazine-4-carboxynitrile

[0702] To a solution of 3,6-dichloropyridazine-4-carboxynitrile (5.0 g, 28.9 mmol) in MeCN (50 mL) and water (50 mL), 4-(benzyloxy)butyric acid (8.42 g, 43.4 mmol), K₂S₂O₈ (8.42 g, 43.4 mmol), and AgNO₃ (983 mg, 5.78 mmol) were added. The mixture was degassed three times with N₂ and stirred at 60 °C for 16 h under N₂ atmosphere. The mixture was cooled to room temperature and extracted twice with EtOAc. The organic layers were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: PE containing 0–30% EtOAc) 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)+.

[0703] Step 2: 3,6-Dichloro-5-(3-hydroxypropyl)pyridazine-4-carboxynitrile

[0704] To a solution of 5-(3-(benzyloxy)propyl)-3,6-dichloropyridazine-4-carboxynitrile (12.0 g, 37.4 mmol) dissolved in dichloromethane (DCM, 240 mL), boron trichloride (BCl3, 74.8 mL, 74.8 mmol, 1 M DCM solution) was added dropwise at -10 °C; the mixture was then stirred at -10 °C for 2 hours. The reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate solution and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–50% ethyl acetate) to give the title compound (4.80 g) as an oil. LC-MS (ESI) m / z: 232.3 (M+H)+.

[0705] Step 3: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((6-chloro-4-cyano-5-(3-hydroxypropyl)pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0706] To a solution of 4.8 g (20.8 mmol) of 3,6-dichloro-5-(3-hydroxypropyl)pyridazine-4-carboxynitrile (EtOH) (50 mL), 1-(tert-butyl)-2-ethyl(2S,5R)-5-aminopiperidine-1,2-dicarboxylate (6.22 g, 22.9 mmol) was added at room temperature, followed by stirring at 60 °C for 12 hours. The mixture was concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: PE containing 0–30% EtOAc) to give the title compound (3.6 g) as a solid. LC-MS (ESI) (m / z): 468.4 (M+H) + .

[0707] Steps 4-7: (2S,5R)-5-((4-cyano-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0708] The compound in this title is prepared according to the method and procedure described in steps 1, 3, 4 and 5 of intermediate 7, and is in solid form. 1 H 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)+.

[0709] Example 24

[0710] (2S,5R)-5-((13-hydroxy-4-(((methoxycarbonyl)amino)methyl)-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0711]

[0712] Step 1: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-(aminomethyl)-13-(methoxymethoxy)-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0713] 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]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (60 mg, 0.090 mmol) dissolved in MeOH (3 mL), one drop of formic acid (FA) and Raney Ni (20 mg) were added under a nitrogen atmosphere, followed by stirring of the mixture for 6 hours at room temperature under hydrogen balloon protection. 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)+.

[0714] 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]oxa-non-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0715] 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]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (60 mg, 0.090 mmol) dissolved in dichloromethane (DCM, 2 mL), triethylamine (TEA, 27 mg, 0.27 mmol) and methyl chloroformate (13 mg, 0.14 mmol) were added sequentially under nitrogen protection and at 0 °C; the mixture was then stirred at room temperature for 1.5 h under nitrogen protection. The reaction was quenched with water and extracted with ethyl acetate (EtOAc). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound (40 mg) as a solid. LC-MS (ESI) (m / z): 728 (M+H)+.

[0716] Step 3: (2S,5R)-5-((13-hydroxy-4-(((methoxycarbonyl)amino)methyl)-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0717] 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]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (40 mg, 0.05 mmol) dissolved in dichloromethane (DCM, 0.5 mL), trifluoroacetic acid (TFA, 0.5 mL) was added at 0 °C, followed by stirring at 25 °C for 20 minutes. The mixture was then concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18; mobile phase: aqueous solution containing 0.1% NH3·H2O and acetonitrile, gradient elution range 20–95%) to give the title compound (3.61 mg) solid. 1 H 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) + .

[0718] Example 25

[0719] (2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0720]

[0721] Step 1: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((6-(2-(acetoxymethyl)-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-(3-((tert-butyldimethylsilyl)oxy)propyl)pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0722] To a mixture of 3-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-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), K3PO4 (78.8 mg, 0.371 mmol) and SPhos Pd G2 (17.8 mg, 0.025 mmol) were added at room temperature under a nitrogen atmosphere; the mixture was then subjected to three nitrogen degassing treatments and then... The reaction was carried out at °C under a nitrogen atmosphere with stirring for 3 hours. After the reaction, the mixture was diluted with EtOAc, washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel, eluent: PE containing 0–60% EtOAc) to give the title compound (55 mg) in an oily form. LC-MS (ESI) m / z: 799 (M+H)+.

[0723] Step 2: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-(2-(hydroxymethyl)-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0724] To a mixture of EtOH (2 mL) containing 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), K₂CO₃ (19.1 mg, 0.138 mmol) was added at room temperature, followed by stirring at 30 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (40 mg) as a solid. LC-MS (ESI) m / z: 757 (M+H)⁺.

[0725] Step 3: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((6-(2-(hydroxymethyl)-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-(3-hydroxypropyl)pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0726] 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) dissolved in THF (1 mL), TBAF (0.106 mL, 0.106 mmol, 1 M THF solution) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: DCM containing 0–5% MeOH) to give the title compound (30 mg) as a solid. LC-MS (ESI) m / z: 643.4 (M+H)+.

[0727] Step 4: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((6-(2-(bromomethyl)-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-(3-hydroxypropyl)pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0728] 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 dichloromethane (5 mL), 4A molecular sieve (20 mg), PPh3 (19.1 mg, 0.138 mmol), and CBr4 (23.2 mg, 0.070 mmol) were added at -78 °C. The mixture was degassed three times with N2 gas and stirred at 30 °C for 30 min under N2 atmosphere. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: dichloromethane containing 0–15% MeOH) to give the title compound (15 mg) as a solid. LC-MS (ESI) m / z: 705 / 707 (M+H)+.

[0729] Step 5: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0730] 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) dissolved in chloroform (2 mL), DTBMP (10.9 mg, 0.053 mmol) and AgOTf (8.2 mg, 0.032 mmol) were added at room temperature. The mixture was degassed three times with N2 gas, followed by stirring at room temperature for 1 hour under N2 atmosphere. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: DCM containing 0–15% MeOH) to give the title compound (9 mg) as a solid. LC-MS (ESI) m / z: 625 (M+H)+.

[0731] Step 6: (2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0732] Trifluoroacetic acid (TFA, 0.5 mL) was added to a solution of 1-(tert-butyl)-2-ethyl(2S,5R)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (9 mg, 0.014 mmol) dissolved in dichloromethane (DCM, 0.5 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*20 mm; mobile phase: aqueous solution containing 0.1% NH4HCO3 and acetonitrile, gradient 10–95%) to give the title compound (1.4 mg) 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) + .

[0733] Example 26

[0734] (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid ethyl ester (formic acid fractional salt)

[0735]

[0736] Step 1: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-(2-(hydroxymethyl)-4-methoxy-6-(methoxymethoxy)phenyl)pyridazine-3-yl)amino)piperidine-1,2-dicarboxylic acid ester

[0737] To a mixed solution of 1,4-dioxane (20 mL) and water (2 mL) containing 1-(tert-butyl)-2-ethyl(2S,5R)-5-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-6-chloropyridazin-3-yl)amino)piperidine-1,2-dicarboxylic acid ester (intermediate 2, 1.3 g, 2.34 mmol), 5-methoxy-7-(methoxymethoxy)benzo[c][1,2]oxoborhecylpenten-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) were added under a nitrogen atmosphere and at room temperature. The mixture was degassed three times with nitrogen and then stirred at 100 °C for 1.5 h under a nitrogen atmosphere. The mixture was diluted with water and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether / ethyl acetate = 100:0 to 30:70) to give the title compound (1.4 g) as a solid. LC-MS (ESI) (m / z): 719 (M+H)+.

[0738] Step 2: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((6-(2-(hydroxymethyl)-4-methoxy-6-(methoxymethoxy)phenyl)-5-(3-hydroxypropyl)pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0739] 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) dissolved in THF (15 mL), TBAF (1 g, 2.68 mmol, 70% aqueous solution) was added under a nitrogen atmosphere at 0 °C. The mixture was then stirred for 3 hours under a nitrogen atmosphere at room temperature. The reaction was terminated at 0 °C with a saturated aqueous solution of NH4Cl, and the mixture was extracted three times with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: DCM containing 0–10% MeOH) to give the title compound (800 mg) as a solid. LC-MS (ESI) (m / z): 605 (M+H)+.

[0740] Step 3: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((6-(2-(bromomethyl)-4-methoxy-6-(methoxymethoxy)phenyl)-5-(3-hydroxypropyl)pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0741] Under a nitrogen atmosphere and at -78 °C, 4A molecular sieve (250 mg), carbon tetrabromide (657 mg, 1.98 mmol), and triphenylphosphine (415 mg, 1.58 mmol) were added sequentially 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 dichloromethane (32 mL). The mixture was degassed three times with nitrogen, and then stirred for 30 min under a nitrogen atmosphere at 30 °C. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: dichloromethane containing 0–15% methanol) to give the title compound (480 mg) as a solid. LC-MS (ESI) (m / z): 667 (M+H) + .

[0742] Step 4: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0743] To a chloroform (5 mL) 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), AgOTf (290 mg, 1.13 mmol) and DTBMP (385 mg, 1.88 mmol) were added under nitrogen protection at room temperature, followed by stirring of the mixture overnight under nitrogen at room temperature. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: DCM containing 0–15% MeOH) to give the title compound (248 mg) solid. LC-MS (ESI) (m / z): 587 (M+H)+.

[0744] Step 5: (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid ethyl ester (partial TFA salt)

[0745] To a solution of 1-(tert-butyl)-2-ethyl(2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanonylcyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (50 mg, 0.085 mmol) dissolved in dichloromethane (DCM, 1 mL), a solution of HCl in 1,4-dioxane (1 mL, 4 M) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*21 mm; mobile phase: water / acetonitrile system containing 0.1% formic acid, gradient 10–95%) to give the title compound (6 mg) as a solid. 1 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)+.

