Gut-directed inhibitors of NLRP3 activity and therapeutic uses thereof

Abstract

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

Description

[0001] GUT-DIRECTED INHIBITORS OF NLRP3 ACTIVITY AND THERAPEUTIC USES THEREOF CROSS-REFERENCES TO RELATED APPLICATIONS This application claims priority and benefits to International Patent Application No. PCT / CN2024 / 109507, filed on August 2, 2024, and Application No. PCT / CN2025 / 076802, filed on February 11, 2025, the disclosures of both of which are incorporated herein by reference in their entireties. FIELD OF THE DISCLOSURE This application relates to pyridazine compounds and analogues as modulators of cytokines such as IL-1β and IL-18, or NLRP3, and their methods of preparation and therapeutic uses. BACKGROUND OF THE DISCLOSURE Nucleotide-binding oligomerization domain-like receptors (or NOD-like receptors, NLRs) are a family of pattern recognition receptors (PPRs), acting as intracellular sensors of pathogen-associated molecular patterns (PAMPs) and damage- or danger- associated molecular patterns (DAMPs). NLRP3 can be activated by a large assortment of stimuli. Accumulating evidence indicates that NLRs play important roles in innate immune responses against infection and cellular damages. Among numerous NOD-like receptors, Nucleotide-binding oligomerization domain, leucine-rich repeat receptor and pyrin-domain containing protein 3 (NLRP3) has been wellcharacterized to form inflammasome involving its oligomers which recruits theadaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and the effector zymogen pro-caspase-1. The formation of NLRP3 inflammasome activates caspase-1, which in turn catalyzes proteolytic reactions, releasing pro-inflammatory cytokines such as interleukin-1β (IL-lβ) and IL- 18 [Nat. Rev. Immunol. 2013, 13(6):397-411]. NLRP3 inflammasome activation also leads to cleavage of Gasdermin D (GSDMD) which causes pyroptosis, a rapid and pro- inflammatory form of cell death resulting from membrane pore-forming fragments from GSDMD. It has been shown that dysregulated NLRP3 inflammasome activation contributes to the pathogenesis of several human diseases. Most notably, gain-of- function mutations in NLRP3 cause hereditary diseases such as Cryopyrin-associated periodic syndrome (CAPS). In addition, aberrant activation of NLRP3 inf1ammasomes exacerbates chronic human diseases such as neurodegenerative disorders (multiple sclerosis, Alzheimer disease and Parkinson disease), metabolic ailments (atherosclerosis and type 2 diabetes), and inflammatory diseases (gout flares and osteoarthritis). More recently, roles of NLRP3 in the initiation and progression of cancers have been documented [Nat. Immunol. 2021, 22(5):550-559]. A few biologic therapies targeting NLRP3 / IL-1β innate immunity pathway have been approved. They include Anakinra (recombinant IL-1 receptor antagonist), Canakinumab (a human monoclonal antibody targeting IL-1β), and Rilonacept (a soluble decoy receptor that binds both IL-1β and IL-1α and prevents their interaction with cell surface receptors). Findings from the CANTOS study, where treatment with Canakinumab resulted in a significantly lower rate of recurrent cardiovascular events, demonstrating a clear benefit of targeting inflammation in high-risk patients with cardiovascular diseases. Targeting NLRP3 activation by small molecules is also feasible as exemplified by CRID3 (also known as MCC950). The direct binding of CRID3 with full-length NLRP3 and one of its analogs with NACHT domain of NLRP3 have been demonstrated by cryo-EM or X-ray crystal structures [Nature 2022, 604:184-189; J. Mol. Biol. 2021, 433(24);167309]. Potential benefits of targeting NLRP3 using specific small molecule inhibitors instead of targeting IL-1β using biologics include sparing the other IL-1β producing inflammasomes with specific NLRP3 inhibitors and typically much shorter half-life of small molecule drugs compared to biologics (for example, the half-life of Canakinumab in humans is 28 days). The latter enables quick withdrawal when needed, for example, in the event of an infection. Inhibition of the NLRP3 / IL- lβ innate immunity pathway via small molecule modulators may be a useful and practical approach to treat and prevent many diseases [Na. Rev. Drug Disco.2018, 18(5):1141-1160; Pharmacol. Rev. 2021, 73:968-1000]. This list includes, but not limited to, hereditary diseases (Cryopyrin-associated periodic syndrome, CAPS), neurodegenerative disorders (Alzheimer disease, Parkinson disease, traumatic brain injury), metabolic ailments (atherosclerosis and type 2 diabetes), inflammatory diseases (gout flares and osteoarthritis), cancer, among other related human diseases. NLRP3 inhibitors may have a role in the treatment of inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis [Front Immunol. 2019, 10:276]. A gut- restricted NLPR3 inhibitor may have advantages over systemic NLRP3 inhibitor in this application. Therefore, gut-restricted NLRP3 inhibitors may have practical utility in treating human diseases. Various pyridazine derivatives or analogs have been disclosed to be NLRP3 inhibitors. See, e.g., WO2020 / 234715, WO2021 / 193897, WO2022 / 135567, WO2022 / 166890, WO2022 / 216971, US Patent No.11,319,319, US patent No.11,618,751B1, WO2022 / 230912, WO2022 / 238347, CN115417856, WO2022 / 253326, WO2023 / 275366, WO2023 / 278438, WO2023 / 003002, WO2023 / 028534, WO2023 / 028536, WO2023 / 066377, WO2023 / 066825, WO2023 / 088856, WO2023 / 088987, CN115947691, WO2023 / 129987, WO2023 / 131277, WO2023 / 159148, WO2023 / 178099, WO2023 / 183943, WO2023 / 186020, WO2023 / 194964, WO2023 / 220408, WO2023 / 232917, WO2024 / 006559, WO2024.013395, WO2024 / 017924, WO2024 / 023266, WO2024 / 028782, WO2024 / 033845, WO2024 / 041460, WO2024 / 064245, WO2024 / 090469, WO2024 / 094150, WO2024 / 094185, WO2024 / 097598, WO2024 / 097629, WO2024 / 099992, WO2024 / 099993, WO2024 / 099996, WO2024 / 109922, WO2024 / 121086, WO2024 / 121184, WO2024 / 137319, WO2024 / 138045, WO2024 / 140704, WO2024 / 140824, WO2024 / 141534, WO2024 / 141535, WO2024 / 145623, WO2024 / 148029, WO2024 / 157205, WO2024 / 157953, WO2024 / 157953, WO2024 / 158941, WO2024 / 160690, WO2024 / 160691, WO2024 / 160692, WO2024 / 160693, WO2024 / 160694, WO2024 / 169858, WO2024 / 169895, WO2024 / 188994, WO2024 / 193541, WO2024 / 193699, WO2024 / 193703, WO2024 / 213552, WO2024 / 217442, WO2024 / 218100, WO2024 / 218188, WO2024 / 240153, WO2024 / 251073, WO2025 / 003288, WO2025 / 006681, WO2025 / 026252, WO2025 / 026882, WO2025 / 036275, WO2025 / 045961, WO2025 / 046419, WO2025 / 059069, WO2025 / 117439, US2025 / 0206745, WO2025 / 133307, WO2025 / 146160, WO2025 / 153624, and WO2025153625. However, there remains a need to develop new compounds with good gut-restricted distribution and suitable pharmacokinetic, safety, and chemical / physical properties as NLRP3 inhibitors useful for treatment of various diseases and conditions. SUMMARY OF THE DISCLOSURE The present disclosure aims to meet the foregoing need by providing pyridazine compounds and analogues as NLRP3 inhibitors, in particular gut-restricted NLRP3 inhibitors, and their therapeutic uses. In one aspect, the present disclosure provides a compound of formula (I): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, phenyl, or C3-6cycloalkyl; X is NR5, S, O, or CR6R7; Y is a bond or CHR7; W is H or C1-6alkyl; R1at each occurrence is independently selected from H, oxo (=O), halogen, NO2, C1-8alkyl, CN, C1-8alkyl-CN, OR9, C1-8alkyl-OR10, NRaRb, C1-8alkyl-NRaRb, C(O)OR11, C1-8alkyl- C(O)OR12, C1-8alkyl-O-C1-6alkylene-C(O)OR12, NHC(O)R13, C(O)NH-C1-8alkylene-OR9, C(O)NRcRd, C(O)NHR11, -C(O)-C1-8alkylene-NRaRb, -C(O)O-C1-8alkylene-NRcRd, -C(O)-C1-8alkylene-C(O)NRcRd, -C(O)-C1-8alkylene-OR11, C1-8alkyl-C(O)NRcRd, C1-8alkyl- OC(O)NRcRd, and C1-8alkyl-S(O)2R14, provided that R1is not oxo (=O) when A is phenyl or 5- to 6-membered heteroaryl; wherein two adjacent R1together with the atoms in Ring A to which they are attached form a 5- or 6-membered carbocyclyl or heterocyclyl group optionally substituted by one, two, or three substituents independently selected from halogen, CN, OH, C1-6alkyl, C1-6haloalkyl, O-C1-6alkyl, O-C1-6haloalkyl, and oxo (=O); R2is H, OH, -C1-4alkyl, or -C1-4alkyl-O-C1-4alkyl; R3at each occurrence is independently selected from H, halogen, OH, CN, C1-6alkyl, C1-6haloalkyl, O-C1-6alkyl, C1-6alkyl-OR9, O-C1-6haloalkyl, S(O)2NRcRd, S(O)2R15, C3-6cycloalkyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl; or alternatively two adjacent R3together with the carbon atoms in the phenyl ring to which they are attached form a 5-membered heteroaryl or 5-membered heterocyclyl fused to the phenyl ring, wherein the fused 5-membered heteroaryl or 5-membered heterocyclyl is optionally substituted by one, two, or three substituents independently selected from R23; R4is H, -C1-6alkyl, or -C1-4alkyl-O-C1-4alkyl, provided that when W is H, then R4is not

[0002] H; R5at each occurrence is independently H, C1-8alkyl, -C(O)-C1-6alkyl, or -C(O)-OC1-6alkyl; R6at each occurrence is independently H, OR16, or NHR17; R7at each occurrence is independently H, C1-6alkyl, or OR16; or alternatively when X is CR6R7, R6and R7together may form oxo (=O); R8is independently selected from H, C1-6alkyl, CN, C1-6alkyl-CN, C1-6alkyl-OR10, C(O)OR18, C1-6alkyl-C(O)OR19, CON(RcRd), C1-6alkyl-NRcRd, C1-6alkyl-OC(O)N(RcRd), C1-6alkyl-C(O)N(RcRd), C1-6alkyl-NHC(O)R20, C1-6alkyl-NHC(O)OR21, C1-6alkyl- NHC(O)N(RcRd), C1-6alkyl-NHC(=N-R22)N(RcRd), C(O)-NHC(O)N(RcRd), C(O)-NHC(=N- R22)N(RcRd), and - C1-6alkyl-S(O)2NRcRd; or alternatively, R5and R8together with the carbon and nitrogen atoms between them form a 5- or 6-membered heterocyclyl ring optionally comprising one additional heteroatom selected from N, O, and S; or alternatively, R6and R8together with the carbon atoms between them form a 5- or 6-membered carbocyclyl or heterocyclyl ring comprising one or two heteroatoms independently selected from N, O, and S; wherein the heterocyclyl formed between R5and R8and carbocyclyl or heterocyclyl formed between R6and R8are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O-C1-4haloalkyl, and oxo (=O). R9at each occurrence is independently hydrogen or C1-6alkyl; R10at each occurrence is independently hydrogen, C1-6alkyl, benzyl, or C(O)N(RcRd); R11at each occurrence is independently hydrogen, C1-8alkyl or C3-8cycloalkyl each optionally substituted by one, two, or three substituents independently selected from OR9and N(RcRd); R12at each occurrence is independently hydrogen, C1-8alkyl, 4- to 6-membered heterocyclyl, or C3-8 cycloalkyl; R13at each occurrence is independently hydrogen or C1-6alkyl; R14at each occurrence