[0746] Example 27

[0747]

[0748] The target compound was prepared using the same method and steps as intermediate 7 and was in solid form. 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) + .

[0749] Example 28

[0750] Isopropyl(2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylate

[0751]

[0752] Step 1: (2S,5R)-1-(tert-Butoxycarbonyl)-5-((11-methoxy-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid

[0753] To a mixture of MeOH (1 mL) and water (0.5 mL) containing 1-(tert-butyl)-2-ethyl(2S,5R)-5-((11-methoxy-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (50 mg, 0.085 mmol), LiOH (6.1 mg, 0.255 mmol) was added at room temperature, and the mixture was stirred at room temperature for 3 hours. Subsequently, the mixture was acidified with 1 N hydrochloric acid aqueous solution and extracted twice with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure to give the title compound (30 mg) as a solid. LC-MS (ESI) (m / z): 559 (M+H)+.

[0754] Step 2: Isopropyl(2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylate

[0755] To a solution of (2S,5R)-1-(tert-butyloxycarbonyl)-5-((11-methoxy-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid (30 mg, 0.054 mmol) dissolved in isopropanol (1.5 mL), SOCl2 (0.1 mL) was added at room temperature, and the mixture was stirred at 70 °C for 2 hours. The mixture was purified by preparative HPLC (column: YMC-Actus Triart C18 250*20 mm; mobile phase: a mixture of aqueous solution containing 0.1% NH4HCO3 and MeCN, gradient 5–95%) 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)+.

[0756] Example 29

[0757] Isopropyl(2R,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylate

[0758]

[0759] Step 1: (2R,5R)-1-(tert-Butoxycarbonyl)-5-((11-methoxy-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid

[0760] To a solution of 1-(tert-butyl)-2-ethyl(2S,5R)-5-((11-methoxy-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (90 mg, 0.154 mmol) in EtOH (1 mL), an EtONa / EtOH solution (1 mL, 20% w / w) was added at room temperature. The mixture was stirred at 30 °C for 6 hours. Subsequently, the mixture was acidified to pH approximately 5 with 1 N HCl aqueous solution and extracted twice with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by chiral SFC to give solid products: (2S,5R)-1-(tert-butyloxycarbonyl)-5-((11-methoxy-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid (60 mg, peak 1, Rt = 4.156 min) and (2R,5R)-1-(tert-butyloxycarbonyl)-5-((11-methoxy-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid (15 mg, peak 2, Rt = 8.972 min). Chiral SFC conditions: Column: (R,R)-WHELK, 250×30 mm ID, 5 µm; Mobile phase: A = CO2, B = IPA (MeOH containing 0.1% 2 mol / L DEA); Gradient: B 33%; Flow rate: 60 mL / min. LC / MS (ESI) m / z: 559.3 (M+H) + .

[0761] Step 2: Isopropyl(2R,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylate

[0762] SOCl2 (0.05 mL) was added to a solution of (2R,5R)-1-(tert-butoxycarbonyl)-5-((11-methoxy-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid (15 mg, 0.027 mmol) dissolved in EtOH (1 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18250*21 mm, mobile phase: a mixture of aqueous solution containing 0.1% NH4HCO3 and MeCN, gradient 10–95%) to give the title compound (3.8 mg) as a solid. 1 H 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) + .

[0763] Example 30

[0764] (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)-1-methylpiperidine-2-carboxylic acid ethyl ester

[0765]

[0766] Step 1: (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered cyclo[5,6-c]pyridazine-3-yl)amino)-1-methylpiperidine-2-carboxylic acid ethyl ester

[0767] To a mixture of ethyl (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate (10 mg, 0.022 mmol) dissolved in MeOH (1 mL) and 0.1 mL of 37% formaldehyde aqueous solution, AcOH (2.7 mg, 0.045 mmol) and NaBH3CN (4.3 mg, 0.068 mmol) were added at 0 °C, followed by stirring of the mixture at room temperature for 20 min. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*20 mm; mobile phase: aqueous solution containing 0.1% NH4HCO3 and MeCN, gradient 10–95%) to finally obtain the title compound (2.2 mg) solid. 1 H 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 LC-MS (ESI) (m / z): 457.2 (M+H) + .

[0768] Example 31

[0769] (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid

[0770]

[0771] To a mixture of MeOH (0.2 mL) and water (0.2 mL) containing ethyl(2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate (10 mg, 0.02 mmol), LiOH (2.7 mg, 0.11 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was purified by preparative HPLC (YMC – Actus TriartC18 250*20 mm, 5 µm; mobile phase: aqueous solution containing 0.1% NH4HCO3 and MeCN, gradient 30–95%) to give the title compound (1.2 mg) as a solid. 1 H 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) + .

[0772] Example 32

[0773] (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)-1-methylpiperidine-2-carboxylic acid

[0774]

[0775] To a mixture of MeOH (0.5 mL) and water (0.5 mL) containing ethyl(2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)-1-methylpiperidin-2-carboxylate (15.0 mg, 0.033 mmol), LiOH (6.9 mg, 0.164 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 3 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC (column: YMC – ActusTriart C18 250*20 mm, 5 µm; mobile phase: aqueous solution containing 0.1% NH4HCO3 and MeCN, gradient 15–95%) to give the title compound (2 mg) solid. 1 H 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 (bs, 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) + .

[0776] Examples 33 and 34

[0777] Ethyl (2R,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate and ethyl (2R,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)-1-methylpiperidine-2-carboxylate

[0778]

[0779] The title compound was prepared according to the methods and procedures described in Examples 29 and 30, and was in solid form. Example 33: LC-MS (ESI) (m / z): 443.2 (M+H)+. Example 34: 1 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) + .

[0780] Example 35

[0781] (2R,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid

[0782]

[0783] The title compound was prepared in solid form according to the method and steps described in Preparation Example 31. 1¹H NMR (400MHz, 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) + .

[0784] Example 36

[0785] (2R,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)-1-methylpiperidine-2-carboxylic acid

[0786]

[0787] The title compound was prepared in solid form using the same methods and steps as described in the synthesis of Example 32. 1¹H 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) + .

[0788] Example 37

[0789] (2S,5R)-5-((13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid methyl ester

[0790]

[0791] The compound in this title was prepared according to the synthetic method and steps of Example 28 and is in solid form. 1 H NMR (400MHz, 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) + .

[0792] Example 38

[0793] (2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid methyl ester

[0794]

[0795] The compound in this title was prepared according to the synthetic method and steps of Example 28, and the resulting product was a solid. 1 H 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) + .

[0796] Example 39

[0797] (2S,5R)-5-((13-hydroxy-4-(hydroxymethyl)-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0798]

[0799] 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]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0800] The preparation method and procedures for this title compound were performed following steps 1-4 of intermediate 7, and the resulting product was a solid. LC-MS (ESI) m / z: 707 (M+H) + .

[0801] Step 5: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-(hydroxymethyl)-11-methoxy-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0802] 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]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (110 mg, 0.20 mmol) in MeOH (2 mL), Pd / C (5 mg, 10% wt.) was added under a nitrogen atmosphere, followed by stirring at 45 °C for 6 h under H2 balloon protection. The reaction 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) + .

[0803] Step 6: (2S,5R)-5-((13-hydroxy-4-(hydroxymethyl)-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0804] 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]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (35 mg, 0.057 mmol) dissolved in dichloromethane (DCM, 2 mL), trifluoroacetic acid (TFA, 1 mL) was added at 0 °C, and the mixture was stirred at room temperature for 8 hours. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*21 mm; mobile phase: a mixture of aqueous solution containing 0.1% NH4HCO3 and acetonitrile, gradient 20–95%) to give the title compound (2.3 mg) as a solid. 1H NMR (400MHz, 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) + .

[0805] Example 40

[0806] (2S,5R)-5-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0807] Example 41

[0808] (2S,5R,Sa)-5-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0809] Example 42

[0810] (2S,5R,Ra)-5-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0811]

[0812] Step 1: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-((benzyloxy)methyl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0813] To a mixture of MeCN (1 mL) and water (1 mL) containing 1-(tert-butyl)-2-ethyl(2S,5R)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (45 mg, 0.072 mmol), 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) were added sequentially at room temperature. The mixture was degassed three times with N₂ gas, followed by stirring at 60 °C for 6 hours under N₂ atmosphere. The mixture was cooled to room temperature, diluted with ice water, and extracted twice with EtOAc. The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: DCM containing 0–5% MeOH) to give the title compound (20 mg) in an oil. LC-MS (ESI) m / z: 745.4 (M+H) + .

[0814] Step 2: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-(hydroxymethyl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0815] To a MeOH solution (2 mL) containing 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-((benzyloxy)methyl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (20 mg, 0.027 mmol), Pd / C (5 mg, 10% w / w) and one drop of formic acid (FA) were added under a nitrogen atmosphere; the mixture was then stirred at 35 °C under hydrogen balloon protection for 4 hours. The mixture was filtered, and the filtrate was concentrated to dryness to give the target product (16 mg) as an oil. LC-MS (ESI) m / z: 655.3 (M+H) + .

[0816] Step 3: (2S,5R)-5-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0817] Trifluoroacetic acid (TFA, 0.5 mL) was added 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]oxononacyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (16 mg, 0.043 mmol) dissolved in dichloromethane (DCM, 1 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*20 mm; mobile phase: aqueous solution containing 0.1% NH4HCO3 and MeCN, gradient 5–95%) to obtain the solid product "Example 40" (1.5 mg). This solid product was further resolved by preparative HPLC (column: YMC-Actus Triart C18 250*20 mm; mobile phase: aqueous solution containing 0.1% NH3·H2O and MeCN, gradient 5–95%) to obtain solid products "Example 41" (second elution peak) and "Example 42" (first elution peak), respectively. For epimers such as Examples 41 and 42, which arise due to axial chirality, their structural assignment was initially determined based on the principle that the more active epimer should have a conformation similar to that observed in the cryo-electron microscopy (Cryo-EM) structure of "Example 6" when binding NLRP3 protein. This interpretation of the data also aligns with the results of computational docking. This attribution method is also applicable to other embodiments. Embodiment 40: 11H 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. Hz, 3H). LC-MS (ESI) (m / z): 511.3 (M+H) + Example 41: LC-MS (ESI) (m / z): 511.3 (M+H) + Example #42: 1 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, IH), 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) + .

[0818] Example 43

[0819] (2S,5R)-5-((13-hydroxy-4-(hydroxymethyl)-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0820]

[0821] The title compound was prepared into a solid product using intermediates 3 and 12 as raw materials, according to the method and procedure described in steps 4 to 9 of Example 39. 1 H 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) + .

[0822] Example 44

[0823] (2S,5R)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0824]

[0825] Step 1: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-((carbamoyloxy)methyl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0826] 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]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (60 mg, 0.091 mmol) and triethylamine (TEA, 28.1 mg, 0.275 mmol), trichloroacetyl isocyanate (25.7 mg, 0.136 mmol) was added at 0 °C, followed by stirring at room temperature for 1 hour. The mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in methanol (MeOH, 1 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was then concentrated to dryness under reduced pressure to give the title compound (40 mg) as a solid. LC-MS (ESI) m / z: 698.3 (M+H) + .

[0827] Step 2: (2S,5R)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0828] Trifluoroacetic acid (TFA, 0.5 mL) was added 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]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (40 mg, 0.057 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*20 mm; mobile phase: aqueous solution containing 0.1% NH4HCO3 and acetonitrile (MeCN), gradient 5–95%) to give the title compound (8 mg) as a solid. 1¹H 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) + .

[0829] Example 45

[0830] (2S,5R)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0831]

[0832] The title compound was prepared in solid form according to the method and steps described in Preparation Example 44. 1H NMR (400MHz, 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) + .

[0833] Example 46

[0834] (R)-13-fluoro-N-(1-methylpiperidin-3-yl)-11-(trifluoromethyl)-7,8-dihydro-5H-benzo[8,9][1,4]dioxonocyclo[7,6-c]pyridazine-3-amine, formate hemisalt

[0835]

[0836] Step 1: tert-Butyldimethyl(2-(prop-2-yn-1-yloxy)ethoxy)silane

[0837] To a solution of 2-(propan-2-yn-1-yloxy)ethanol (30 g, 299 mmol) in dichloromethane (DCM, 240 mL), imidazole (30.6 g, 449 mmol) and TBSCl (54.2 g, 359 mmol) were added at 0 °C, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted twice with DCM. The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–10% ethyl acetate) 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).

[0838] Step 2: 4-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-3,6-dichloropyridazine

[0839] To a toluene solution (200 mL) of tert-butyldimethyl(2-(prop-2-yn-1-yloxy)ethoxy)silane (28 g, 132 mmol), 3,6-dichloro-1,2,4,5-tetraazine (10 g, 66 mmol) was added at room temperature under a nitrogen atmosphere, followed by stirring at 100 °C overnight. The mixture was concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: petroleum ether / ethyl acetate 0–20%) to give the target product (10 g) as an oil. 1 H 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) + .

[0840] Step 3: tert-butyl(R)-3-((5-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-6-chloropyridazine-3-yl)amino)piperidine-1-carboxylate

[0841] To a solution of 4-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-3,6-dichloropyridazine (5.7 g, 16.9 mmol) dissolved in DMSO (80 mL), DIPEA (6.55 g, 50.7 mmol) and tert-butyl(R)-3-aminopiperidine-1-carboxylate (6.77 g, 33.8 mmol) were added at room temperature. The mixture was stirred at 150 °C for 16 hours. The mixture was then diluted with deionized water and extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: PE containing 0–50% EtOAc) to give the target product (2.6 g) as an oil. LC-MS (ESI) (m / z): 501.2 (M+H) + .

[0842] Step 4: tert-butyl(3R)-3-((5-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-6-(2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)pyridazine-3-yl)amino)piperidine-1-carboxylate

[0843] To a mixed solution of 1,4-dioxane (30 mL) and water (6 mL) containing 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), (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) were added sequentially at room temperature and under a nitrogen atmosphere. The mixture was degassed three times with nitrogen and then stirred at 100 °C for 4 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–30% ethyl acetate) 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) + .

[0844] Step 5: (3R)-3-((6-(2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)-5-((2-hydroxyethoxy)methyl)pyridazine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0845] To a solution of (3R)-3-((5-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-6-(2-fluoro-6-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidin-1-carboxylic acid tert-butyl ester (580 mg, 0.899 mmol) dissolved in THF (6 mL), TBAF (469 mg, 1.80 mmol) was added at 0 °C, followed by stirring at room temperature for 4 hours. The reaction mixture was diluted with EtOAc, washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: PE containing 0–50% EtOAc) to give the title compound (357 mg) as an oil. LC-MS (ESI) (m / z): 531.5 (M+H) + .

[0846] Step 6: (R)-3-((13-fluoro-11-(trifluoromethyl)-7,8-dihydro-5H-benzo[8,9][1,4]dioxononacyclo[7,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

[0847] Under a nitrogen atmosphere, tri-tert-butylphosphine (99.3 mg, 0.491 mmol) and TMAD (84.5 mg, 0.491 mmol) were added to a THF (3 mL) solution of (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (130 mg, 0.245 mmol). The reaction mixture was degassed three times with nitrogen and stirred at 50 °C for 8 hours. The reaction mixture was diluted with EtOAc, washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative thin-layer chromatography (PE: EtOAc = 1:1) to give the title compound (14 mg) as a solid. LC-MS (ESI) m / z: 513.5 (M+H) + .

[0848] Step 7: (R)-13-fluoro-N-(piperidin-3-yl)-11-(trifluoromethyl)-7,8-dihydro-5H-benzo[8,9][1,4]dioxononacyclo[7,6-c]pyridazine-3-amine

[0849] To a solution of (R)-3-((13-fluoro-11-(trifluoromethyl)-7,8-dihydro-5H-benzo[8,9][1,4]dioxane-9-cyclo[7,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (14 mg, 0.023 mmol) dissolved in 0.5 mL of 1,4-dioxane, an HCl solution of 1,4-dioxane (0.5 mL, 4 M) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the target compound (10 mg) as an oil. LC-MS (ESI) m / z: 413.2 (M+H) + .

[0850] Step 8: (R)-13-fluoro-N-(1-methylpiperidin-3-yl)-11-(trifluoromethyl)-7,8-dihydro-5H-benzo[8,9][1,4]dioxononacyclo[7,6-c]pyridazine-3-aminocarbamate

[0851] To a solution of (R)-13-fluoro-N-(piperidin-3-yl)-11-(trifluoromethyl)-7,8-dihydro-5H-benzo[8,9][1,4]dioxonocyclo[7,6-c]pyridazin-3-amine (10 mg, 0.024 mmol) in MeOH (0.5 mL), 37% formaldehyde aqueous solution (0.1 mL), AcOH (2.9 mg, 0.048 mmol), and NaBH3CN (4.6 mg, 0.073 mmol) were added sequentially, followed by stirring of the mixture at room temperature under N2 atmosphere for 30 minutes. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*21 mm; mobile phase: 5–95% MeCN / H2O solution containing 0.1% FA) to give the title compound (0.5 mg) solid. LC-MS (ESI) m / z: 427.2 (M+H) + .

[0852] Example 47

[0853] (2S,5R,Ra)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0854] Example 48

[0855] (2S,5R,Sa)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0856]

[0857] The target compounds were prepared following the methods and procedures described in Synthesis Example 44, and purified by preparative HPLC (Welch-Ultimate AQ-C18, 21.2 × 250 mm, 5 μm; mobile phase: acetonitrile in an aqueous solution containing 0.1% NH4HCO3 at a concentration of 10%–95%), thus obtaining Examples 47 (eluted first) and 48 (eluted subsequently) in solid form. Example 47: 11H 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: 1 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,​​​​​​​(2S,5R,Ra)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0860] Example 50

[0861] (2S,5R,Sa)-5-((4-((carbamoyloxy)methyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0862]

[0863] The epimers of Example 44 were separated by preparative HPLC (WELCH ultimate XB-C18 250*21.2 mm, mobile phase: a mixture of aqueous solution containing 0.1% NH4HCO3 and MeCN, gradient 5–90%), yielding solid products Example 49 (eluted first) and Example 50 (eluted subsequently). Example 49: 1 H 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 (400MHz, 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) + .

[0864] Example 51

[0865] (2S,5R,Ra)-5-((11-(difluoromethoxy)-13-hydroxy-4-(hydroxymethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0866] Example 52

[0867] (2S,5R,Sa)-5-((11-(difluoromethoxy)-13-hydroxy-4-(hydroxymethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0868]

[0869] Steps 1-4: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((11-(difluoromethoxy)-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0870] The title compound was prepared using intermediates 2 and 6 as starting materials, following the same method and procedure as described in Synthesis Example 26. LC-MS (ESI) (m / z): 623.3 (M+H) + .

[0871] Step 5: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((11-(difluoromethoxy)-4-(hydroxymethyl)-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0872] To a solution of 1-(tert-butyl)-2-ethyl(2S,5R)-5-((11-(difluoromethoxy)-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (150 mg, 0.24 mmol) dissolved in MeOH (10 mL), H₂O₂ (54 mg, 0.48 mmol, 30% aqueous solution), TFA (55 mg, 0.48 mmol), and dppfO₂ (13.8 mg, 0.024 mmol) were added sequentially at room temperature. The reaction mixture was degassed three times under a nitrogen atmosphere and then irradiated at 40 °C for 18 hours using a 50 W, 390 nm LED light source. After the reaction was complete, the reaction was quenched with saturated Na₂S₂O₃ aqueous solution and neutralized with saturated Na₂CO₃ aqueous solution. The mixture was then extracted twice with DCM. The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by rapid chromatography (silica gel; eluent: DCM / MeOH = 100:0 to 90:10) to give the title compound (48 mg) as an oil. LC-MS (ESI) (m / z): 544 (M+H) + .