is independently C1-6alkyl; R15at each occurrence is independently C1-6alkyl or C1-6haloalkyl; 5 R16at each occurrence is independently hydrogen or C1-6alkyl; R17at each occurrence is independently hydrogen or C(O)-C1-6alkyl; R18at each occurrence is independently hydrogen or C1-6alkyl; R19at each occurrence is independently hydrogen or C1-6alkyl; R20at each occurrence is independently hydrogen or C1-6alkyl; R21at each occurrence is independently C1-6alkyl or benzyl; R22at each occurrence is independently hydrogen or C1-6alkyl; R23at each occurrence is independently halogen, OH, CN, C1-6alkyl, C1-6alkyl-OR9, C3-6cycloalkyl, C1-6haloalkyl, O-C1-6alkyl, or O-C1-6haloalkyl; Raat each occurrence is independently hydrogen or C1-8alkyl, or C(O)OR21; Rbat each occurrence is independently hydrogen or C1-6alkyl; Rcat each occurrence is independently hydrogen or C1-6alkyl; Rdat each occurrence is independently hydrogen or C1-6alkyl; m is 0, 1, 2, 3, or 4; and n is 0, 1, or 2. This aspect, as well as any other pertinent aspect, of the disclosure encompasses any compound of formula (I)-(VII), (II-1)-(II-5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), including any compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, provided that certain compounds that have already been disclosed in any of the patent references listed in the background section are excluded. In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound according to any embodiments of formulas (I)-(VII), (II-1)-(II-5), (III- 1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides use of a compound according to any embodiments of formulas (I)-(VII), (II-1)-(II-5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof. In another aspect, the present disclosure provides use of a pharmaceutical composition comprising a compound according to any one of the embodiments of formula (I)- (VII), (II-1)-(II-5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof. In another aspect, the present disclosure provides a method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any embodiments of formulas (I)-(VII), (II-1)-(II-5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound according to any embodiments of formulas (I)-(VII), (II-1)-(II-5), (III- 1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides use of a compound according to any embodiments of formulas (I)-(VII), (II-1)-(II-5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII- 1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a disease or condition selected from neurodegenerative disorders, metabolic ailments, cardiovascular disease, inflammatory syndromes, autoinflammatory diseases, cancers, and hereditary diseases. In some embodiments, in the disease or condition treatable by the NLRP3 inhibitors disclosed, the neurodegenerative disorder is Parkinson’s disease or Alzheimer’s disease; the

[0003] metabolic ailment is type 2 diabetes, the cardiovascular ailment is atherosclerosis; the inflammatory disease is gout flares, osteoarthritis, ulcerative colitis, or Crohn’s disease; the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis; the cancer is lung cancer; and the hereditary disease is Cryopyrin-associated periodic syndrome. In another aspect, the present disclosure provides the methods and processes for preparation of the compounds according to any embodiments of formulas (I)-(VII), (II-1)-(II- 5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt thereof. Other aspects and advantages will be better understood in view of the detailed description, examples, and claims that follow. DETAILED DESCRIPTION OF THE DISCLOSURE The present disclosure provides novel substituted pyridazine compounds and analogues as therapeutic agents for treating diseases or disorders associated with modulation of cytokines such as IL-1β and IL-18, modulation of NLRP3, or inhibition of the activation of NLRP3 or related components of the inflammatory process. In one aspect, the present disclosure provides a compound of formula (I): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, phenyl, or C3-6cycloalkyl; X is NR5, S, O, or CR6R7; Y is a bond or CHR7; W is H or C1-6alkyl; R1at each occurrence is independently selected from H, oxo (=O), halogen, NO2, C1-8alkyl, CN, C1-8alkyl-CN, OR9, C1-8alkyl-OR10, NRaRb, C1-8alkyl-NRaRb, C(O)OR11, C1-8alkyl- 8 C(O)OR12, C1-8alkyl-O-C1-6alkylene-C(O)OR12, NHC(O)R13, C(O)NH-C1-8alkylene-OR9, C(O)NRcRd, C(O)NHR11, -C(O)-C1-8alkylene-NRaRb, -C(O)O-C1-8alkylene-NRcRd, -C(O)-C1-8alkylene-C(O)NRcRd, -C(O)-C1-8alkylene-OR11, C1-8alkyl-C(O)NRcRd, C1-8alkyl- OC(O)NRcRd, and C1-8alkyl-S(O)2R14, provided that R1is not oxo (=O) when A is phenyl or 5- to 6-membered heteroaryl; wherein two adjacent R1together with the atoms in Ring A to which they are attached form a 5- or 6-membered carbocyclyl or heterocyclyl group optionally substituted by one, two, or three substituents independently selected from halogen, CN, OH, C1-6alkyl, C1-6haloalkyl, O-C1-6alkyl, O-C1-6haloalkyl, and oxo (=O); R2is H, OH, -C1-4alkyl, or -C1-4alkyl-O-C1-4alkyl; R3at each occurrence is independently selected from H, halogen, OH, CN, C1-6alkyl, C1-6haloalkyl, O-C1-6alkyl, C1-6alkyl-OR9, O-C1-6haloalkyl, S(O)2NRcRd, S(O)2R15, C3-6cycloalkyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl; or alternatively, sometimes preferably when both R2and R4are H, two adjacent R3together with the carbon atoms in the phenyl ring to which they are attached form a 5-membered heteroaryl or 5- membered heterocyclyl fused to the phenyl ring, wherein the fused 5-membered heteroaryl or 5-membered heterocyclyl is optionally substituted by one, two, or three substituents independently selected from R23; R4is H, -C1-6alkyl, or -C1-4alkyl-O-C1-4alkyl, provided that when W is H, then R4is not H; R5at each occurrence is independently H, C1-8alkyl, -C(O)-C1-6alkyl, or -C(O)-OC1-6alkyl; R6at each occurrence is independently H, OR16, or NHR17; R7at each occurrence is independently H, C1-6alkyl, or OR16; or alternatively when X is CR6R7, R6and R7together may form oxo (=O); R8is independently selected from H, C1-6alkyl, CN, C1-6alkyl-CN, C1-6alkyl-OR10, -6- - or alternatively, R5and R8together with the carbon and nitrogen atoms between them form a 5- or 6-membered heterocyclyl ring optionally comprising one additional heteroatom selected from N, O, and S; or alternatively, R6and R8together with the carbon atoms between them form a 5- or 6-membered carbocyclyl or heterocyclyl ring comprising one or two heteroatoms independently selected from N, O, and S; wherein the heterocyclyl formed between R5and R8and carbocyclyl or heterocyclyl formed between R6and R8are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O-C1-4haloalkyl, and oxo (=O). R9at each occurrence is independently hydrogen or C1-6alkyl; R10at each occurrence is independently hydrogen, C1-6alkyl, benzyl, or C(O)N(RcRd); R11at each occurrence is independently hydrogen, C1-8alkyl or C3-8cycloalkyl each optionally substituted by one, two, or three substituents independently selected from OR9and N(RcRd); R12at each occurrence is independently hydrogen, C1-8alkyl, 4- to 6-membered heterocyclyl, or C3-8cycloalkyl; R13at each occurrence is independently hydrogen or C1-6alkyl; R14at each occurrence is independently C1-6alkyl; R15at each occurrence is independently C1-6alkyl or C1-6haloalkyl; R16at each occurrence is independently hydrogen or C1-6alkyl; R17at each occurrence is independently hydrogen or C(O)-C1-6alkyl; R18at each occurrence is independently hydrogen or C1-6alkyl; R19at each occurrence is independently hydrogen or C1-6 alkyl; R20at each occurrence is independently hydrogen or C1-6alkyl; R21at each occurrence is independently C1-6alkyl or benzyl; R22at each occurrence is independently hydrogen or C1-6alkyl; R23at each occurrence is independently halogen, OH, CN, C1-6alkyl, C1-6alkyl-OR9, C3-6cycloalkyl, C1-6haloalkyl, O-C1-6alkyl, or O-C1-6haloalkyl; Raat each occurrence is independently hydrogen or C1-8alkyl, or C(O)OR21; Rbat each occurrence is independently hydrogen or C1-6alkyl; Rcat each occurrence is independently hydrogen or C1-6alkyl; Rdat each occurrence is independently hydrogen or C1-6alkyl; m is 0, 1, 2, 3, or 4; and n is 0, 1, or 2; provided that the compounds of formulas (A), (A-1), (B), (B-1), and (C) as defined or individually listed below are excluded: , wherein: m is 1 or 2; R1ais H, CH3, isopropyl, or cyclopropyl; R1is H, OH, =O, or CH3; R2is OH; R3ais H, F, CN, CH3, or CF3; R3is H or F; R4is H or CH3; R7is H, OH, or OCH3; R7is H, CH3, OH, or OCH3; R8is H or CH3; and W is H or CH3; m is 1, 2, or 3; n is 1 or 2; R1ais H, CH3, CH2CH3, CH(CH3)2, CH2CH2F, CH2CF3, CH2CH2OH, or CH2C(CH3)2OH; R1is H, CO2H, OH, =O, CH3, CF3, or F; R2is OH; R3ais H, F, Cl, CN, CH3, CF3; CH2CH3, CO2H, OCF3, or cyclopropyl; R3is H or CH3; R4is H or CH3; R5is H or CH3; R8is H, CH3, CN, CH2OH, or CF3; and wherein: W is CH3; R8is H or CH3; and R1ais CH2CH2NH2, CH2CH2NHBoc, C(O)CH2NH2, C(O)CH2NHBoc, CO2But, CH2CO2H, CH2CO2But, CH2CH2CO2H, CH2CH2CO2Et, CH2C(CH3)2CO2H, or CH2C(CH3)2CO2CH3; , wherein: R1ais CH3; R2is OH; R3ais H, F, CN, or CF3; R4is H or CH3; R8is H or CH3; and W is H or CH3; and , In some embodiments, the compound of formula (I) is selected from: or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a ring structure selected from phenyl, pyridinyl, pyrazolyl, imidazolyl, piperidinyl, piperazinyl, cyclobutyl, cyclopentyl, and cyclohexyl; and W, m, n, and R1through R8are each as defined in formula (I). In some embodiments, in the compound of any of the formulas (I)-(VII), or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof: X is NR5, S, or CHR6; Y is a bond or CHR7; W is H or C1-4alkyl; m is 0, 1, 2, or 3; and n is 0, 1, or 2. R1at each occurrence is independently selected from H, oxo (=O), halogen, NO2, C1-6alkyl, CN, C1-6alkyl-CN, OR9, C1-6alkyl-OR10, NRaRb, C1-6alkyl-NRaRb, C(O)OR11, C1-8alkyl-C(O)OR12, C1-6alkyl-O-C1-4alkylene-C(O)OR12, NHC(O)R13, C(O)NH-C1-6alkylene- OR9, C(O)NRcRd, C(O)NHR11, -C(O)-C1-6alkylene-NRaRb, -C(O)O-C1-8alkylene-NRcRd, - C(O)-C1-6alkylene-C(O)NRcRd, -C(O)-C1-6alkylene-OR11, C1-8alkyl-C(O)NRcRd, C1-6alkyl- OC(O)NRcRd, and C1-6alkyl-S(O)2R14, provided that R1is not oxo (=O) when A is phenyl or 5- to 6-membered heteroaryl; wherein two adjacent R1together with the atoms in Ring A to which they are attached form a 5- or 6-membered carbocyclyl or heterocyclyl group optionally substituted by one, two, or three substituents independently selected from halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O-C1-4haloalkyl, and oxo (=O); R2is H, OH, CH3, or CH2OCH3; R3at each occurrence is independently selected from H, halogen, OH, CN, C1-4alkyl, C3-6cycloalkyl, C1-4haloalkyl, C1-4alkyl-OR9, O-C1-4alkyl, O-C1-4haloalkyl, S(O)2NRcRd, S(O)2R15, 