[0873] Step 6: Ethyl (2S,5R,Ra)-5-((11-(difluoromethoxy)-13-hydroxy-4-(hydroxymethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate with (2S,5R,Sa)-5-((11-(difluoromethoxy)-13-hydroxy-4-(hydroxymethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate)

[0874] 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]oxanonane[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate (48 mg, 0.073 mmol) in 1,4-dioxane (1 mL), a solution of HCl / 1,4-dioxane (1 mL, 4 M) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness, and the resulting residue was purified by preparative HPLC (Welch-Ultimate AQ-C18, 21.2*250 mm, 5 μm; mobile phase: a mixture of aqueous solution containing 0.1% NH4HCO3 and MeCN, gradient 10–95%) to obtain solid products: Example 51 (6 mg, eluted first) and Example 52 (5 mg, eluted second). Example 51: 1 H NMR (400 MHz, CD3OD) δ6.86 (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, 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 = 13.2Hz, 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) + .

[0875] Example 53

[0876] (2S,5R,Ra)-5-((13-hydroxy-4-(hydroxymethyl)-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0877] Example 54

[0878] (2S,5R,Sa)-5-((13-hydroxy-4-(hydroxymethyl)-11-methoxy-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0879]

[0880] The epimers of Example 39 were separated by preparative HPLC (WELCH ultimate XB-C18 250*21.2mm; mobile phase: water containing 0.1% NH4HCO3 and 5–90% MeCN) to obtain Example 53 (eluted first) and Example 54 (eluted subsequently) as solids. Example 53: 11H NMR (400 MHz, CD3OD) δ 6.47 (d, J = 2.3Hz, 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: 1 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) + .

[0881] Example 55

[0882] (2S,5R)-5-((11-Cyclopropyl-13-hydroxy-5,6,7,9-Tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0883]

[0884] Steps 1-4: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((11-(benzyloxy)-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0885] The preparation method and steps of this title compound are the same as those described in steps 1-4 of intermediate 7, and the obtained product is a solid. LC-MS (ESI) m / z: 663.3 (M+H) + .

[0886] Step 5: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((11-hydroxy-13-(methoxymethoxy)-6,7,8,9-tetrahydro-5H-benzo[8,9]cyclononene[1,2-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0887] Pd / C (50 mg, 10% wt.) was added to a solution of 1-(tert-butyl)-2-ethyl(2S,5R)-5-((11-(benzyloxy)-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (500 mg, 0.755 mmol) in EtOH (5 mL) under a nitrogen atmosphere and at room temperature. The mixture was then stirred for 4 hours at room temperature under hydrogen balloon protection. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (400 mg) solid. This product was used directly in the next reaction without purification. LC / MS (ESI) (m / z): 573.3 (M+H) + .

[0888] Step 6: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((13-(methoxymethoxy)-11-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0889] To a DMF (3 mL) solution of 1-(tert-butyl)-2-ethyl(2S,5R)-5-((11-hydroxy-13-(methoxymethoxy)-6,7,8,9-tetrahydro-5H-benzo[8,9]cyclononacarben[1,2-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (150 mg, 0.262 mmol), triethylamine (TEA, 79 mg, 0.782 mmol) and N,N-bis(trifluoromethanesulfonyl)aniline (140 mg, 0.392 mmol) were added, and the mixture was stirred at 60 °C for 3 hours. The mixture was diluted with ethyl acetate (EtOAc), washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: petroleum ether (PE) containing 0–60% EtOAc) to give the title compound (141 mg) as a solid. LC / MS (ESI) m / z: 705.3 (M+H) + .

[0890] Step 7: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((11-cyclopropyl-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0891] Under a nitrogen atmosphere, cyclopropylboronic acid (32 mg, 0.372 mmol), K₂CO₃ (76 mg, 0.551 mmol), and Pd(dppf)Cl₂ (14 mg, 0.019 mmol) were added sequentially to a mixture of 1,4-dioxane (5 mL) of 1-(tert-butyl)-2-ethyl(2S,5R)-5-((13-(methoxymethoxy)-11-(((trifluoromethyl)sulfonyl)oxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanone[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate (130 mg, 0.185 mmol) and water (1 mL). The mixture was then degassed three times with nitrogen and stirred overnight at 80 °C under nitrogen protection. After the reaction was complete, the mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–50% ethyl acetate) to give the title compound (71 mg) solid. LC / MS (ESI) (m / z): 597.4 (M+H)+ .

[0892] Step 8: (2S,5R)-5-((11-cyclopropyl-13-hydroxy-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0893] To a solution of 1-(tert-butyl)-2-ethyl(2S,5R)-5-((11-cyclopropyl-13-(methoxymethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanone ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (70 mg, 0.117 mmol) dissolved in 1,4-dioxane (2 mL), HCl / 1,4-dioxane solution (2 mL) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness, and the residue was purified by preparative HPLC (YMC-Actus Triart C18 250*20 mm, mobile phase: a mixture of aqueous solution containing 0.1% NH4HCO3 and MeCN, gradient 5–95%) to give the title compound (20 mg) as a solid. 1 H NMR (400 MHz, CD3OD) δ 6.72 (s, 1H), 6.60 (s, 1H), 6.57 (s, 1H), 4.55 (dd, J = 13.0, 3.8Hz, 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) + .

[0894] Example 56

[0895] ((2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidin-2-yl)methylcarbamate

[0896]

[0897] Step 1: tert-butyl(2S,5R)-2-(hydroxymethyl)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1-carboxylate

[0898] To a solution of 1-(tert-butyl)-2-ethyl(2S,5R)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanone-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (130 mg, 0.21 mmol) dissolved in THF (5 mL), LiBH4 (13.6 mg, 0.62 mmol) was added at 0 °C, followed by stirring at 60 °C for 2 hours. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted twice with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: DCM containing 0–5% MeOH) to give the title compound (60 mg) in an oil. LC-MS (ESI) m / z: 583.3 (M+H) + .

[0899] Step 2: tert-butyl(2S,5R)-2-((carbamoyloxy)methyl)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-1-carboxylate

[0900] To a mixture of tert-butyl(2S,5R)-2-(hydroxymethyl)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanone-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (60 mg, 0.10 mmol) and triethylamine (30.6 mg, 0.3 mmol), trichloroacetyl isocyanate (28.2 mg, 0.15 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. Subsequently, the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to give the target product (40 mg) as an oil. LC-MS (ESI) m / z: 626.3 (M+H) + .

[0901] Step 3: ((2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidin-2-yl)methylcarbamate

[0902] Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl(2S,5R)-2-((carbamoyloxy)methyl)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1-carboxylate (20 mg, 0.03 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness, and the residue was purified by preparative HPLC (column: YMC-Actus Triart C18250*21 mm; mobile phase: aqueous solution containing 0.1% NH4HCO3 and acetonitrile, gradient 10–95%) 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) + .

[0903] Example 57

[0904] ((2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)-1-methylpiperidin-2-yl)methylcarbamate

[0905]

[0906] The title compound (in solid form) was prepared according to the method and procedure described in step 13 of Example 13. 1HNMR (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) + .

[0907] Example 58

[0908] 3-(((3R,6S)-6-(hydroxymethyl)piperidin-3-yl)amino)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-13-ol

[0909]

[0910] The title compound was prepared in solid form according to the method and steps described in Example 56. 1H NMR (400MHz, 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) + .

[0911] Example 59

[0912] 3-(((3R,6S)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazine-13-ol

[0913]

[0914] The title compound was prepared in solid form by following the method and procedure described in step 13 of Example 13. 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) + .

[0915] Example 60

[0916] (2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid 2-hydroxyethyl ester

[0917]

[0918] Step 1: (2S,5R)-1-(tert-Butoxycarbonyl)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid

[0919] LiOH (33.6 mg, 0.8 mmol) was added to a solution of 1-(tert-butyl)-2-ethyl(2S,5R)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[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), and the mixture was stirred at room temperature for 2 hours. The mixture was then acidified to pH 5 with 2 N hydrochloric acid aqueous solution and extracted twice with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: DCM containing 0–5% MeOH) to give the title compound (60 mg) as a solid. LC-MS (ESI) m / z: 597.4 (M+H) + .

[0920] Step 2: 1-(tert-butyl)-2-(2-hydroxyethyl)(2S,5R)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0921] To a solution of (2S,5R)-1-(tert-butoxycarbonyl)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidin-2-carboxylic acid (60 mg, 0.10 mmol) dissolved in dichloromethane (DCM, 2 mL), ethylene glycol (9.4 mg, 0.15 mmol), EDCI (38.6 mg, 0.2 mmol), and DMAP (6.1 mg, 0.05 mmol) were added sequentially at room temperature; the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; elution system: dichloromethane / methanol = 100:0 to 90:10) to give the title compound (40 mg) as an oil. LC-MS (ESI) m / z: 641.5 (M+H) + .

[0922] Step 3: 2-Hydroxyethyl(2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylate

[0923] Trifluoroacetic acid (TFA, 1 mL) was added to a solution of 1-(tert-butyl)-2-(2-hydroxyethyl)(2S,5R)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (40 mg, 0.06 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness, and the residue was purified by preparative HPLC (column: YMC-ActusTriart C18 250*21 mm; mobile phase: aqueous solution containing 0.1% NH4HCO3 and acetonitrile, gradient 20–95%) to give the title compound (13 mg) as a solid. 1 H 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) + .

[0924] Example 61

[0925] 3-Hydroxypropyl(2S,5R)-5-((13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylate

[0926]

[0927] The title compound was prepared in solid form according to the method and steps described in Example 60. 1 H NMR (400MHz, 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) + .

[0928] Example 62

[0929] Example 62

[0930] (2S,5R,Ra)-5-((13-hydroxy-11-(trifluoromethyl)-4-(ureomethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0931] Example 63

[0932] (2S,5R,Sa)-5-((13-hydroxy-11-(trifluoromethyl)-4-(ureomethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0933]

[0934] Step 1: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-4-(ureomethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0935] 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]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (prepared according to the method and procedure described in Synthetic Example 24) (40 mg, 0.06 mmol), triethylamine (TEA, 18.6 mg, 0.18 mmol) and 2,2,2-trichloroacetyl isocyanate (17.3 mg, 0.09 mmol) were added at 0 °C, followed by stirring of the reaction mixture at room temperature for 1 hour. The mixture was then concentrated to dryness under reduced pressure. The residue was dissolved in ethanol (EtOH), and potassium carbonate (K₂CO₃, 16.9 mg, 0.12 mmol) was added. The resulting mixture was stirred at 40 °C for 2 hours. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (30 mg) as an oil. LC-MS (ESI) m / z: 697.3 (M+H) + .

[0936] Step 2: Ethyl (2S,5R,Ra)-5-((13-hydroxy-11-(trifluoromethyl)-4-(ureomethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate and ethyl (2S,5R,Sa)-5-((13-hydroxy-11-(trifluoromethyl)-4-(ureomethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

[0937] To a solution of 1-(tert-butyl)-2-ethyl(2S,5R)-5-((13-(methoxymethoxy)-11-(trifluoromethyl)-4-(ureomethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (30 mg, 0.04 mmol) dissolved in dichloromethane (DCM, 1 mL), a solution of HCl / 1,4-dioxane (1 mL, 4 M) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated to dryness under reduced pressure. The resulting residues were purified by preparative HPLC (column: WELCH ultimate XB-C18 250*21.2 mm; mobile phase: a mixture of aqueous solution containing 0.1% NH4HCO3 and acetonitrile, gradient 10–95%), ultimately yielding Example 62 (6 mg, eluted first) and Example 63 (5 mg, eluted subsequently) in solid form. Example 62: 1 H 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, CD33OD) 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) + .

[0938] Example 64

[0939] (2S,5R,Ra)-5-((4-(acetamidomethyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0940] Example 65

[0941] (2S,5R,Sa)-5-((4-(acetamidomethyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononacyclo[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0942]

[0943] Step 1: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-(acetamidomethyl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0944] 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]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (50 mg, 0.077 mmol) dissolved in dichloromethane (DCM, 1 mL), triethylamine (TEA, 23 mg, 0.231 mmol) and acetyl chloride (7.2 mg, 0.092 mmol) were added at room temperature, and the mixture was stirred at room temperature for 1 hour. The mixture was then diluted with ethyl acetate (EtOAc), washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–40% EtOAc) to give the title compound (30 mg) as a solid. LC-MS (ESI) (m / z): 696.4 (M+H) + .

[0945] Step 2: (2S,5R)-5-((4-(acetamidomethyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0946] To a solution of ethyl (2S,5R)-5-((4-(acetamidomethyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate (30 mg, 0.043 mmol) dissolved in dichloromethane (DCM, 1 mL), a solution of HCl / 1,4-dioxane (1 mL, 4 M) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated to dryness. The resulting residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*20 mm; mobile phase: a mixture of aqueous solution containing 0.1% NH4HCO3 and acetonitrile, gradient range 15–95%) to give solid products: Example 64 (4 mg, eluted first) and Example 65 (4 mg, eluted subsequently). Example 64: 11H 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: 1 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) + .

[0947] Example 66

[0948] (2S,5R,Ra)-5-((13-hydroxy-4-(3-methoxy-3-oxopropyl)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanonane[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0949] Example 67

[0950] (2S,5R,Sa)-5-((13-hydroxy-4-(3-methoxy-3-oxopropyl)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0951]

[0952] Step 1: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-formyl-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0953] 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]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (500 mg, 0.76 mmol) in dichloromethane (5 mL), Dess-Martin oxidant (421 mg, 0.99 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. The mixture was then quenched with saturated aqueous sodium bicarbonate solution and extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by rapid column chromatography (silica gel; eluent: petroleum ether containing 0–50% ethyl acetate) to give the title compound (400 mg) as a solid. LC-MS (ESI) (m / z): 653.4 (M+H) + .

[0954] Step 2: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-((E)-3-methoxy-3-oxopropyl-1-en-1-yl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0955] 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]oxanon-membered ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (180 mg, 0.28 mmol) dissolved in dichloromethane (DCM, 5 mL), methyl (triphenylphosphine)acetate (111 mg, 0.33 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure. The residue was purified by rapid chromatography (silica gel; eluent: petroleum ether containing 0–40% ethyl acetate) to give the title compound (120 mg) as a solid. LC-MS (ESI) (m / z): 709.4 (M+H) + .

[0956] 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]oxa-9-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0957] Pd / C (20 mg, 10% wt.) was added to a solution of 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-((E)-3-methoxy-3-oxopropyl-1-en-1-yl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (120 mg, 0.17 mmol) dissolved in EtOH (3 mL), under a nitrogen atmosphere. Hydrogen was then introduced through a hydrogen balloon at room temperature and the mixture was stirred for 1 hour. 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) + .

[0958] Step 4: (2S,5R)-5-((13-hydroxy-4-(3-methoxy-3-oxopropyl)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0959] To a solution of (2S,5R)-5-((4-(3-methoxy-3-oxopropyl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanone ring[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-ethyl ester (50 mg, 0.07 mmol) in dichloromethane (2 mL), HCl / 1,4-dioxane (1 mL, 4 M) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated to dryness under reduced pressure. The resulting residues were purified by preparative HPLC (column: YMC-Actus Triart C18 250*20 mm; mobile phase: a mixture of aqueous solution containing 0.1% NH4HCO3 and acetonitrile, gradient 10–95%) to obtain solid forms of Example 66 (7 mg, eluted first) and Example 67 (6 mg, eluted second). Example 66: 1 H NMR (400 MHz, CD3OD) δ7.16 (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 (400MHz, 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) + .

[0960] Example 68

[0961] (2S,5R,Ra)-5-((4-(3-amino-3-oxopropyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0962] Example 69

[0963] (2S,5R,Sa)-5-((4-(3-amino-3-oxopropyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0964]

[0965] 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]oxononane[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0966] 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]oxononacyclo[5,6-c]pyridazin-4-yl)propionic acid (60 mg, 0.086 mmol), HATU (100 mg, 0.258 mmol), DIEA (56 mg, 0.43 mmol), and NH4Cl (12 mg, 0.172 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (EtOAc), washed successively with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by rapid chromatography (silica gel; eluent: DCM containing 0–10% MeOH) to give the title compound (30 mg) as a solid. LC-MS (ESI) (m / z): 696.4 (M+H) + .

[0967] Step 2: Ethyl (2S,5R,Ra)-5-((4-(3-amino-3-oxopropyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate and ethyl (2S,5R,Sa)-5-((4-(3-amino-3-oxopropyl)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate)

[0968] To a solution of (2S,5R)-5-((4-(3-amino-3-oxopropyl)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-ethyl ester (28 mg, 0.04 mmol) dissolved in dichloromethane (DCM, 1 mL), a solution of HCl / 1,4-dioxane (1 mL, 4 M) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness, and the residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250*20 mm; mobile phase: a mixture of aqueous solution containing 0.1% NH4HCO3 and acetonitrile, gradient 25–90%) to obtain solid products: Example 68 (2.1 mg, eluted first) and Example 69 (1.8 mg, eluted later). 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: 1 H 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) + .

[0969] Example 70

[0970] 3-(3-(((3R,6S,Ra)-6-(ethoxycarbonyl)piperidin-3-yl)amino)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-4-yl)propionic acid

[0971] Example 71

[0972] 3-(3-(((3R,6S,Sa)-6-(ethoxycarbonyl)piperidin-3-yl)amino)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-4-yl)propionic acid

[0973]

[0974] Step 1: 3-(3-(((3R,6S)-1-(tert-butyloxycarbonyl)-6-(ethoxycarbonyl)piperidin-3-yl)amino)-13-(methoxymethoxy)-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxa-non-membered cyclo[5,6-c]pyridazin-4-yl)propionic acid

[0975] 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]oxanone-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (90 mg, 0.127 mmol) dissolved in THF / water (2 mL, v / v = 3 / 1), LiOH·H₂O (6 mg, 0.14 mmol) was added at 0 °C, and the mixture was stirred at 0 °C for 4 hours. The mixture was then acidified to approximately pH 4 with 1 N hydrochloric acid aqueous solution and extracted twice with dichloromethane (DCM). The organic layers were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness to give the title compound as a solid (60 mg). LC-MS (ESI) m / z: 697.4 (M+H) + .

[0976] Step 2: 3-(3-(((3R,6S,Ra)-6-(ethoxycarbonyl)piperidin-3-yl)amino)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazin-4-yl)propionic acid and 3-(3-(((3R,6S,Sa)-6-(ethoxycarbonyl)piperidin-3-yl)amino)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazin-4-yl)propionic acid

[0977] To a solution of 3-(3-(((3R,6S)-1-(tert-butyloxycarbonyl)-6-(ethoxycarbonyl)piperidin-3-yl)amino)-13-hydroxy-11-(trifluoromethyl)-5,6,7,9-tetrahydrobenzo[3,4]oxononane[5,6-c]pyridazin-4-yl)propionic acid (30 mg, 0.046 mmol) in dichloromethane (1 mL), HCl / 1,4-dioxane (1 mL, 4 M) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated to dryness. The resulting residues were purified by preparative HPLC (YMC-ActusTriart C18 250*20 mm, mobile phase: a mixture of aqueous solution containing 0.1% NH4HCO3 and MeCN, gradient 25–95%) to obtain solid products: Example 70 (1.8 mg, eluted first) and Example 71 (1.6 mg, eluted later). Example 70: 1 H 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) δ7.16 (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 = 7.1Hz, 3H). LC-MS (ESI) m / z: 553.3 (M+H) + .

[0978] Example 72

[0979] (2S,5R,Ra)-5-((4-carbamoyl-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0980] Example 73

[0981] (2S,5R,Sa)-5-((4-carbamoyl-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered ring[5,6-c]pyridazine-3-yl)amino)piperidine-2-carboxylic acid ethyl ester

[0982]

[0983] Step 1: 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-carbamoyl-13-(methoxymethoxy)-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered cyclo[5,6-c]pyridazine-3-yl)amino)piperidine-1,2-dicarboxylate

[0984] To a mixture of DMSO (2 mL) containing 1-(tert-butyl)-2-ethyl(2S,5R)-5-((4-cyano-13-(methoxymethoxy)-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (100 mg, 0.15 mmol), K₂CO₃ (104 mg, 0.75 mmol) and H₂O₂ (170 mg, 1.5 mmol, 30% aqueous solution) were added at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated aqueous Na₂S₂O₃ and extracted twice with EtOAc. The combined organic layers were washed with saturated 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) + .