5-membered heteroaryl, and 5-membered heterocyclyl; or alternatively, sometimes preferably when both R2and R4are H, two adjacent R3together with the carbon atoms in the phenyl ring to which they are attached form a 5-membered heteroaryl fused to the phenyl ring, wherein the fused 5-membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from R23; R4is H, CH3, or -C1-4alkyl-O-C1-4alkyl, provided that when W is H, then R4is not H; R5at each occurrence is independently H or C1-6alkyl; R6is H, OR16, or NHR17; R7is H, C1-4alkyl, or OR16; R8is independently selected from H, C1-4alkyl, CN, C1-4alkyl-CN, C1-4alkyl-OR10, C(O)OR18, C1-4alkyl-C(O)OR19, CON(RcRd), C1-4alkyl-NRcRd, C1-4 alkyl-OC(O)N(RcRd), C1-4alkyl-C(O)N(RcRd), C1-4alkyl-NHC(O)R20, C1-4alkyl-NHC(O)OR21, C1-4alkyl- NHC(O)N(RcRd), C1-4alkyl-NHC(=N-R22)N(RcRd), C(O)-NHC(O)N(RcRd), C(O)-NHC(=N- R22)N(RcRd), and C1-4alkyl-S(O)2NRcRd; or alternatively, R5and R8together with the carbon and nitrogen atoms between them form a 6-membered heterocyclyl ring optionally comprising one additional heteroatom selected from N, O, and S; or alternatively, R6and R8together with the carbon atoms between them form a 6-membered carbocyclyl or heterocyclyl ring comprising a heteroatom selected from N, O, and S; wherein the heterocyclyl formed between R5and R8and carbocyclyl or heterocyclyl formed between R6and R8are each optionally substituted by one, two or three substituents independently selected from halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O-C1-4haloalkyl, and oxo (=O); R9at each occurrence is independently hydrogen or C1-4alkyl; R10at each occurrence is independently hydrogen, C1-4 alkyl, benzyl, or C(O)N(RcRd); R11at each occurrence is independently hydrogen, C1-6 alkyl or C3-6 cycloalkyl each optionally substituted by one, two, or three substituents independently selected from OR9and N(RcRd); R12at each occurrence is independently hydrogen, C1-6alkyl, or C3-6cycloalkyl; R13at each occurrence is independently hydrogen or C1-4alkyl; R14at each occurrence is independently C1-4alkyl; R15at each occurrence is independently C1-4alkyl or C1-4haloalkyl; R16at each occurrence is independently hydrogen or C1-4alkyl; R17at each occurrence is independently hydrogen or C(O)-C1-4alkyl; R18at each occurrence is independently hydrogen or C1-4alkyl; R19at each occurrence is independently hydrogen or C1-4alkyl; R20at each occurrence is independently hydrogen or C1-4alkyl; R21at each occurrence is independently C1-4alkyl or benzyl; R22at each occurrence is independently hydrogen or C1-4alkyl; R23at each occurrence is independently halogen, OH, CN, C1-4alkyl, C1-4alkyl-OR9, C3-6cycloalkyl, C1-4haloalkyl, O-C1-4alkyl, or O-C1-4haloalkyl; Raat each occurrence is independently hydrogen or C1-6alkyl, or C(O)OR21; Rbat each occurrence is independently hydrogen or C1-4alkyl; Rcat each occurrence is independently hydrogen or C1-4alkyl; and Rdat each occurrence is independently hydrogen or C1-4alkyl. In these embodiments, the aforementioned provisos are applicable where appropriate. In some embodiments, in the compound of any of the formulas (I)-(VII), or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof: X-Y is selected from , and ; W is H or CH3; n is 1 or 2; m is 1, 2, or 3; R1at each occurrence is independently selected from H, CH3, OH, =O, NH2, NHCOCH3, CH2OH, CH2OCONH2, CH2CH2CH2OH, CH2CO2H, CH2CH2CO2H, CO2H, CO2CH3, CO2Et, CO2iPr, CH2CN, CH2CH2CN, CH2CH2CH2CN, CH2CONH2, CH2CH2CONH2, CH2CH2CH2CONH2, CH2CO2CH3, CH2CO2Et, CH2CH2CO2CH3, CH2CH2CO2Et, CH2CH2CO2CH2CH2CH3, CH2CH2CO2CH2(CH2)2CH3, CH2CH2CO2iPr, CH2CH2CO2But, CH2CH2CO2-cyclobutyl, CH2(CH2)2CO2H, CH2(CH2)2CO2CH3, CH2(CH2)2CO2Et, CH2(CH2)3CO2H, CH2(CH2)3CO2CH3, CH2(CH2)3CO2Et, CH2(CH2)4CO2H, CH2(CH2)4CO2CH3, CH2(CH2)4CO2Et, CH2(CH2)5CO2H, CH2(CH2)5CO2CH3, CH2(CH2)5CO2Et, CH(CH3)CH2CO2H, CH(CH3)CH2CO2CH3, CH(CH3)CH2CO2Et, CH2CH(CH3)CO2H, CH2CH(CH3)CO2CH3, CH2CH(CH3)CO2Et, CH2CH(CH3)CH2CH2CO2H, CH2CH(CH3)CH2CH2CO2CH3, CH2CH(CH3)CH2CH2CO2Et, CH2C(CH3)2CO2H, CH2C(CH3)2CO2CH3, CH2C(CH3)2CO2Et, CH2CH2OCH2CO2H, CH2CH2CONHEt, CH2CH2CONHBut, CH(CH3)CO2H, CH(CH3)CO2Et, CON(CH3)2, CONHCH3, CONHCH2CH2OH, CO2CH2CH2OH, CO2CH2CH2CH2OH, CO2CH2(CH2)3OH, CO2CH2(CH2)4OH, CO2CH2CH(OH)CH2OH, CO2CH(CH2OH)2, CO2CH2CH2NH2, CO2CH(CH2NH2)2, CH2CH2SO2CH3, CO2But, CO2CH2CH2CH2C(O)NH2, CO2CH2C(O)NH2, CO2CH2C(O)NHCH3, CO2-cyclopentyl-NH2, CH2CH2NH2, and CH2CH2OH, and - C(CH3)2OH; R2is H or OH; R3is selected from halogen, OH, -CF3, -CH3, -CH2CH3, isopropyl, cyclopropyl, -OCF3, CF3S O -OCHF2, -OCH3, -CH2OH, , O , and ; or alternatively, sometimes preferably when both R2and R4are H, two adjacent R3together with the carbon atoms in the phenyl ring to which they are attached form a pyrrole ring fused to the phenyl ring, wherein the fused pyrrole ring is optionally substituted by one or two substituents independently selected from R23; R4is H, CH3, or CH2OCH3, provided that when W is H, then R4is not H; R5at H or C(O)CH3; R6is H, OH, NH2, or NHC(O)CH3; R7is H, CH3, or OH; and R8is selected from H, -CN, -CO2H, -CONH2, -CH2NH2, -CH2OH, -CH2CH2CO2CH3, - - R23at each occurrence is independently halogen, OH, CN, -CF3, -CH3, -CH2CH3, isopropyl, cyclopropyl, -OCF3, -OCHF2, -OCH3, or -CH2OH. In these embodiments, the aforementioned provisos are applicable where appropriate. In some embodiments, the present disclosure provides a compound of formula (II): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or piperidinyl; R5is H, C1-6alkyl, or C(O)-C1-4alkyl; and m, n, W, R1to R4, and R8are each independently as defined in any one of the foregoing embodiments of formula (I) or formula (II). In some embodiments, the present disclosure provides a compound of formula (II- 1): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: W is H or C1-4alkyl; n is 1 or 2; m is 1, 2, or 3; R1ais selected from H, C1-4alkyl, C1-6alkyl-OR10, C1-6alkyl-NRaRb, C(O)OR11, C1-8alkyl-C(O)OR12, C1-6alkyl-O-C1-4alkylene-C(O)OR12, C1-8alkyl-C(O)NRcRd, C1-6alkyl-CN, C(O)NRcRd, and C(O)NHR11; R1at each occurrence is independently selected from H, C1-4alkyl, OH, =O, CN, NRaRb, NHC(O)R13, C1-4alkyl-OR10, C1-4alkyl-OC(O)NRcRd, C1-8alkyl-C(O)OR12, C(O)OR11, C1-6alkyl-CN, C1-4alkyl-C(O)NRcRd, C(O)NRcRd, C(O)NHR11, C(O)NH-C1-4alkylene-OR9, - C(O)-C1-4alkylene-OR11, -C(O)-C1-4alkylene-NRaRb, CO2CH(CH2NH2)2, -C(O)-C1-4alkylene- C(O)NRcRd, CO2-cyclopentyl-NH2, and C1-4alkyl-S(O)2R14; or alternatively, R1aand an adjacent R1together with the nitrogen and carbon atoms to which they are attached form a 6-membered heterocyclyl optionally substituted by one, two or three substituents independently selected from halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O- C1-4alkyl, O-C1-4haloalkyl, and oxo (=O); R2is H or OH; R3at each occurrence is independently selected from H, halogen, OH, CN, C1-4alkyl, C1-4haloalkyl, C3-6cyclopropyl, O-C1-4alkyl, O-C1-4haloalkyl, C1-4alky9 d, S(O)2R15, and 5-membered heteroaryl; or alternatively, sometimes prefe ra y w en ot R2and R4are H, two adjacent R3together with the carbon atoms in the phenyl ring to which they are attached form a pyrrole ring fused to the phenyl ring, wherein the fused pyrrole ring is optionally substituted by one or two substituents independently selected from R23; R4is H, C1-4alkyl, or CH2OCH3, provided that when W is H, then R4is not H; R5is H, C1-4alkyl, or -C(O)-C1-4alkyl; R8is selected from H, C1-4alkyl, CN, C1-4alkyl-CN, C1-4alkyl-OR10, C(O)OR18, C1-4alkyl-C(O)OR19, CON(RcRd), C1-4alkyl-NRcRd, C1-4alkyl-OC(O)N(RcRd), C1-4alkyl- C(O)N(RcRd), C1-4alkyl-NHC(O)R20, C1-4alkyl-NHC(O)OR21, C1-4alkyl-NHC(O)N(RcRd), C1-4alkyl-NHC(=N-R22)N(RcRd), C(O)-NHC(O)N(RcRd), C(O)-NHC(=N-R22)N(RcRd), and - CH2S(O)2NRcRd; or alternatively, R5and R8together with the nitrogen and carbon atoms between them form a 6-membered heterocyclyl optionally substituted by one, two or three substituents independently selected from halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O-C1-4haloalkyl, and oxo (=O); R9at each occurrence is independently hydrogen or C1-4alkyl; R10at each occurrence is independently hydrogen, C1-4alkyl, benzyl, or C(O)N(RcRd); R11at each occurrence is independently hydrogen, C1-6alkyl or C3-6cycloalkyl each optionally substituted by one, two, or three substituents independently selected from OR9and N(RcRd); R12at each occurrence is independently hydrogen, C1-6alkyl, or C3-6cycloalkyl; R13at each occurrence is independently hydrogen or C1-4alkyl; R14at each occurrence is independently C1-4alkyl; R15at each occurrence is independently C1-4alkyl or C1-4haloalkyl; R18at each occurrence is independently hydrogen or C1-4alkyl; R19at each occurrence is independently hydrogen or C1-4alkyl; R20at each occurrence is independently hydrogen or C1-4alkyl; R21at each occurrence is independently C1-4alkyl or benzyl; R22at each occurrence is independently hydrogen or C1-4alkyl; R23at each occurrence is independently halogen, OH, CN, C1-4alkyl, C1-4alkyl-OR9, C3-5cycloalkyl, C1-4haloalkyl, O-C1-4alkyl, and O-C1-4haloalkyl; Raat each occurrence is independently hydrogen or C1-6alkyl, or C(O)OR21; Rbat each occurrence is independently hydrogen or C1-4alkyl; Rcat each occurrence is independently hydrogen or C1-4alkyl; and Rdat each occurrence is independently hydrogen or C1-4alkyl. In some embodiments, the present disclosure provides a compound of formula (II- 2): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: R1ais selected from H, CH3, CH2CH3, -CH2-cyclopropyl, CH2CO2H, CH2CO2CH3, CH2CO2Et, CH2CH2CO2H, CH2CH2CO2CH3, CH2CH2CO2Et, CH2CH2CO2CH2CH2CH3, CH2CH2CO2CH2(CH2)2CH3, CH2CH2CO2iPr, CH2CH2CO2But, CH2CH2CO2-cyclobutyl, CH2(CH2)2CO2H, CH2(CH2)2CO2CH3, CH2(CH2)2CO2Et, CH2(CH2)3CO2H, CH2(CH2)3CO2CH3, CH2(CH2)3CO2Et, CH2(CH2)4CO2H, CH2(CH2)4CO2CH3, CH2(CH2)4CO2Et, CH2(CH2)5CO2H, CH2(CH2)5CO2CH3, CH2(CH2)5CO2Et, CH(CH3)CH2CO2H, CH(CH3)CH2CO2CH3, CH(CH3)CH2CO2Et, CH2CH(CH3)CO2H, CH2CH(CH3)CO2CH3, CH2CH(CH3)CO2Et, CH2CH(CH3)CH2CH2CO2H, CH2CH(CH3)CH2CH2CO2CH3, CH2CH(CH3)CH2CH2CO2Et, CH2C(CH3)2CO2H, CH C CH CO CH CH C CH CO E CH CH OCH CO H CH CH CONHEt, R1at each occurrence is independently selected from H, CO2H, CO2CH3, CO2Et, CO2iPr, CO2But, CH2CONH2, CONHCH3, CON(CH3)2, CONHCH2CH2OH, CO2CH2CH2NH2, CO2CH2CH2OH, CO2CH(CH2OH)2, CO2CH2CH2CH2OH, CO2CH2CH2CH2CH2OH, CO2CH2CH2CH2CH2CH2OH, CO2CH2CH(OH)CH2OH, CO2CH(CH2NH2)2, CO2CH2CH2CH2C(O)NH2, CO2CH2C(O)NH2, CO2CH2C(O)NHCH3, CO2-cyclopentyl-NH2, CH2OH, C(CH3)2OH, CH(CH3)CO2H, CH(CH3)CO2CH3, CH(CH3)CO2Et, CH2CO2H, CH2CO2CH3, CH2CO2Et, and CH2OCONH2; R3is CF3, CH3, CH2CH3, isopropyl, cyclopropyl, CN, OCF3, OCHF2, CH2OH, OCH3, CF3S O CH2OCH3, , O , or ; R4is H, CH3, or CH2OCH3; R5is H, C1-4alkyl, or -C(O)-C1-2alkyl; and R8is selected from H, -CN, -CO2H, -CONH2, -CH2NH2, -CH2OH, -CH2CH2CO2CH3, -CH2NHCOCH3, -CH2NHCOOCH3, -CH2OCONH2, -CH2CH2CO2H, -CH2CH2CONH2, - CH2NH-Cbz, CH2S(O)2NH2, , , , and . In any embodiment of the compounds according to formula (II), (II-1), or (II-2), the compounds of formula (B) or formula (B1) as defined below, to the extent that they have been disclosed in any known references, including the patent references cited in the background section, are excluded: , wherein: m is 1, 2, or 3; n is 1 or 2; R1ais H, CH3, CH2CH3, CH(CH3)2, CH2CH2F, CH2CF3, CH2CH2OH, or CH2C(CH3)2OH; R1is H, CO2H, OH, =O, CH3, CF3, or F; R2is OH; R3ais H, F, Cl, CN, CH3, CF3, CH2CH3, CO2H, OCF3, or cyclopropyl; R3is H or CH3; R4is H or CH3; R5is H or CH3; R8is H, CH3, CN, CH2OH, or CF3; and W is H, F, CF3, or CH3; wherein: W is CH3; R8is H or CH3; and R1ais CH2CH2NH2, CH2CH2NHBoc, C(O)CH2NH2, C(O)CH2NHBoc, CO2But, CH2CO2H, CH2CO2But, CH2CH2CO2H, CH2CH2CO2Et, CH2C(CH3)2CO2H, or CH2C(CH3)2CO2CH3In some embodiments, the present disclosure provides a compound of formula (II- , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Q is O, S, NR5a, or CHR8b, wherein: R5ais hydrogen or C1-4alkyl; R8aand R8bare independently hydrogen, halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, or O-C1-4haloalkyl; and m, n, W, R1a, and R1to R4are each independently as defined in any one of the foregoing embodiments of formula (I), formula (II), or formula (II-1), provided that the compound of formula below, or analogs thereof disclosed in any existing references, including the patent references cited in the background section, are excluded: . In some embodiments, the present disclosure provides a compound of formula (II- 4): ( or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: T is O, S, NR1c, or CHR1b; i is 0, 1, or 2; R1cis hydrogen or C1-4alkyl; R1bat each occurrence is independently hydrogen, halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, or O-C1-4haloalkyl; and m, n, W, R1a, R1to R5, and R8are each independently as defined in any one of the foregoing embodiments of formula (I), formula (II), or formula (II-1). In some embodiments, the compound of Formula (II) or (II-1) has the structure of Formula (II-5): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: j is 0, 1, or 2; R23ais H or C1-4alkyl; R23at each occurrence is independently halogen, OH, CN, -CF3, -CH3, -CH2CH3, isopropyl, cyclopropyl, -OCF3, -OCHF2, -OCH3, or -CH2OH; and W, m, R1a, R1, R2, R4, R5, and R8are each independently as defined in any of the aforementioned embodiments of Formula (I), (II), or (II-1), and sometimes preferably both R2and R4are H, provided that the following compounds are excluded: , . In some embodiments, the present disclosure provides a compound of formula (III): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or piperidinyl; R6is H, OH, C1-4 alkyl, O-C1-4alkyl, or NHR17; and m, n, W, R1to R4, R8, and R17are each independently as defined in any one of the foregoing embodiments of formula (I) or formula (III). In some embodiments, the present disclosure provides a compound of formula (III- 1): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, or 3; W is H or CH3; R1ais selected from H, C1-4alkyl, C1-4alkyl-CN, C1-4alkyl-OR10, C1-4alkyl-NRaRb, C(O)OR11, -CO2H, -C(O)OR12, C(O)NH-C1-4alkylene-OR9, C1-4alkyl-C(O)NRcRd, C1-4alkyl- OC(O)NRcRd, and C1-4alkyl-S(O)2R14; R1at each occurrence is independently selected from H, oxo (=O), C1-4alkyl, OR9, C1-4alkyl-OR10, NRaRb, C1-4alkyl-NRaRb, and C(O)OR11; R2is OH; R3and R3aare independently selected from C1-4alkyl, C1-4haloalkyl, cyclopropyl, O-C1-4alkyl, O-C1-4haloalkyl, S(O)2NRcRd, S(O)2R15, and 5-membered heteroaryl; R4is H or CH2OCH3; R6is H, OH, C1-4alkyl, O-C1-4alkyl, or NHR17; and R8is selected from H, -CN, -CO2H, -C(O)OC1-4alkyl, -CONH2, -CH2NH2, and - CH2OH. In some embodiments, in the compound of formula (III-1), or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: m is 1 or 2; R1ais selected from CH3, CH2OH, CH2CH2CH2OH, CH2CO2H, CH2CH2CO2H, CH2CN, CH2CH2CN, CH2CH2CH2CN, CH2CONH2, CH2CH2CONH2, CH2CH2CH2CONH2, CH2CO2CH3, CH2CH2CO2CH3, CH2CH2CO2Et, CH2CH2CO2iPr, CH2CH2CO2But, CH2CH2CH2CO2CH3, and CH2CH2S(O)2CH3; R1at each occurrence is independently selected from H, OH, =O, NH2, NHCOCH3, CO2H, CO2CH3, and CO2Et; CF R6is H, NH2, or NHC(O)CH3; and R8is H, -CN, -CO2H, -CONH2, or -CH2NH2. In any embodiment of the compounds according to formula (III) or (III-1), the compounds of formula (A-1) as defined below, to the extent that they have been disclosed in any known references, including the patent references cited in the background section, are excluded: wherein: m is 1 or 2; R1ais H, CH3, isopropyl, or cyclopropyl; R1is H, OH, =O, or CH3; R2is H or OH; R3ais H, F, CN, CH3, or CF3; R3is H or F; R4is H or CH3; R6is H, OH, or OCH3, R8is H or CH3; and W is H or CH3. In some embodiments, the present disclosure provides a compound of formula (IV): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl, piperidinyl, or C3-6cycloalkyl; R6at each occurrence is independently H, OR16, or NHR17; R7at each occurrence is independently H, C1-6alkyl, or OR16; and m, n, W, R1to R4, R8, R16, and R17are each independently as defined in any one of the foregoing embodiments of formula (I) or formula (IV). In some embodiments, the present disclosure provides a compound of formula (IV- 1): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: W is H or CH3; R1at each occurrence is independently selected from H, halogen, OH, NH2, CN, NO2, NHCOCH3, CO2H, CO2CH3, and CO2Et, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, and O-C1-4haloalkyl; R2is OH; R3is CF3, OCF3, OCHF2, or OCH3; R4is H or CH2OCH3; R6is H, OH, NH2, NHC(O)CH3; R7is H, OH, or C1-4alkyl; and In some embodiments, the present disclosure provides a compound of formula (IV- 2 or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, or 3; R1ais selected from H, C1-4alkyl, C1-4alkyl-CN, C1-4alkyl-OR10, C1-4alkyl-NRaRb, C(O)OR11, -CO2H, -C(O)OR12, C(O)NH-C1-4alkylene-OR9, C1-4alkyl-C(O)NRcRd, C1-4alkyl- OC(O)NRcRd, and C1-4alkyl-SO2R14; R1at each occurrence is independently selected from H, oxo (=O), C1-4alkyl, OR9, C1-4alkyl-OR10, NRaRb, C1-4alkyl-NRaRb, and C(O)OR11; R7is H or C1-4alkyl; and R8is selected from H, -CN, -CO2H, -C(O)OC1-4alkyl, -CONH2, -CH2NH2, and - CH2OH; and W, R2-R4, R6, R9-R11, Ra, and Rbare each independently as defined in any foregoing embodiment of formula (I) or (IV). In some embodiments, the present disclosure provides a compound of formula (IV- 3): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: j is 1, 2, or 3; m is 0, 1, 2, or 3; R1at each occurrence is independently selected from H, halogen, OH, NH2, CN, NO2, NHCOCH3, CO2H, CO2CH3, and CO2Et, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, and O-C1-4haloalkyl; R2is OH; R3is CF3, OCF3, OCHF2, or OCH3; R4is H or CH2OCH3; R6is H, OH, NH2, NHC(O)CH3; R7is H, OH, or C1-4alkyl; and R8is H, -CN, -CO2H, -CONH2, or -CH2NH2. In some embodiments, the present disclosure provides a compound of formula (V): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or piperidinyl; and m, n, W, R1to R4, and R8are each independently as defined in any one of the foregoing embodiments of formula (I) or formula (V). In some embodiments, the present disclosure provides a compound of formula (V- 1): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, or 3; R1ais selected from H, C1-4alkyl, C1-4alkyl-CN, C1-4alkyl-OR10, C1-4alkyl-NRaRb, C(O)OR11, -CO2H, -C(O)OR12, C1-6alkyl-C(O)OR12, C(O)NH-C1-4alkylene-OR9, C1-4alkyl- C(O)NRcRd, C1-6alkyl-OC(O)NRcRd, and C1-4alkyl-SO2R14; R1at each occurrence is independently selected from H, oxo (=O), C1-4alkyl, OR9, C1-4alkyl-OR10, NRaRb, C1-4alkyl-NRaRb, and C(O)OR11; R8is selected from H, -CN, -CO2H, -C(O)OC1-4alkyl, -CONH2, -CH2NH2, and - CH2OH; and n, W, R2to R4, R9-R12, R14, Ra, Rb, Rc, and Rdare each independently as defined in any one of the foregoing embodiments of formula (I) or formula (V). In some embodiments, the present disclosure provides a compound of formula (VI): , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or piperidinyl; R7is H or C1-4alkyl; and m, n, W, R1to R4, and R8are each independently as defined in any one of the foregoing embodiments of formula (I) or formula (VI). In some embodiments, the present disclosure provides a compound of formula (VI- 1): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, or 3; R1at each occurrence is independently selected from H, halogen, OH, NH2, CN, NO2, NHCOCH3, CO2H, CO2CH3, and CO2Et, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, and O-C1-4haloalkyl; R2is OH; R3is CF3, OCF3, OCHF2, or OCH3; R8is H, -CN, -CO2H, -CONH2, or -CH2NH2; and W, R4, and R7are as defined in any one of the foregoing embodiments of formula (I) or formula (VI) In some embodiments, the present disclosure provides a compound of formula (VII): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or piperidinyl; and m, n, W, R1to R4, and R8are each independently as defined in any one of the foregoing embodiments of formula (I) or formula (VII). In some embodiments, the present disclosure provides a compound of formula (VII- 1): or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, or 3; R1ais selected from H, C1-4alkyl, C1-4alkyl-CN, C1-4alkyl-OR10, C1-4alkyl-NRaRb, C(O)OR11, -CO2H, C1-6alkyl-C(O)OR12, C(O)NH-C1-4alkylene-OR9, C1-6alkyl-C(O)NRcRd, C1-4alkyl-OC(O)NRcRd, and C1-4alkyl-SO2R14; R1at each occurrence is independently selected from H, oxo (=O), C1-4alkyl, OR9, C1-4alkyl-OR10, NRaRb, C1-4alkyl-NRaRb, and C(O)OR11; R8is selected from H, -CN, -CO2H, -C(O)OC1-4alkyl, -CONH2, -CH2NH2, and - CH2OH; and n, W, R2to R4, R9-R12, R14, Ra, Rb, Rc, and Rdare each independently as defined in any one of the foregoing embodiments of formula (I) or formula (VII). In these embodiments, as well as any pertinent embodiments, the compounds of formula (C) below are excluded from the compounds of formula (VII) or formula (VII-1): wherein: R1ais CH3; R2is OH; R3ais H, F, CN, or CF3; R4is H or CH3; R8is H or CH3; and W is H or CH3. In some embodiments, the present disclosure provides a compound selected from List 1, Examples 1 to 382: 9 10 11 50 51 52 110 & 111 (isomers) 112 113

[0004] 42

[0005] , or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound selected from List 2 shown below, based on their superior performance in gut PK in mouse and other measures, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof. . In some embodiments, the present disclosure provides a compound selected from List 3 shown below, based on their superior performance in gut PK in mouse and other measures, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof.