[0985] Step 2: Ethyl (2S,5R,Ra)-5-((4-carbamoyl-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate with (2S,5R,Sa)-5-((4-carbamoyl-13-hydroxy-11-(trifluoromethoxy)-5,6,7,9-tetrahydrobenzo[3,4]oxa-9-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-2-carboxylate

[0986] Trifluoroacetic acid (TFA, 1 mL) was added 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]oxanon-membered cyclo[5,6-c]pyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (50 mg, 0.07 mmol) dissolved in dichloromethane (DCM, 2 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was then concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (WELCH ultimate XB-C18 250*21.2 mm, mobile phase: aqueous solution containing 0.1% NH4HCO3 and acetonitrile, gradient 0–95%) to give solid products: Example 72 (8 mg, eluted first) and Example 73 (7 mg, eluted later). 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: 1 HNMR (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) + .

[0987] The examples listed in Table 3 were prepared using suitable starting materials according to the methods and procedures outlined below.

[0988] Table 3. Examples of preparations using the aforementioned method

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001] Error! Reference source not found. Table 4 below lists the four sets of conditions for the resolution of the diastereomer pairs of compounds in Table 3. By convention, the fraction with the smaller number in each pair of compounds is eluted first on the column.

[1002] Table 4. Conditions for the resolution of epimers

[1003]

[1004] Examples of biological assays

[1005] The compounds of this invention underwent various assays to assess their suitability as potential drug candidates. It should be understood that a successful drug candidate must possess excellent efficacy, pharmacokinetic properties, and safety profile. Given that this study aims to develop systemic (peripheral) or tissue-directed (e.g., targeting the central nervous system or intestine) inhibitors, compounds intended for these uses must ensure adequate drug exposure levels in the corresponding target tissues.

[1006] Example of biological assay 1: Inhibition assay of IL-1β in THP-1 cells

[1007] The following protocol was used to evaluate the ability of the test compound to inhibit IL-1β production in human THP-1 cells:

[1008] 1. THP-1 cells (ATCC #TIB-202) were maintained in complete RPMI-1640 medium (Gibco A1049101); this medium contained 10% heat-inactivated fetal bovine serum (FBS, Gibco 10099141C), 1% L-glutamine (Gibco 25030149), and 1% penicillin / streptomycin (Gibco 15140122).

[1009] 2. On the day of the experiment, THP-1 cells (concentration approximately 5.5 × 10⁻⁶) were... 5 Cells were seeded at 1,000 cells / mL into 384-well plates, and 45 μL of RPMI-1640 medium (FBS-free) was added to each well. Cells were then pre-stimulated with 1.0 μg / mL LPS (SIGMA, L6529).

[1010] 3. Add 5 μL of serially diluted compound solution (10 dose points in total, starting concentration of 5 μM, diluted at a ratio of 1:3) or solvent control (medium containing 0.05% DMSO) to the corresponding well.

[1011] 4. Incubate the cells at 37°C and 5% CO2 for 3 hours. Add 5 μL of Nigericin (MEC, HY-100381) (final concentration 5 μM) to the sample wells and positive control wells to stimulate the cells; add 5 μL of RPMI-1640 medium (without FBS) to the negative control wells.

[1012] 5. After incubating at 37℃ and 5% CO2 for 1 hour, transfer 8 μL of the supernatant to a 384-well plate and add 8 μL of RPMI-1640 medium (FBS-free) to each well; simultaneously prepare standard solutions in parallel.

[1013] 6. Following the manufacturer's instructions, determine IL-1β levels using the Human IL-1β Assay Kit (PerkinElmer, 62HIL1BPEH); subsequently, read the assay plate using a plate reader compatible with HTRF® technology (PE Nivo).

[1014] 7. Data Analysis: The concentration of IL-1β in the treated wells was calculated based on the standard curve. IC50 data were fitted using a nonlinear regression equation (inhibitor logarithmic vs. response value – a four-parameter model with variable slope).

[1015] The obtained IC50 values ​​(or the geometric mean of IC50 values ​​from THP-1 cell data) are listed in Table 5. Data ≥ 3000 nM were denoted as "+"; < 3000 nM and ≥ 1000 nM as "++"; < 1000 nM and ≥ 300 nM as "+++"; < 300 nM and ≥ 50 nM as "++++"; < 50 nM and ≥ 15 nM as "+++++"; and < 15 nM as "++++++". These results indicate that the compounds disclosed herein exhibit potent inhibitory effects on IL-1β production in THP-1 cells. Table 5. Inhibitory effect of IL-1β in THP-1 cells.

[1016]

[1017]

[1018]

[1019] While this disclosure mentions various embodiments or examples, it should be understood that these embodiments and examples are merely illustrative of the principles and applications of specific aspects of the invention. Numerous modifications and other arrangements may be conceived to the exemplary embodiments without departing from the spirit and scope of the invention; all such modifications and arrangements are intended to be covered within this disclosure. All patent or non-patent references cited in this application are incorporated herein by reference in their entirety and are not construed as an admission that any of them constitutes prior art.

Claims

1. A compound having the structure of formula (I): Or its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein: X is NR 4 , S, O or CR 5 R 6 ; Y is CR 5 R 6 or a bond; Z is N or CR 7 ; 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 R 1 when A is C 6-10 aryl or 5-6 membered heteroaryl, R 1 is not oxo (=0); W 1 W 3 and W 5 Each independently selected from CR 5 R 6 O, S and NR 4 And W 2 W 4 and W 6 Each is independently selected from key, CR 5 R 6 O, S and NR 4 But the condition is: in W 1 W 2 W 3 W 4 W 5 and W 6 In this context, no two non-carbon atoms are directly connected, nor are they connected to the same carbon atom; or, where R... 5 With R 6 R 4 With R 5 、or R 4 With R 6 Additional 3-4 element helical rings or 5-7 element bridge rings can be formed; m is 0, 1, 2, or 3; and n is 0, 1, or 2 R 1 independently at each occurrence selected from -H, C 1-8 alkyl, C 3-7 cycloalkyl, C 1-8 alkyl-CO-, 4-7 membered heterocyclyl, OR 8 , CO2R 8 , C(O)NR 8 R 9 , halogen, CN, NR 8 R 9 and oxo (=0); wherein, C 1-8 alkyl, C 3-7 cycloalkyl, C 1-8 alkyl-CO-, and 4-7 membered heterocyclyl, each can be optionally substituted with 1-3 groups independently selected from R 10 ; R 2 It can be -OH, -OCHF2, -OCF3, -CHF2, -CF3, -CH2CF3, -OMe, -F, or -H; R 3 Each time it appears, it is independently selected from -H, C. 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, halogens, -CN, -SF5, -NR 8 R 9 -OR 8 -SR 8 , aryl and heteroaryl; of which, C 3-6 cycloalkyl and C 1-6 Each alkyl group may optionally be surrounded by 1-3 independently selected from halogens, oxo groups, and C. 1-4 The alkyl group is substituted; and wherein the aryl and heteroaryl groups are each optionally replaced by 1-3 groups independently selected from halogens and C. 1-4 Alkyl group substitution; R 4 Each time it appears, it is independently selected from -H, C. 1-4 Alkyl, -C(O)-C 1-4 Alkyl and C 3-7 cycloalkyl; wherein, C 1-4 Alkyl and C 3-7 Each cycloalkyl group may optionally be independently selected from 1 to 3 R groups. 10 Substitution of groups; R 5 and R 6 Each occurrence is independently selected from -H, halogen, -OR. 8 -NR 8 R 9 C 1-4 Alkyl, C 3-7 Cycloalkyl and 4-7 membered heterocyclic groups, wherein C 1-4 Alkyl, C 3-7 Each of the cycloalkyl and 4-7 membered heterocyclic groups may optionally be replaced by 1-3 independently selected R 10 Substitution of groups; Or, R connected to the same atom 5 and R 6 Together they form = O; Alternatively, R connected to the same or different atoms 5 and R 6 It can form a 3-6 membered carbon ring or heterocycle, which can optionally be divided by 1-3 R... 10 Group substitution; R 7 Independently selected from H and C 1-8 Alkyl, C 3-7 Cycloalkyl, aryl, heteroaryl, halogen, -CN, -OR 8 -NR 8 R 9 -CO2R 11 and -C(O)N(R) 11 R 12 ); where C 1-4 Alkyl, C 3-7 Each of the cycloalkyl, aryl, and heteroaryl groups may be optionally substituted by 1 to 3 groups independently selected from R13; Or, R 7 Can be used with R 4 R 5 or R 6 Together they form a 5-7 membered carbon ring or heterocycle, which can be optionally divided by 1-3 R atoms. 10 Group substitution; R 8 and R 9 Independently selected from -H, -C(O)R 12 -C(O)N(R) 11 R 12 -C(=NR) 12 )N(R 11 R 12 C 1-6 Alkyl, C 3-7 cycloalkyl and aryl; wherein, C 1-6 Alkyl, C 3-7 Each of the cycloalkyl and aryl groups may optionally be composed of 1 to 3 independently selected from R 10 The group is substituted, but when R 8 or R 9 When it is aryl, R 10 It cannot be =O; R 10 Each time it appears, it is independently selected from -H, -CO2R. 11 -C(O)N(R) 11 )2、-CN、-OR 11 Halogen, C 1-6 Alkyl, cyclopropyl, aryl, =O, -SR 11 and -N(R) 11 R 12 ); Each occurrence of R 11 Each is independently selected from -H, -CO2R 12 -C(O)R 12 -C(O)NR 12 C(=NR 12 )N(R 12 )2、-C(=NR 12 )N(R 12 )2、-C(O)N(R 12 2. Aryl and C 1-6 Alkyl groups, wherein each aryl group and C 1-6 The alkyl group may optionally be substituted with 1 to 3 groups independently selected from halogens, -OH and -NH2; Each occurrence of R 12 Each is independently selected from -H, aryl, and C. 1-4 Alkyl groups, wherein each aryl group or C 1-4 The alkyl group may optionally be substituted with 1 to 3 groups independently selected from halogens, -OH and -NH2; R 13 Each time it appears, it is independently selected from -H, halogen, -OH, -N(R) 12 )2、-NR 12 C(=NR 12 )N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 C(O)R 12 -NR 12 C(O)OR 12 -OC(O)N(R) 12 )2、-CO2R 12 -COR 12 -C(O)NR 12 C(=NR 12 )N(R 12 )2、-C(=NR 12 )N(R 12 )2、-C(O)N(R 12 2. Aryl and C 1-6 Alkyl; wherein the aryl and C 1-6 Each alkyl group may optionally be substituted with one to three independent groups selected from halogens, -OH and -NH2.