[0006] . In some embodiments, the present disclosure provides a compound selected from List 4 shown below, based on their superior performance in gut PK in mouse and other measures, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof. . In some embodiments, sometimes preferably, the present disclosure provides a list of exemplified compounds as shown in Examples that fall into the definitions of formulas (I)- (VII), (II-1)-(II-5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), respectively, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound according to any one of the embodiments of formulas (I)-(VII), (II-1)- (II-5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides use of a compound according to any one of the embodiments of formulas (I)-(VII), (II-1)-(II-5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof. In another aspect, the present disclosure provides use of a pharmaceutical composition comprising a compound according to any one of the embodiments of formulas (I)- (VII), (II-1)-(II-5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof. In another aspect, the present disclosure provides a method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any embodiment of formulas (I)-(VII), (II-1)-(II-5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound according to any embodiment of formulas (I)-(VII), (II-1)-(II-5), (III- 1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the disease or condition treatable by the NLRP3 inhibitors disclosed is a neurodegenerative disorder, a metabolic ailment, a cardiovascular ailment, an inflammatory syndrome, an autoinflammatory disease, a cancer, or a hereditary disease. In some embodiments, in the disease or condition treatable by the NLRP3 inhibitors disclosed, the neurodegenerative disorder is Parkinson’s disease or Alzheimer’s disease; the metabolic ailment is type 2 diabetes, the cardiovascular ailment is atherosclerosis; the inflammatory disease is gout flares, osteoarthritis, ulcerative colitis, or Crohn’s disease; the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis; the cancer is lung cancer; and the hereditary disease is Cryopyrin-associated periodic syndrome. In another aspect, the present disclosure provides use of a compound according to any one of embodiment of formulas (I)-(VII), (II-1)-(II-5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, or a stereoisomer, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a disease or condition selected from neurodegenerative disorders, metabolic ailments, cardiovascular disease, inflammatory syndromes, autoinflammatory diseases, cancers, and hereditary diseases. In some embodiments, in the disease or condition treatable by the NLRP3 inhibitors disclosed, the neurodegenerative disorder is Parkinson’s disease or Alzheimer’s disease; the metabolic ailment is type 2 diabetes, the cardiovascular ailment is atherosclerosis; the inflammatory disease is gout flares, osteoarthritis, ulcerative colitis, or Crohn’s disease; the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis; the cancer is lung cancer; and the hereditary disease is Cryopyrin-associated periodic syndrome. In some embodiments, the disease or condition is an inflammatory disease selected from gout flares, osteoarthritis, ulcerative colitis, and Crohn’s disease. In some embodiments, the disease or condition is a metabolic ailment selected from type 2 diabetes or atherosclerosis. In some embodiments, the disease or condition is an autoinflammatory disease selected from multiple sclerosis or rheumatoid arthritis. In some embodiments, the disease or condition is a cancer, which is lung cancer. In some embodiments, the disease or condition is a hereditary disease, which is Cryopyrin-associated periodic syndrome. In another aspect, the present disclosure provides the methods and processes for preparation of the compounds according to any embodiments of formulas (I)-(VII), (II-1)-(II- 5), (III-1), (IV-1)-(IV-3), (V-1), (VI-1), or (VII-1), or a compound selected from List 1, List 2, List 3, and List 4, or a stereoisomer, or a stereoisomer, a tautomer, an isotopic derivative, a pharmaceutically acceptable salt thereof. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The term “alkyl" refers to a branched or unbranched monovalent aliphatic hydrocarbon radical derived from an alkane containing 1 to 12 carbon atoms by removal of one hydrogen atom. In certain embodiments, an alkyl group contains 1 to 10 carbons. In certain embodiments, an alkyl group contains 1 to 8 carbons. In certain embodiments, sometimes preferably, an alkyl group contains 1 to 6 carbons, and in certain embodiments, sometimes more preferably, an alkyl group contains 1 to 4 carbons. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl, or the like, and their isomeric counterparts. The alkyl group can be substituted or unsubstituted. The term “alkenyl” refers to any univalent aliphatic hydrocarbon radical derived from an alkene containing 2 to 12 carbons by removal of one hydrogen atom. In certain embodiments, an alkenyl group contains 2 to 12 carbons. In certain embodiments, an alkenyl group contains 2 to 8 carbons. In certain embodiments, sometimes preferably, an alkenyl group contains 2 to 6 carbons, and in certain embodiments, sometimes more preferably, an alkenyl group contains 2 to 4 carbons. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, or the like, and their isomeric counterparts. The alkenyl group can be substituted or unsubstituted. The term “alkynyl" refers to a univalent aliphatic hydrocarbon radical derived from an alkyne containing 2 to 12 carbon atoms by removal of one hydrogen atom. In certain embodiments, an alkynyl group contains 2 to 10 carbons. In certain embodiments, an alkynyl group contains 2 to 8 carbons. In certain embodiments, sometimes preferably, an alkynyl group contains 2 to 6 carbons, and in certain embodiments, sometimes more preferably, an alkynyl group contains 2 to 4 carbons. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, or the like, and their isomeric counterparts. The alkynyl group can be substituted or unsubstituted. The term “carbocyclyl” refers to any monocyclic or polycyclic ring radical with a nonaromatic hydrocarbon ring bonding to the rest of molecular moiety. A carbocyclyl can include a bicyclic, tricyclic, or polycyclic ring system in which two adjacent rings can share a pair of atoms (fused ring system) or share a single carbon atom (spiro system), wherein any of the rings can have any degree of saturation. A carbocyclyl can comprise a conjugated pi- electron ring system, either aryl or heteroaryl, or a non-aromatic heterocyclic ring, but the ring bonding to the rest of molecular moiety is a non-aromatic hydrocarbon ring. A “carbocyclyl” group may contain 4 to 14 ring member atoms, sometimes preferably 5 to 10 ring member atoms, and sometimes more preferably 5 to 6 ring member atoms. The carbocyclyl may be substituted or unsubstituted. The term "cycloalkane" refers to a cyclic saturated hydrocarbon. In certain embodiments, a cycloalkane contains 3 to 12 ring carbons. In certain embodiments, a cycloalkane contains 3 to 8 ring carbons. In certain embodiments, sometimes preferably, cycloalkane contains 3 to 6 ring carbons. Examples of cycloalkanes include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or the like. The cycloalkane may be substituted or unsubstituted. The term "cycloalkyl" refers to a univalent radical formed by removal of one hydrogen atom from a cycloalkane. In certain embodiments, cycloalkyl group contains 3 to 12 carbons. In certain embodiments, cycloalkyl group contains 3 to 8 carbons. In certain embodiments, sometimes preferably, cycloalkyl group contains 3 to 6 carbons. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. The cycloalkyl can be substituted or unsubstituted. The term " " refers to a monocyclic or polycyclic ring radical containing at least one non-aromatic ring comprising 1 to 4, sometimes preferably 1 to 3, and sometimes preferably 1 or 2, heteroatoms independently selected from N, O, and S and said non-aromatic heterocyclic ring radical bonding to the rest of molecular moiety. A heterocyclyl can include a bicyclic, tricyclic, or polycyclic ring system in which two adjacent rings can share a pair of atoms (fused ring system) or share a single carbon atom (spiro system), wherein any of the rings can have any degree of saturation. A heterocyclyl can comprise a conjugated pi-electron ring system, either aryl or heteroaryl, or a non-aromatic hydrocarbon ring, but the ring bonding to the rest of molecular moiety is a non-aromatic heterocyclic ring. The heterocyclyl can have 3 to 14, sometimes preferably 3 to 10, sometimes preferably 5 to 10, and sometimes preferably 5 to 6, ring atoms (i.e., the number of atoms constituting the ring skeleton, including the number of carbon atoms and heteroatoms). Sometimes a heterocyclyl group may preferably be a 3-, 4-, 5-, 6-, or 7-membered monocyclic group, and sometimes a heterocyclyl may preferably be an 8-, 9, or 10-membered bicyclic group. Examples of heterocyclyl include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thietanyl, piperidinyl, piperazinyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathianyl, 1,4- oxathianyl , 2H-1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinone, oxazolidinone, thiazolidinyl, 1,3-oxathiolyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl and tetrahydroquinolinyl. The term “alkylene” refers to a saturated linear or branched divalent aliphatic hydrocarbon group, derived by removing two hydrogen atoms the parent alkane containing 1 to 12 carbon atoms (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 carbon atom(s)), sometimes preferably 1 to 8 carbon atom(s), sometimes more preferably 1 to 6 carbon atom(s), and sometimes more preferably 1 to 4 carbon atom(s). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (- CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2- propylene (-CH2CH(CH3)-), 1,3-propylene (- CH2CH2CH2-), 1,4-butylidene (-CH2CH2CH2CH2-), etc. The alkylene group can be substituted or unsubstituted. The term “alkenylene” refers to an alkylene containing 2 to 12 carbon atoms defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, preferably C2-10alkenylene, more preferably C2-8alkenylene, sometimes more preferably C2-6alkenylene, and sometimes even more preferably C2-4alkenylene. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, - CH2CH=CHCH2- etc. The alkenylene group can be substituted or unsubstituted. The term “aryl” refers to a 6 to 14 membered monocyclic ring or polycyclic ring radical having an aromatic hydrocarbon ring bonding to the rest of molecular moiety. The aryl can comprise another aromatic or non-aromatic carbocyclic or heterocyclic ring fused with an aromatic hydrocarbon ring, but the ring bonding to the rest of molecular moiety is the aromatic hydrocarbon ring. Preferably, aryl is 6 to 10 membered, such as phenyl and naphthyl, sometimes more preferably phenyl. The aryl group can be substituted or unsubstituted. The term “heteroaryl” refers to a 5 to 14 membered monocyclic or polycyclic ring radical having 1 to 4, sometimes preferably 1 to 3, sometimes more preferably 1 or 2, heteroatom(s) independently selected from O, S and N in an aromatic ring bonding to the rest of molecular moiety. A heteroaryl can comprise one or more aromatic or non-aromatic carbocyclic or heterocyclic ring fused with an aromatic heterocyclic ring, but the ring bonding to the rest of molecular moiety is an aromatic heterocyclic ring. Preferably a heteroaryl is 5- to 10- membered (such as 5, 6, 7, 8, 9 and 10 membered), more preferably 5- or 6- membered, for example, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, benzothienyl, and the like. The heteroaryl group can be substituted or unsubstituted. The term “alkoxy” refers to both an -O-(alkyl), for example, methoxy, ethoxy, propoxy, butoxy, and the like. The term “cycloalkoxy” refers to -O-(cycloalkyl), for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The term “bond” refers to a covalent bond using a sign of “ ”. The term “hydroxyl” refers to an -OH group. The term “halogen” or “halo” refers to fluoro, chloro, bromo or iodo atoms, sometimes preferably fluoro (F), sometimes preferably chloro (Cl), and sometimes preferably bromo (Br). The term “amino” refers to a -NH2group. The term "alkylthio" refers to alkyl-S-. The term “alkylamino” refers to “alkyl-NH-”, or sometimes dialkyl amino (-NRaRb), where the two alkyl groups (Raand Rb) can be the same or different. Sometimes preferably, the alkyl group is a C1-C6alkyl, and sometimes more preferably, the alkyl is a C1-C4alkyl. Examples of alkylamino include, but are not limited to, CH3-NH-, -N(CH3)2, -N(CH2CH3)2, - NHCH2CH3, -N(CH3)(CH2CH3), -NH-But, -N(CH3)(But), or the like. The term “cyano” refers to a -CN group. The term "haloalkyl" means an alkyl group substituted by one or more halogen atoms, wherein the halogen atoms can be the same or different. The term “nitro” refers to a -NO2group. The term “oxo group” refers to a =O group. The term “carboxyl” refers to a -C(O)OH group. The term “alkoxycarbonyl” refers to a -C(O)O(alkyl) group. The term “alkylcarbonyl” refers to a -C(O)-alkyl group. The term “optional” or “optionally” means that the event or circumstance described subsequently can, but need not, occur, and the description includes the instances in which the event or circumstance may or may not occur. For example, “the heterocyclyl group optionally substituted by an alkyl” means that an alkyl group can be, but need not be, present, and the description includes the case of the heterocyclyl group being substituted with an alkyl and the heterocyclyl group being not substituted with an alkyl. The term “substituted” refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atom(s), independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable. The term “covalent bonding principle”, as used herein, refers to those basic rules and principles in formation of covalent bonds in an organic compound, as generally understood by a person of ordinary skill in the art. For example, a carbon atom is tetravalent and can form only four covalent bonds (e.g., four single bonds, or a double bond plus two single bonds, etc.), an oxygen is divalent and can only form two covalent bonds (two single bond in -O-, or a double bond in =O). In some embodiments, when an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl group, or the like, or a moiety thereof, is substituted, the substituent group(s) can be substituted at any available connection point(s), and the substituents can be one or more, sometimes preferably 1 to 5, and sometimes more preferably 1 to 3, group(s) independently selected from C1-C6alkyl, halogen, C1-C6alkoxy, C1-C6alkenyl, C1-C6alkynyl, C1-C6alkylthio, C1-C6 alkylamino, di-(C1-C6 alkyl)amino, thiol, hydroxyl, nitro, cyano, amino, C3- C6cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, C3- C6 cycloalkoxy, C1-C6 cycloalkylthio, 5- to 10-membered heterocyclylthio and oxo group. In some embodiments, sometimes preferably, the substituents are independently selected from C1-C6alkyl, halogen, C1-C6alkoxy, C1-C6alkylthio, C1-C6alkylamino, di-(C1-C6alkyl)amino, thiol, hydroxyl, nitro, cyano, amino, and oxo group. In some embodiments, sometimes more preferably, the substituents are independently selected from C1-C4alkyl, halogen, C1-C4alkoxy, C1-C4alkylthio, C1-C4alkylamino, di-(C1-C4alkyl)amino, thiol, hydroxyl, nitro, cyano, and amino. As a person of ordinary skill in the art would understand, an oxo (=O) group cannot be a substituent of an aryl or heteroaryl group, or at an unsaturated carbon in any other group. Denotation of carbon atoms or ring atoms in a substituent group, such as alkyl, cycloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, or the like, may take different forms but they should be understood to mean a same thing as would be understood by those skilled in the art. For example, an alkyl group containing 1 to 6 carbon atoms may be denoted as “C1-C6alkyl,” “C1-C6alkyl,” “C1-6alkyl,” “C1-6alkyl,” or the like, which may occur for other substituent groups as well. In the present disclosure, “alkyl” and “alkylene,” “alkenyl” and “alkenylene,” “aryl” and “arylene,” “cycloalkyl” and “cycloalkylene,” or the like, may sometimes be used interchangeably. Thus, interpretation of these terms should be based on the context as would be understood by a person of ordinary skill in the art. For example, when the term “alkyl” appears in an expression such as “-C(O)-C1-6alkyl,” “-C(O)O-C1-6alkyl,” “O-C1-4haloalkyl,” or the like, the term should be interpreted as monovalent alkyl group; however, the term “alkyl” in an expression such as “C1-6alkyl-NRaRb”, “C1-6alkyl-O-C1-4alkyl-C(O)OR12”, “C(O)NH-C1-6alkyl-OR9”, or the like, should be interpreted as a divalent “alkylene”. In addition, some terms sometimes may include a hyphen “-” in the end to indicate a bond, such as “-C(O)-C1-6alkyl”, “-C1-6alkyl-NRaRb”, “-C(O)OH”, or the like, and sometimes may not, such as “C(O)-C1-6alkyl”, “C1-6alkyl-NRaRb”, “C(O)OH”, or the like, but they represent the same groups, respectively, as would be understood by those skilled in the art. As would be understood by those skilled in the art, the present disclosure encompasses any and all possible and reasonable combinations of the embodiments with regards to the structures of compounds disclosed, provided that such combinations would not violate covalent bond principles. The term “isomer,” as used herein, refers to all possible types of isomerism a compound may have, as suitable in the context. They may include stereoisomers, configurational isomers, geometrical isomers, conformational isomers, or the like. The term “stereoisomer” refers to isomers that are structurally identical but differ in the arrangement of the atoms in space, which may or may not by caused by asymmetric (chiral) centers in the structure. It includes enantiomers, diastereomers, atropisomers, or the like, and their respective mixtures. The term “atropisomers” refers to a special type of stereoisomer, i.e., conformational stereoisomers, which result from steric hindrance in a molecule such that rotation about a single bond is hindered or greatly slowed. Some atropisomers could be separated and isolated in a stable form. For example, certain compounds of the present disclosure may exist in the form of a mixture of atropisomers (e.g., an equal ratio mixture, a mixture enriched in one atropisomer) or a purified atropisomer under different conditions. All such stereoisomers and mixtures thereof are encompassed within the scope of the present disclosure, whether a compound is presented as a chiral form or not, whether only one single isomer or multiple isomers are presented. The present disclosure also encompasses cis- / trans- (or Z- / E-) isomers caused by the different configurations of substituents on a double bond, especially C=C, which are sometimes called geometrical isomers. The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term “tautomer” or “tautomeric form” refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form into another. Non-limiting examples include keto-enol tautomerism, imine-enamine tautomerism, or the like. As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. The terms “a” and “an” and “the” and similar references in the present disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like. The term “and / or” as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items. When used in a list of two or more items, the term “and / or” means that any one of the listed items can be employed by itself, or any combination of two or more of the listed items can be employed. A “pharmaceutical composition” refers to a mixture of one or more of the compounds described in the present disclosure or physiologically / pharmaceutically acceptable salts thereof and other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biological activity. The term “pharmaceutically acceptable,” as used herein, refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and are effective for their intended use. “Pharmaceutically acceptable salts” refer to salts of the compounds of the disclosure, such salts being safe and effective when used in a mammal and have corresponding biological activity. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable nitrogen atom with a suitable acid. Pharmaceutically acceptable salts are well known in the art. See, e.g., S. M. Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids. Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen bisulfide as well as organic acids, such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and related inorganic and organic acids. Preferred pharmaceutically acceptable salts include the hydrochloride or hydrobromide salts. Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, and N-methylmorpholine. When it is possible that, for use in therapy, therapeutically effective amounts of a compound of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the disclosure further provides pharmaceutical compositions, which include any compounds of the present disclosure, or pharmaceutically acceptable salts thereof, and one or more, preferably one to three, pharmaceutically acceptable carriers, diluents, or other excipients. The carrier(s), diluent(s), or other excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the subject being treated. In the compounds disclosed herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. For example, substitution with heavier isotopes, such as replacing hydrogen (H) with deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half- life or reduced dosage requirements) and hence may be preferred in some circumstances. In addition, certain isotopically-labeled compounds (e.g., with3H and14C) are useful in compound and / or substrate tissue distribution assays. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent. The present disclosure also encompasses all suitable isotopic derivatives of the compounds disclosed. The term “isotopic derivative” refers to a compound in which at least one atom is replaced with an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, boron, nitrogen, oxygen, phosphorus, or the like, such as2H (deuterium, D),3H (deuterium, T),11C,13C,14C,15N,17O,18O, etc. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Typically, the pharmaceutical compositions of this disclosure will be administered from once every 1 to 5 days to about 1-5 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compound is most desirably administered at a concentration level that will generally afford effective results without causing substantial harmful or deleterious side effects. When the compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more, preferably one or two, additional therapeutic or prophylactic agent, both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen. Pharmaceutical formulations may be adapted for administration by any appropriate route, for example, by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Oral administration or administration by injection are preferred. Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present. Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and / or and absorption agent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages. Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added. Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release, for example, by coating or embedding particulate material in polymers, wax, or the like. It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. The term “subject,” "patient,” or the like, includes both humans and other mammalian animals, including but not limited to cats, dogs, pigs, horses, sheep, goats, monkeys, chimpanzees, and so on, preferably humans. The term “disease,” “disorder,” and “condition,” or the like, as used herein, are often used interchangeably. The term “therapeutically effective amount" refers to an amount of a compound or composition that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. A "therapeutically effective amount" can vary depending on, inter alia, the compound, the disease and its severity, and the age, weight, or other factors of the subject to be treated. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously. The term “treat”, “treating”, “treatment”, or the like, refers to: (i) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (ii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and / or condition. In addition, the compounds of present disclosure may be used for their prophylactic effects in preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder, and / or condition but has not yet been diagnosed as having it. When the term “about” is applied to a parameter, such as pH, concentration, temperature, or the like, it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%, and sometimes more preferably with ±2%. As would be understood by a person skilled in the art, when a parameter is not critical, a number is often given only for illustration purpose, instead of being limiting. The following non-limiting synthetic schemes, preparation methods and processes, and examples further illustrate certain aspects of the present disclosure. Compound Preparation and Biological Assays As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. Abbreviations The following abbreviations have the indicated meanings: AcCl = Acetyl chloride AcOH = Acetic acid AIBN = Azodiisobutyronitrile BINAP = 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl Boc = t-Butyloxy carbonyl BOP = Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate B2Pin2 =Bis(pinacolato)diboron BPO = Benzoyl peroxide BrettPhos = 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2-4'-6'-tri-i-propyl-1,1'-biphenyl CbzOSu = N-(Benzyloxycarbonyloxy)succinimide CD3OD = Methanol CDI = 1,1'-Carbonyldiimidazole CuI = Cuprous iodide 4CzIPN = 2,4,5,6-Tetrakis(carbazol-9-yl)-1,3-dicyanobenzene CyJohnPhos = (2-Biphenyl)dicyclohexylphosphine DCE = 1,2-Dichloroethane DCM = Dichloromethane DEA = diethylamine Dess-Martin = (1,1,1-Triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one DIEA or DIPEA = Diisopropylethylamine DMA = N,N-Dimethylacetamide DMAP = 4-Dimethylaminopyridine DMB = 2,4-Dimethoxybenzyl DMF = N,N-Dimethylformamide DMSO = Dimethyl sulfoxide EtOH = Ethanol EtOAc = Ethyl acetate EDCI = 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride FA = Formic acid HATU = Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium HBpin = Pinacolborane or 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane HBTU = Hexafluorophosphate Benzotriazole Tetramethyl Uronium HCHO = Formaldehyde HPLC = High-performance liquid chromatography hr or h = Hour IPA = Isopropyl alcohol IPrAuNTf2= [1,3-Bis[2,6-bis(1-methylethyl)phenyl]-1,3-dihydro-2H-imidazol-2-ylidene]- [1,1,1-trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamidato-κN]gold K2S2O8= Potassium persulfate LC-MS = Liquid chromatography – mass spectrometry LDA = Lithium