2. The compound according to claim 1, or its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts, wherein: X is NR 4 S, O or CR 5 R 6 ; Y is CR 5 R 6 OR key; Z is N or CR 7 ; Ring A is a 5-6 membered heterocyclic group, a 5-6 membered carbocyclic group, or a phenyl group, each of which is independently selected from R. 1 One to three groups are substituted; W 1 W 3 and W 5 Each independently for CR 5 R 6 O or S; and W 2 W 4 and W 6 Each independently forms a bond, CR 5 R 6 O or S, but only if: in W 1 W 2 W 3 W 4 W 5 and W 6 In this process, no two non-carbon atoms may be directly connected to each other, nor may they be connected to the same carbon atom. m can be 0, 1, 2, or 3; n is 0, 1, or 2; i is independently 1 or 2 each time it appears; R 1 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl-CO-, 4-6 membered heterocyclic groups, -OR 8 -CO2R 8 -C(O)NR 8 R 9 Halogen, -CN, -NR 8 R 9 Oxygenation (=O), -C 1-6 Alkylene-(R 10 ) i -C 3-6 Cycloalkylene-(R 10 ) i -C(O)-C 1-6 Alkyl-(R) 10 ) i And -(4-6 heterocyclic subunit)-(R 10 ) i ; R 2 It can be -OH, -OCHF2, -OCF3, -CHF2, -CF3, -CH2CF3, -OMe, -F, or -H; R in various places 3 Independently selected from -H, C 3-6 cycloalkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, halogens, -CN, -NR 8 R 9 -OR 8 -SR 8 , phenyl and 5-6 heteroaryl; wherein, the C 3-6 cycloalkyl, C 1-6 Alkyl, phenyl, and 5-6 heteroaryl groups may each optionally be surrounded by 1-3 independently selected halogens and C 1-4 Alkyl groups are substituted; R in various places 4 Independently selected from -H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 3-6 cycloalkyl, -C 1-6 Alkylene-(R 10 ) i and -C 3-6 Cycloalkylene-(R 10 ) i ; R 5 and R 6 Each occurrence is independently selected from -H, halogen, or -OR. 8 -NR 8 R 9 C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic groups, -C 1-6 Alkylene-(R 10 ) i -C 3-6 Cycloalkylene-(R 10 ) i -C(O)-C 1-6 Alkyl-(R) 10 ) i and -(4-6 heterocyclic subunit)-(R 10 ) i ; Or, R 5 and R 6 They combine to form an oxygen group (=O); R 7 Selected from -H, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 heteroaryl, halogen, -CN, -OR 8 -NR 8 R 9 -CO2R 11 -C(O)N(R) 11 R 12 -C 1-6 Alkylene-(R 13 ) i and -C 3-6 Cycloalkylene-(R 13 ) i ; R 8 Each occurrence is independently selected from -H, -C(O)R 12 -C(O)N(R) 11 R 12 C 1-6 Alkyl, C 3-6 cycloalkyl, phenyl, -C 1-6 Alkylene-(R 10 ) i -C 3-6 Cycloalkylene-(R 10 ) i and -phenylene-(R 10 ) i ; R 9 Each time it appears, it is independently selected from -H, C. 1-4 Alkyl and C 3-6 cycloalkyl; R 10 Each occurrence is independently selected from -H, -CN, halogen, and C. 1-4 Alkyl, cyclopropyl, phenyl, =O, -OR 11 -SR 11 -CO2R 11 -C(O)N(R) 11 )2 and -N(R 11 R 12 ); Each occurrence of R 11 Each is independently selected from -H, -CO2R 12 -C(O)R 12 -C(O)NR 12 C(=NR 12 )N(R 12 )2、-C(=NR 12 )N(R 12 )2、-C(O)N(R 12 2. Phenyl and C 1-6 Alkyl groups, including phenyl and C 1-6 Alkyl groups can be selectively substituted by 1-3 groups independently selected from halogens, -OH and -NH2; Each occurrence of R 12 Each is independently selected from -H, aryl, and C. 1-4 Alkyl, wherein aryl or C 1-4 Alkyl groups can be selectively substituted by 1-3 groups independently selected from halogens, -OH and -NH2; R 13 Each time it appears, it is independently selected from -H, halogen, -OH, -N(R) 12 )2、-NR 12 C(=NR 12 )N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 C(O)R 12 -NR 12 C(O)OR 12 -OC(O)N(R) 12 )2、-CO2R 12 -C(O)R 12 -C(O)NR 12 C(=NR 12 )N(R 12 )2、-C(=NR 12 )N(R 12 )2、-C(O)N(R 12 2. Aryl and C 1-6 Alkyl; wherein the aryl and C 1-6 Each alkyl group may optionally be substituted with 1 to 3 groups independently selected from halogens, OH and NH2.

3. The compound according to claim 1, or its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts, wherein: X is NR 4 S, O or CR 5 R 6 ; Y is CR 5 R 6 OR key; Z is CR 7 ; m can be 0, 1, 2, or 3; n is 0, 1, or 2; A is a 5-6 membered heterocyclic group; W 1 For CR 5 R 6 Or O; W 2 For O, S, CR 5 R 6 OR key; W 3 For CR 5 R 6 Or O; W 4 For CR 5 R 6 OR key; W 5 For CR 5 R 6 、O or S; W 6 For CR 5 R 6 Or key; but only if it is in W 1 W 2 W 3 W 4 W 5 and W 6 In this process, no two non-carbon atoms may be directly connected to each other, nor may they be connected to the same carbon atom. R 1 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl-CO-, 4-6 membered heterocyclic groups, -OR 8 -CO2R 8 -CONR 8 R 9 Halogen, -CN, -NR 8 R 9 Oxygenation (=O), -C 1-6 Alkylene-CN, -C 1-6 Alkylene halogen, -C 1-6 alkylene-cyclopropyl, -C 1-6 alkylene-phenyl, -C 1-6 Alkylene-OR 11 -C 1-6 Alkylene-SR 11 -C 1-6 Alkylene-CO2R 11 -C 1-6 Alkylene-C(O)N(R) 11 )2、-C 1-6 Alkylene-N(R) 11 R 12 -OC(O)R 12 -OC(O)N(R) 11 R 12 -OC (=NR) 12 )N(R 11 R 12 -OC 3-6 Cycloalkyl, -O-phenyl, -OC 1-6 Alkylene-CN, -OC 1-6 Alkylene-halogen, -OC 1-6 alkylene-cyclopropyl, -OC 1-6 alkylene-phenyl, -OC 1-6 Alkylene-OR 11 -OC 1-6 Alkylene-SR 11 -OC 1-6 Alkylene-CO2R 11 -OC 1-6 Alkylene-C(O)N(R) 11 )2、-OC 1-6 Alkylene-N(R) 11 R 12 -C(O)OC 1-6 Alkylene-CN, -C(O)OC 1-6 Alkylene-halogen, -C(O)OC 1-6 alkylene-cyclopropyl, -C(O)OC 1-6 alkylene-phenyl, -C(O)OC 1-6 Alkylene-OR 11 -C(O)OC 1-6 Alkylene-SR 11 , -C(O)OC 1-6 Alkylene-CO2R 11 , -C(O)OC 1-6 Alkylene-C(O)N(R) 11 )2, -C(O)OC 1-6 Alkylene-N(R) 11 R 12 ); R 2 It can be -OH, -OCHF2, -OCF3, -CHF2, -CF3, -CH2CF3, -OMe, -F, or -H; R 3 Each time it appears, it is independently selected from H and C. 3-6 cycloalkyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Haloalkyl, CN and halogen; R 4 Each time it appears, it is independently selected from H and C. 1-4 Alkyl groups and -C(O)-C 1-4 alkyl; R 5 Each occurrence is independently selected from H, halogen, and -OR. 8 , -NR 8 R 9 and C 1-4 alkyl; R 6 Each time it appears, it is independently selected from H and C. 1-4 alkyl; R 7 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 heteroaryl, halogen, -CN, -OR 8 , -NR 8 R 9 , -CO2R 11 , -CON(R 11 R 12 ), -C 1-6 Alkylene halogen, -C 1-6 alkylene -OH, -C 1-6 Alkylene-N(R) 12 )2、-C 1-6 Alkylene-NR 12 C(=NR 12 )N(R 12 )2、-C 1-6 Alkylene-NR 12 C(O)N(R 12 )2、-C 1-6 Alkylene-NR 12 C(O)R 12 -C 1-6 Alkylene-NR 12 C(O)OR 12 -C 1-6 Alkylene-OC(O)N(R) 12 )2、-C 1-6 Alkylene-CO2R 12 -C 1-6 Alkylene-C(O)R 12 -C 1-6 Alkylene-C(O)N(R) 12 )2、-C 1-6 Alkylene-CO2R 12 -C 1-6 Alkylene-C(O)R 12 -C 1-6 Alkylene-C(O)NR 12 C(=NR 12 )N(R 12 )2、-C 1-6 Alkylene-C(=NR) 12 )N(R 12 )2、-C 1-6 Alkylene-C(O)N(R) 12 )2、-C 1-6 alkylene-phenyl, -OC(O)R 12 -OC(O)N(R) 11 R 12 -OC (=NR) 12 )N(R 11 R 12 -OC 3-6 Cycloalkyl, -O-phenyl, -OC 1-6 Alkylene -OH, -OC 1-6 Alkylene-CO2R 11 -OC 1-6 Alkylene-C(O)N(R) 11 )2、-OC 1-6 Alkylene-CN, -OC 1-6 Alkylene-SR 11 -OC 1-6 Alkylene-C(O)N(R) 11 R 12 ) and -OC 1-6 Alkylene-C(O)N(R) 11 )2; Each R 8 Independently H or C 1-4 alkyl; Each R 9 Independently H or C 1-4 alkyl; Each R 10 Independently selected from H, -CN, halogens, C 1-4 Alkyl, cyclopropyl, phenyl, =O, -OR 11 , -SR 11 , -CO2R 11 ,-CON(R 11 )2 and -N(R 11 R 12 ); R in various places 11 Independently selected from -H, -CO2R 12 , -COR 12 , -C(O)N(R 12 )2, and C 1-6 Alkyl, wherein C 1-6 The alkyl group may optionally be substituted with 1-3 groups independently selected from halogens, OH, and NH2; and R in various places 12 Independently selected from H, aryl and C 1-4 Alkyl groups, wherein each aryl group or C 1-4 The alkyl group may optionally be substituted with 1 to 3 groups independently selected from halogens, OH and NH2.

4. The compound according to claim 1, or its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts, wherein: X is NR 4 S or O; Y is CR 5 R 6 , or key; Z is CR 7 ; m is 0, 1, or 2; n is 0 or 1; A is a 6-membered heterocyclic group; W 1 For CR 5 R 6 , or O; W 2 For O, S or CR 5 R 6 ,; W 3 For CR 5 R 6 , or O; W 4 For CR 5 R 6 OR key; W 5 For CR 5 R 6 O or S; W 6 For CR 5 R 6 Or chemical bonds; but only if, in W 1 W 2 W 3 W 4 W 5 and W 6 In this process, no two non-carbon atoms may be directly connected to each other, nor may they be connected to the same carbon atom. R 1 Each occurrence is independently selected from -H, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkyl-CO-, 4-6 membered heterocyclic groups, -OR 8 , -CO2R 8 , -CONR 8 R 9 Halogen, -CN, -NR 8 R 9 Oxygenation (=O), -C 1-6 Alkylene-OR 10 -C 1-6 Alkylene -OC(O)NH2, -C 1-6 Alkylene-C(O)OR 11 -C(O)OR 11 and -C(O)OC 1-6 Alkylene-OR 10 ; R 2 It can be -OH, -OCHF2, -OCF3, -OMe, -F, or -H; Each R 3 Independently selected from H and C 3-6 cycloalkyl, C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Alkyl halogens, -CN, and halogens; Each R 4 Independently selected from H and C 1-4 Alkyl groups and -C(O)-C 1-4 alkyl; Each R 5 Independently selected from H or C 1-4 alkyl; Each R 6 Independently selected from H or C 1-4 alkyl; R 7 Selected from -H, -CN, C 1-6 Alkyl, -OR 8 , -NR 8 R 9 , -O-CO2R 11 , -CON(R 11 R 12 ), -C 1-6 alkylene -OH, -C 1-6 Alkylene-N(R) 12 )2、-C 1-6 Alkylene-NR 12 C(=NR 12 )N(R 12 )2、-C 1-6 Alkylene-NR 12 C(O)N(R 12 )2、-C 1-6 Alkylene-NR 12 C(O)R 12 -C 1-6 Alkylene-NR 12 C(O)OR 12 -C 1-6 Alkylene-OC(O)N(R) 12 )2、-C 1-6 Alkylene-CO2R 12 -C 1-6 Alkylene-C(O)R 12 -C 1-6 Alkylene-C(O)N(R) 12 )2、-OC(O)R 12 -OC(O)N(R) 11 R 12 -OC 1-6 Alkylene -OH, -OC 1-6 Alkylene-CO2R 11 -OC 1-6 Alkylene-C(O)N(R) 11 )2、-OC 1-6 Alkylene-CN, -OC 1-6 Alkylene-SR 11 -OC 1-6 Alkylene-C(O)N(R) 11 R 12 ) and -OC 1-6 Alkylene-C(O)N(R) 11 )2; R 8 It is independently H or C each time it appears. 1-4 alkyl; R 9 It is independently H or C each time it appears. 1-4 alkyl; R 10 Each occurrence is independently selected from H, -CN, halogen, C. 1-4 Alkyl, cyclopropyl, phenyl, =O, -OR 11 , -SR 11 ,-CO2R 11 , -CON(R 11 )2, and -N(R 11 R 12 ); R 11 Each occurrence is independently selected from -H, -CO2R. 12 , -C(O)R 12 , -C(O)N(R 12 )2, and C 1-6 Alkyl, wherein C 1-6 The alkyl group may optionally be substituted with 1-3 groups independently selected from halogens, -OH, and -NH2; and R 12 Each time it appears, it is independently selected from -H, aryl, and C. 1-4 Alkyl, wherein aryl or C 1-4 Each of the alkyl groups may optionally be substituted with 1 to 3 groups independently selected from halogens, -OH and -NH2.

5. The compound according to claim 1, or its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein: X is NR 4 ; Y is CR 5 R 6 OR key; Z is CR 7 ; m is 0, 1, or 2; n is 0 or 1; A is piperidinyl; W 1 For CR 5 R 6 Or O; W 2 For O, CR 5 R 6 OR key; W 3 For CR 5 R 6 Or O; W 4 For CR 5 R 6 OR key; W 5 For CR 5 R 6 Or O; W 6 For CR 5 R 6 Or key; but only if it is in W 1 W 2 W 3 W 4 W 5 and W 6 In this process, no two non-carbon atoms may be directly connected to each other, nor may they be connected to the same carbon atom. R 1 Each time it appears, it is independently selected from H and C. 1-4 Alkyl, -OR 8 , -CO2R 8 , -CONR 8 R 9 Halogen, -CN, -NR 8 R 9 ,-C 1-4 alkylene -OH, -C 1-4 Alkylene-OC 1-4 Alkyl, -C 1-4 Alkylene -OC(O)NH2, -C 1-6 Alkylene -C(O)OH, -C 1-6 Alkylene-C(O)OC 1-6 Alkyl, -C(O)OH, -C(O)OC 1-6 Alkyl groups and -C(O)OC 1-6 alkylene-OH; R 2 It can be -OH, -OCHF2, -OCF3, -OMe, or -F; R 3 Each time it appears, it is independently selected from H and C. 3-6 cycloalkyl, C 1-2 Alkyl, C 1-2 Halogenated alkyl groups and -OC 1-2 Halogenated alkyl groups; R 4 Each occurrence is independently selected from H and -C(O)-C. 1-2 alkyl; R 5 It is independently H or C each time it appears. 1-2 alkyl; R 6 It is independently H or C each time it appears. 1-2 alkyl; R 7 Selected from -H, -CN, C 1-6 Alkyl, -CON(R) 11 R 12 -C 1-4 alkylene -OH, -C 1-4 Alkylene-N((R) 12 )2、-C 1-4 Alkylene-NR 12 C(O)N(R 12 )2, -C 1-4 Alkylene-NR 12 C(O)R 12 -C 1-4 Alkylene-NR 12 C(O)OR 12 -C 1-4 Alkylene-OC(O)N(R) 12 )2、-C 1-6 Alkylene-CO2R 12 -C 1-6 Alkylene-C(O)R 12 and -C 1-4 Alkylene-C(O)N(R) 12 )2; R 8 It is independently H or C each time it appears. 1-4 alkyl; R 9 It is independently H or C each time it appears. 1-4 alkyl; R 11 It is independently H or C each time it appears. 1-4 Alkyl; and R 12 It is independently H or C each time it appears. 1-4 alkyl.

6. The compound according to claim 1, or its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein: Y = key; Z = CR 7 ; A = ； W 1 = CH2 or O; W 2 = O, CH2 or bond; W 3 = CH2 or O; W 4 = CH2 or bond; W 5 = CH2 or O; W 6 = CH2 or bond; but only if, in W 1 W 2 W 3 W 4 W 5 , and W 6 In this process, no two non-carbon atoms may be directly connected to each other, nor may they be connected to the same carbon atom. m = 0, 1, or 2; n = 0 or 1; R 1 = 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; R 2 = OH or F; R 3 = -CF3, -OCH3, -OCHF2, -OCF3 or cyclopropyl; and R 7 = 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, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein the structure is selected from formula (Ia) to formula (Id): , , , 。 8. The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, having formula (Ie) to formula (Ih): , , , 。 9. The compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein W 1 W 3 and W 5 Each is CH2; and W 2 W 4 and W 6 Each is independently CH2 or a bond.

10. The compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein W 1 W 2 W 3 and W 5 Each is CH2; and W 4 and W 6 Each is a key.

11. The compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein W 1 W 2 W 3 W 4 and W 5 Each is CH2; and W 6 For key.

12. The compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein W 1 W 2 W 3 W 4 W 5 and W 6 Each is CH2.

13. The compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein W 1 W 3 W 5 and W 6 Each is CH2; W 2 It is O; and W 4 It is CH2 or a bond.

14. The compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein W 1 W 2 W 5 and W 6 Each is CH2; W 3 It is O; and W 4 It is CH2 or a bond.

15. The compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, wherein W 1 For O; W 2 W 3 and W 5 Each is CH2; W 4 It is O; and W 6 It is CH2 or a bond.

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

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

18. A method for treating or preventing a disease or condition in a subject who responds to inhibition of NLRP3, said subject being a subject in need of such treatment; the method comprising administering to said subject an effective amount of a compound (or a stereoisomer, tautomer, isotope derivative or pharmaceutically acceptable salt thereof) according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 17.

19. A method for treating or preventing a disease or condition in a subject with such need, comprising administering to the subject an effective amount of the compound of any one of claims 1 to 16, its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 17; wherein, The disease or condition mentioned is a neurodegenerative disease, a metabolic disease, an inflammatory syndrome, an autoinflammatory disease, cancer, or a genetic disease.

20. The method of claim 19, wherein the neurodegenerative disease is Parkinson's disease or Alzheimer's disease; the metabolic disease is type 2 diabetes or atherosclerosis; the inflammatory disease is an acute gout attack, 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, or pancreatic cancer; and the hereditary disease is cryoprene-associated periodic syndrome.

21. Use of the compound, stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, in the preparation of a medicament for treating a disease or condition selected from neurodegenerative diseases, metabolic diseases, inflammatory syndromes, autoinflammatory diseases, cancer and hereditary diseases.

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