diisopropylamide M = Mol / L MeCN = Acetonitrile MeOH = Methanol MOMCl = Chloromethyl methyl ether MS = Molecular sieves MsCl = Methane sulfonyl chloride NaBH3CN = Sodium cyanoborohydride NaH = Sodium hydride NaN3= Sodium azide NaSEt = Sodium ethanethiolate NBS = N-Bromosuccinimide NMI = 1-Methylimidazole NMO = 4-methylmorpholine N-oxide NMR = Nuclear magnetic resonance Pd2(dba)3= Tris(dibenzylideneacetone)dipalladium Pd(dppf)Cl2= Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium Pd(dtbpf)Cl2= [1,1'-Bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride Pd(OAc)2= Palladium (II) Acetate Pd-PEPPSI-IPentCl = (SP-4-1)-[1,3-Bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3- dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine- κN)-Palladium Pd(PPh3)2Cl2= Bis(triphenylphosphine)palladium(II) chloride Pd(PPh3)4= Tetrakis(triphenylphosphine)palladium Pd(t-Bu3P)2= Bis(tri-tert-butylphosphine)palladium PE = Petroleum ether POCl3= Phosphorus oxychloride Py = Pyridine RT = Room temperature Rt = Retention time Ruphos = 2-Dicyclohexylphosphino-2,6'-diisopropoxy-1,1'-biphenyl Ruphos Pd G3 = Methanesulfonato(2-dicyclohexylphosphino-2,6'-di-i-propoxy-1,1'- biphenyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) SFC = Supercritical fluid chromatography Selectfluor = 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) SPhos = 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl SPhos Pd G2 = Chloro(2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl)[2-(2-amino- 1,1-biphenyl)]palladium(II) TCFH = N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate TEA = Triethylamine TFA = Trifluoracetic acid TfOH = Trifluoromethanesulfonic acid THF = Tetrahydrofuran TLC = Thin layer chromatography TMSCl = Chlorotrimethylsilane TosCl = p-Toluenesulfonyl chloride XPhos Pd G4 = Methanesulfonato(2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'- biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) General Conditions and Procedures In the following examples, the chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company and the like) and used without further purification. THF was continuously refluxed and freshly distilled from sodium and benzophenone under nitrogen, dichloromethane was continuously refluxed and freshly distilled from CaH2under nitrogen. Flash chromatography was performed on Biotage Isolera One using columns with silica gel particles of 200-300 mesh. Analytical and preparative TLC plates were HSGF 254 (0.15- 0.2 mm thickness, Shanghai Anbang Company, China). NMR spectra were recorded using Brucker AVANCE NEO 400 (Brucker, Switzerland) at around 20~30 °C unless otherwise specified. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiple; dd, doublet of doublets; dt, doublet of triplets; bs, broad signal. Chemical shifts for1H NMR were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were run with electrospray ionization (ESI) on a LCMS2020 Mass Spectrometer (Shimadzu, Japan). Compound purification was carried out as needed using a variety of methods including, but not limited to, preparative chromatography under acidic, neutral, or basic conditions using either normal phase or reverse phase HPLC, flash columns, or Prep- TLC plates. Preparative HPLC: unless otherwise described, the compounds were purified using a SHIMADZU LH-40 or FRC-40 equipped with a YMC-Triart C18 Column (5 μm, 120A, 250 x 20 mm) and one of the following solvent systems: H2O, MeCN, and 0.1% FA in H2O or H2O, MeOH, and 0.1% FA in H2O or H2O, MeCN, and 0.1% NH4OH / NH4HCO3in H2O or H2O, MeCN, and 0.1% NH4OH / NH4HCO3in H2O. Specific elution gradients were based on the retention times obtained from an analytical LC-MS, however, in general all elution gradients of H2O and MeCN or MeOH were run over a 20 minutes run time with a flow rate of 20 mL / min. An auto-blend method was used to ensure a concentration of 0.1% FA throughout each run. For purifications using eluents containing FA, the final products after lyophilization or drying are full or partial salt of FA as evident from NMR. The qualitative nature of these salts is listed in the descriptions in the Examples. Analytical LC-MS: analytical LC-MS was performed on a SHIMADZU LCMS2020 instrument equipped with a Shim-pack Scepter C18Column (3.0 x 33 mm, 3 μm) at a column temperature of 40 °C and using the following solvent system: Solvent A: 0.05% FA in H2O; and Solvent B: MeCN. All compounds were run using the same elution gradient, i.e., 20% to 95% Solvent B over a 3 min run time with a flow rate of 1.2 mL / min. Preparative Chiral SFC Separation: Stereoisomeric mixtures were separated using a Waters SFC 80 (Waters, USA) or Nexera UC Prep (Shimadzu, Japan) instrument on one of the following columns: ChiralPak AS-H (21.2 x 250 mm,5μm), ChiralPak IA (21.2 x 250 mm,5μm), ChiralPak AD-H (21.2 x 250 mm, 5μm), or ChiralPak IC (21.2 x 250 mm, 5μm); eluting with either 0.05% DEA in MeOH / CO2, or 0.05% DEA in EtOH / CO2or 0.05% DEA in isopropanol / CO2with a flow rate of 40 mL / min and a column temperature of 40 °C. Analytical Chiral SFC Separation: Stereoisomer mixtures or single enantiomers were analyzed using a Waters UPCC (Waters, USA) or UC (Shimadzu, Japan) on one of the following columns: ChiralPak AS-H (4.6 x 100 mm, 3.5μm), ChiralPak IA (4.6 x 100 mm, 3.5μm), ChiralPak AD-H (4.6 x 100 mm, 3.5μm), or ChiralPak IC (4.6 x 100 mm, 3.5μm); eluting with either 0.05% DEA in MeOH / CO2, or 0.05% DEA in EtOH / CO2or 0.05% DEA in isopropanol / CO2, with a flow rate of 1.8 mL / min and a column temperature of 40 °C. Schemes for the preparation of final targets: General Scheme 1 In general scheme 1, formulae II were prepared from commercially available formulae I with appropriate nucleophiles under nucleophilic aromatic substitution reaction conditions (such as DIPEA / DMSO, CsF / DMSO, etc.) or transition metal-catalyzed cross-coupling reactions (such as Buchwald coupling reaction, Negishi reaction, Suzuki coupling, etc.). Treatment of formulae II with phenyl-borate under Suzuki coupling conditions (Such as Ruphos Pd G3 or Pd(dtbpf)Cl2, K2CO3, 1,4-dioxane / H2O, etc.) afforded formulae III. Deprotection of formulae III and functionalization with appropriate conditions (such as: alkylation, reductive amination, Michael addition reaction, etc.) afforded formulae IV. General Scheme 2 In general scheme 2, formulae VI were prepared from commercially available formulae V with appropriate phenyl-borates under Suzuki coupling conditions (such as Pd(dtbpf)Cl2 with base in appropriate solvents, etc.). Halogenation of formulae VI with appropriate reagents (such as POCl3, POBr3, etc.) afforded formulae VII. Treatment of formulae VII with appropriate nucleophiles under nucleophilic aromatic substitution reaction conditions (such as DIPEA / DMSO, CsF / DMSO, etc.) or transition metal-catalyzed cross-coupling reactions (such as Buchwald coupling reaction, Negishi reaction, Suzuki coupling, etc.) afforded formulae III. Deprotection of formulae III and functionalization with appropriate conditions (such as: alkylation, reductive amination, Michael addition reaction, etc.) afforded formulae IV. General Scheme 3 In general scheme 3, formulae IX were prepared using Minisci reaction (oxidant induced, such as K2S2O8, AgNO3or photoinduced) from formulae VIII. Selective deprotection of formulae IX and functionalization under appropriate conditions (such as acylation or reductive amination, etc.) gave formulae XI. Deprotection of formulae XI and functionalization with appropriate conditions (alkylation, reductive amination, Michael addition reaction, etc.) afforded formulae XII. General Scheme 4 In general scheme 4, formulae XIV were prepared from formulae XI under hydrolysis conditions (such as LiOH or NaOH in THF / H2O) or other conditions (such as hydrogenolysis with appropriate catalyst). Treatment of formulae XIV under amide coupling conditions (such as HATU / DIPEA in DMF) or esterification conditions (such as SOCl2in appropriate alcohols) afforded formulae XV. Deprotection of formulae XI and functionalization under appropriate conditions (alkylation, reductive amination, Michael addition reaction, etc.) afforded formulae XVI. General Scheme 5

[0007] Treatment of formulae VII with appropriate boric acid (ester) under Suzuki coupling conditions (such as Pd(dtbpf)Cl2, K2CO3, 1,4-dioxane, H2O, etc.) afforded formulae XVII. Hydrogenation of formulae VII with appropriate catalyst (such as H2, Pd / C, etc.) and deprotection afforded formulae XVIII. Treatment of formulae VII with appropriate reagent under Sonogashira coupling conditions (such as Pd(PPh3)2Cl2, CuI, TEA, etc.) afforded formulae XIX. Functionalization of formulae XIX (such as hydration, hydrogenation, etc.) and deprotection afforded formulae XVI. Intermediate 1 6-Chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine Step 1: 6-(2-Methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-ol To a solution of 6-chloro-5-methylpyridazin-3-ol (20 g, 138 mmol) in 1,4-dioxane (400 mL) and water (100 mL) was added (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (45 g, 205 mmol), K2CO3(57 g, 413 mmol) and Pd(dtbpf)Cl2(5.4 g, 8.29 mmol) under N2atmosphere at RT. The mixture was degassed with N2three times and stirred under N2atmosphere at 90oC for 5 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~75% EtOAc in PE) to give the title compound (35 g) as a solid.1H NMR (400 MHz, CDCl3) δ 11.88 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.17 (s, 1H), 6.81 (s, 1H), 3.86 (s, 3H), 2.02 (s, 3H). LC / MS (ESI) (m / z): 285.1 (M+H)+. Step 2: 6-Chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine To a solution of 6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-ol (20 g, 70.4 mmol) in 1,4-dioxane (200 mL) was added POCl3(22 g, 144 mmol) at RT and the mixture was stirred under N2atmosphere at 60oC overnight. The mixture was concentrated under reduced pressure to dryness. The residue was diluted with EtOAc, washed with sat. aq. NaHCO3solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in PE) to give the title compound (15 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.21 (s, 1H), 3.84 (s, 3H), 2.19 (s, 3H). LC-MS (ESI) (m / z): 303.0 (M+H)+. The intermediates listed in Error! Reference source not found.1 below were prepared following the methods and protocols described for the synthesis of Intermediate 1 from appropriate starting materials. Table 1. Intermediates Prepared Using Procedure for Intermediate 1 Intermediate 5 6-Chloro-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4-methylpyridazine Step 1: 2-(6-Chloro-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol To a solution of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (7.90 g, 26.2 mmol) in DCM (50 mL) was added BBr3(104.8 mL, 104.8 mmol, 1 M in DCM) drop- wisely at -78 ℃ and the mixture was stirred at -78 ℃ to RT for 2 hrs. The mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~70% EtOAc in PE) to give the title compound (5.01 g) as a solid.1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.93 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 2.19 (s, 3H). LC-MS (ESI) (m / z): 289.0 (M+H)+. Step 2: 6-Chloro-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4-methylpyridazine To a solution of 2-(6-chloro-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (5.00 g, 17.4 mmol) in DCM (50 mL) was added DIPEA (4.50 g, 34.9 mmol) followed by drop-wise addition of MOMCl (2.11 g, 26.1 mmol) at 0oC and the mixture was stirred at RT for 3 hrs. The mixture was quenched with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~40% EtOAc in PE) to give the title compound (2.52 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.47- 7.45 (m, 1H), 7.43 – 7.41 (m, 1H), 5.14 (s, 2H), 3.38 (s, 3H), 2.23 (s, 3H). LC-MS (ESI) (m / z): 333.0 (M+H)+. Intermediate 6 Tert-butyl (R)-3-((6-bromo-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of 3,6-dibromo-4-methylpyridazine (5 g, 19.8 mmol) in DMSO (50 mL) were added CsF (9.03 g, 59.4 mmol) and tert-butyl (R)-3-aminopiperidine-1-carboxylate (5.94 g, 29.7 mmol) and the mixture was stirred under N2 atmosphere at 120 °C overnight. The mixture was cooled to RT and diluted with EtOAc. The mixture was washed with sat. aq. NH4Cl solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in PE) to give the title compound (1.7 g) as a solid.1H NMR (400 MHz, CDCl3) δ 6.52 (s, 1H), 3.92 – 3.80 (m, 1H), 3.77 – 3.66 (m, 1H), 3.52 – 3.43 (m, 1H), 3.39 – 3.20 (m, 2H), 2.27 (s, 3H), 2.00 – 1.90 (m, 1H), 1.77 – 1.65 (m, 2H), 1.62 – 1.51 (m, 1H), 1.42 (s, 9H). LC- MS (ESI) (m / z): 371 / 373 (M+H)+. Intermediate 7 Tert-butyl (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-1-carboxylate To a mixture of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (10.0 g, 33.0 mmol) and tert-butyl (R)-3-aminopiperidine-1-carboxylate (19.85 g, 99.1 mmol) in anhydrous DMSO (100 mL) was added CsF (15.06 g, 99.1 mmol) at RT and the reaction mixture was stirred under N2atmosphere at 120 ℃ overnight. The reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~60% EtOAc in PE) to give the title compound (8.1 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.16 (s, 1H), 6.55 (s, 1H), 5.10 – 4.82 (m, 1H), 3.94 – 3.88 (m, 1H), 3.82 (s, 3H), 3.58 – 3.47 (m, 1H), 3.45 – 3.18 (m, 2H), 2.07 (s, 3H), 2.03 – 1.98 (m, 1H), 1.80 – 1.67 (m, 2H), 1.63 – 1.55 (m, 1H), 1.44 (s, 9H). LC / MS (ESI) m / z: 467.3 (M+H)+. Intermediate 8 Tert-butyl (S)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidine-1-carboxylate Step 1: (R)-((1-(tert-butoxycarbonyl)piperidin-3-yl)methyl)zinc(II) iodide To the slurry of activated Zn powder (11.3 g, 174 mmol) in DMF (50 mL) was added a mixture of TMSCl and DCE (4 mL, v / v= 7 / 5) over 10 mins at RT, the internal temperature was maintained below 65 °C during the addition. The slurry was stirred at RT for 15 mins and a solution of tert-butyl (S)-3-(iodomethyl)piperidine-1-carboxylate (45 g, 139 mmol) in DMF (40 mL) was added drop-wisely at a rate to maintain the temperature below 65 °C. The reaction mixture was stirred at 65 °C for 5 mins and cooled to RT to give the title compound as 1.54 M DMF solution, which was directly used in the next reaction without work-up. Step 2: Tert-butyl (S)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidine-1-carboxylate To a solution of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (5.0 g, 16.5 mmol) in DMA (50 mL) was added CuI (627 mg, 3.30 mmol) and Pd(dppf)Cl2dichloromethane complex (1.35 g, 1.65 mmol) under N2atmosphere, the mixture was degassed with N2three times and (R)-((1-(tert-butoxycarbonyl)piperidin-3-yl)methyl)zinc(II) iodide solution (42.9 mL, 66.00 mmol, 1.54 M in DMF) was added. The mixture was degassed with N2three times and stirred under N2atmosphere at 80oC for 2 hrs. The mixture was quenched with ice-water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~25% EtOAc in PE) to give the title compound (6.6 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.20 (s, 2H), 3.94 – 3.85 (m, 1H), 3.82 (s, 3H), 3.00 – 2.82 (m, 3H), 2.80 – 2.59 (m, 1H), 2.16 (s, 3H), 2.13 – 2.03 (m, 1H), 1.98 – 1.74 (m, 2H), 1.73 – 1.64 (m, 1H), 1.57 – 1.45 (m, 1H), 1.43 (s, 9H), 1.35 – 1.25 (m, 1H). LC-MS (ESI) m / z: 466.2 (M+H)+. Intermediate 9 Tert-butyl (R)-3-((4-(hydroxymethyl)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-1-carboxylate Step 1: 4-((Benzyloxy)methyl)-3-chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazine To a mixture of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (3 g, 9.93 mmol) and 2-(benzyloxy)acetic acid (3 g, 19.8 mmol) in MeCN (30 mL) and water (30 mL) was added K2S2O8(4 g, 14.9 mmol) and AgNO3(330 mg, 1.99 mmol) under N2atmosphere at RT, the mixture was degassed with N2three times and stirred at 60 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in PE) to give the title compound (3.3 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.8 Hz, 1H), 7.39 – 7.33 (m, 6H), 7.20 (s, 1H), 4.76 (s, 2H), 4.65 (s, 2H), 3.81 (s, 3H), 2.21 (s, 3H). LC-MS (ESI) m / z: 423.4 (M+H)+. Step 2: Tert-butyl (R)-3-((4-((benzyloxy)methyl)-6-(2-methoxy-4- (trifluoromethyl)phenyl)- 5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a mixture of 4-((benzyloxy)methyl)-3-chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazine (1 g, 2.37 mmol) and tert-butyl (R)-3-aminopiperidine-1-carboxylate (950 mg, 4.74 mmol) in 1,4-dioxane (10 mL) was added BINAP (295 mg, 0.47 mmol), Cs2CO3(2.3 g, 7.11 mmol) and Pd2(dba)3(220 mg, 0.24 mmol) under N2atmosphere at RT, the mixture was degassed with N2three times and stirred at 100 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~70% EtOAc in PE) to give the title compound (700 mg) as a solid. LC-MS (ESI) m / z: 587.3 (M+H)+. Step 3: Tert-butyl (R)-3-((4-(hydroxymethyl)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((4-((benzyloxy)methyl)-6-(2-methoxy-4-(trifluoromethyl)- phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (700 mg, 1.2 mmol) in MeOH (7 mL) was added Pd / C (50 mg, 10% wt.) and Pd(OH)2(50 mg, 10% wt.) under N2temperature, the mixture was degassed with N2three times and stirred with a H2balloon at RT overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~80% EtOAc in PE) to give the title compound (425 mg,) as a solid.1H NMR (400 MHz, CDCl3) 7.48 – 7.41 (m, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H), 4.77 (s, 2H), 4.52 – 4.34 (m, 1H), 3.80 (s, 3H), 3.65 – 3.59 (m, 1H), 3.53 – 3.45 (m, 1H), 3.31 – 3.20 (m, 1H), 2.04 (s, 3H), 1.99 – 1.92 (m, 1H), 1.90 – 1.79 (m, 1H), 1.76 – 1.69 (m, 1H), 1.66 – 1.53 (m, 3H), 1.40 (s, 9H). LC-MS (ESI) m / z: 497.3 (M+H)+. Intermediate 10 2-(2-(Methoxymethoxy)-6-(methoxymethyl)-4-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane Step 1: 2-(2-(Methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl- 1,3,2-dioxaborolane To a mixture of 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (prepared following the procedure in Example 20 from WO2023178099; 5 g, 14.4 mmol) and HBpin (9.25 g,72.2 mmol) in 1,4-dioxane (100 mL) were added TEA (10 mL, 72.2 mmol), CyJohnPhos (0.51 g, 1.5 mmol) and Pd(OAc)2(0.32 g, 1.5 mmol) successively under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 95 °C overnight. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~10% EtOAc in PE) to give the title compound (2.2 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.05 (bs, 2H), 5.16 (s, 2H), 3.47 (s, 3H), 2.39 (s, 3H), 1.39 (s, 12H). Step 2: 2-(2-(Bromomethyl)-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane To a solution of 2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (1.2 g, 3.5 mmol) in CCl4(24 mL) was added NBS (0.68 g, 3.8 mmol) and AIBN (0.06 g, 0.35 mmol) and the mixture was stirred under N2atmosphere at 80 °C for 5 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~5% EtOAc in PE) to give the title compound (1.1 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 7.19 (s, 1H), 5.18 (s, 2H), 4.57 (s, 2H), 3.49 (s, 3H), 1.42 (s, 12H). Step 3: 2-(2-(Methoxymethoxy)-6-(methoxymethyl)-4-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane To a solution of 2-(2-(bromomethyl)-6-(methoxymethoxy)-4-(trifluoromethyl)phenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5 g, 11.79 mmol) in MeOH (50 mL) was added NaOMe (4.4 mL, 23.58 mmol, 5.4 M in MeOH) at 0 ℃ under N2atmosphere and the mixture was stirred at 50 ℃ for 3 hrs. The mixture was quenched with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in PE) to give the title compound (2 g) as an oil.1H NMR (400 MHz, CDCl3) δ 7.17 (s, 1H), 7.15 (s, 1H), 5.18 (s, 2H), 4.51 (s, 2H), 3.47 (s, 3H), 3.33 (s, 3H), 1.39 (s, 12H). Intermediate 11 2-(4-(Difluoromethoxy)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane Step 1: 4-Bromo-3-hydroxyphenyl 4-methylbenzenesulfonate To a mixture of 4-bromobenzene-1,3-diol (20 g, 106 mmol) in acetone (200 mL) was added K2CO3(29 g, 212 mmol) and TosCl (21 g, 111 mmol) at RT and the mixture was stirred under N2atmosphere at 65oC for 4 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0~20 % EtOAc in PE) to give the title compound (27 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.37 – 7.30 (m, 3H), 6.73 – 6.65 (m, 1H), 6.54 – 6.44 (m, 1H), 2.45 (s, 3H). Step 2: 4-Bromo-3-(methoxymethoxy)phenyl 4-methylbenzenesulfonate To a solution of 4-bromo-3-hydroxyphenyl 4-methylbenzenesulfonate (27 g, 78.7 mmol) in DCM (300 mL) was added DIEA (30.51 g, 236.0 mmol) followed by drop-wise addition of MOMCl (9.5 g, 118 mmol) at 0oC and the mixture was stirred under N2atmosphere at 20oC for 4 hrs. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~10% EtOAc in PE) to give the title compound (26 g) as a solid, the regio-chemistry of Step 1 was confirmed by NOE at this step.1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.80 – 6.73 (m, 1H), 6.60 – 6.53 (m, 1H), 5.10 (s, 2H), 3.43 (s, 3H), 2.45 (s, 3H). Step 3: 4-Bromo-3-(methoxymethoxy)phenol To a mixture of 4-bromo-3-(methoxymethoxy)phenyl 4-methylbenzenesulfonate (29.5 g, 76.18 mmol) in EtOH (1.1 L) was added aq. KOH solution (95.2 mL, 380.8 mmol, 4 M) at RT and the mixture was stirred at 70oC for 2 hrs. The mixture was concentrated under reduced pressure to dryness and the residue was dissolved in water (500 mL). The mixture was acidified with 1 N aq. HCl to pH ~ 5 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~20 % EtOAc in PE) to give the title compound (13.1 g) as an oil.1H NMR (400 MHz, CDCl3) δ1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 2.7 Hz, 1H), 6.40 (dd, J = 8.6, 2.7 Hz, 1H), 5.21 (s, 2H), 3.52 (s, 3H). Step 4: 1-Bromo-4-(difluoromethoxy)-2-(methoxymethoxy)benzene To a mixture of 4-bromo-3-(methoxymethoxy)phenol (13 g, 55.8 mmol) in MeCN (130 mL) was added a solution of KOH (62.6 g, 1116 mmol) in water (130 mL) and sodium 2-chloro- 2,2-difluoroacetate (17.2 g, 112 mmol) at 0 °C and the mixture was stirred under N2atmosphere at 20oC for 2 hrs. The mixture was diluted with ice-water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0~20 % EtOAc in PE) to give the title compound (9.3 g) as an oil.1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 2.6 Hz, 1H), 6.69 (dd, J = 8.9, 2.7 Hz, 1H), 6.30 (t, J = 73.5 Hz, 1H), 5.24 (s, 2H), 3.52 (s, 3H).19F NMR (376 MHz, CDCl3) δ -81.13 (s). Step 5: 2-(4-(Difluoromethoxy)-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane To a mixture of 1-bromo-4-(difluoromethoxy)-2-(methoxymethoxy)benzene (9 g, 31.8 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (12.11 g, 47.69 mmol) in 1,4- dioxane (90 mL) were added KOAc (9.36 g, 95.4 mmol) and Pd(dppf)Cl2(2.33 g, 3.18 mmol) successively under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 100 °C overnight. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~20% EtOAc in PE) to give the title compound (7.3 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.75 (dd, J = 8.2, 2.1 Hz, 1H), 6.52 (t, J = 73.9 Hz, 1H), 5.18 (s, 2H), 3.51 (s, 3H), 1.34 (s, 12H).19F NMR (377 MHz, CDCl3) δ -80.98 (s). Intermediate 12 (4-Isopropyl-2-(methoxymethoxy)phenyl)boronic acid Step 1: 2-Iodo-5-isopropylphenol To a solution of 3-isopropylphenol (5 g, 36.8 mmol) in toluene (40 mL) was added NaH (1.62 g, 40.4 mmol, 60% dispersion in mineral oil) portion-wisely at 0 ℃ and the mixture was stirred at 0 ℃ for 30 mins. Then iodine (9.34 g, 36.8 mmol) was added to the above mixture in portions at 0 ℃ and the mixture was stirred at RT for 3 hrs. The mixture was quenched with sat. aq. NH4Cl solution at 0 ℃, acidified with 1 N aq. HCl to pH ~5 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~15% EtOAc in PE) to give the title compound (4 g) as a solid. LC / MS (ESI) (m / z): 261.0 (M-H)-. Step 2: 1-Iodo-4-isopropyl-2-(methoxymethoxy)benzene To a solution of 2-iodo-5-isopropylphenol (4 g, 15.3 mmol) in DCM (40 mL) were added DIEA (5.92 g, 45.8 mmol) followed by drop-wise addition of MOMCl (1.84 g, 22.9 mmol) at 0oC and the mixture was stirred at RT for 2 hrs. The reaction mixture was quenched with sat. aq. NaHCO3solution and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~15 % EtOAc in PE) to give the title compound (4.3 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 6.58 (dd, J = 8.1, 1.9 Hz, 1H), 5.16 (s, 2H), 3.45 (s, 3H), 2.85 – 2.65 (m, 1H), 1.15 (d, J = 6.9 Hz, 6H). Step 3: (2-Hydroxy-4-isopropylphenyl)boronic acid To a solution of 1-iodo-4-isopropyl-2-(methoxymethoxy)benzene (4.2 g, 13.7 mmol) in THF (50 mL) was added n-BuLi (6.0 mL, 15.0 mmol, 2.5 M in hexane) drop-wisely at -78 ℃ under N2atmosphere. After stirred at -78 ℃ for 1 hr, trimethyl borate (2.14 g, 20.6 mmol) was added and the reaction mixture was stirred at -78 ℃ to RT for 16 hrs. The mixture was quenched with 1 N aq. NaOH solution (25 mL) at 0 ℃ and the volatiles was removed under reduced pressure. The left aqueous solution was acidified with 1 N aq. HCl solution to pH ~3 and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (1.6 g) as a solid. LC / MS (ESI) (m / z): 225.1 (M+H)+. Intermediate 13 2-(4-Ethyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: 4-Ethyl-2-methoxyphenyl trifluoromethanesulfonate To a solution of 4-ethyl-2-methoxyphenol (3 g, 19.7 mmol) in DCM (30 mL) was added pyridine (3.1, 39.4 mmol) followed by drop-wise addition of Tf2O (8.17 g, 29.6 mmol) at 0 ℃ and the mixture was stirred at RT for 2 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under the reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~45% EtOAc in PE) to give the title compound (3.1 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 8.3 Hz, 1H), 6.86 (s, 1H), 6.79 (d, J = 8.3 Hz, 1H), 3.90 (s, 3H), 2.66 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H). Step 2: 2-(4-Ethyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 4-ethyl-2-methoxyphenyl trifluoromethanesulfonate (2.6 g, 9.15 mmol) in 1,4- dioxane (26 mL) was added HBpin (5.8 g, 45.7 mmol), TEA (2.8 g, 27.5 mmol) and Pd(dppf)Cl2(670 mg, 0.18 mmol) under N2atmosphere. The mixture was degassed with N2three times and stirred under N2atmosphere at 100 ℃ for 2 hrs. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in PE) to give the title compound (1.6 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.5 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.70 (s, 1H), 3.83 (s, 3H), 2.64 (q, J = 7.6 Hz, 2H), 1.34 (s, 12H), 1.23 (t, J = 7.6 Hz, 3H). Intermediate 14 2-(4-Cyclopropyl-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: 5-Bromo-2-chlorophenol To a solution of 4-bromo-1-chloro-2-(methoxymethoxy)benzene (17 g, 82.1 mmol) in DCM (170 mL) was added DIPEA (16 g, 123 mmol) followed by drop-wise addition of MOMCl (7.9 g, 98.5 mmol) at 0 ℃. The mixture was stirred at RT for 2 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~30 % EtOAc in PE) to give the title compound (18 g) as an oil.1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 2.2 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.08 (dd, J = 8.5, 2.1 Hz, 1H), 5.23 (s, 2H), 3.52 (s, 3H). Step 2: 1-Chloro-4-cyclopropyl-2-(methoxymethoxy)benzene To a mixture of 5-bromo-2-chlorophenol (16.5 g, 66 mmol) and cyclopropylboronic acid (7.37 g, 85.9 mmol) in toluene (429 mL) and water (22 mL) was added K3PO4(49 g, 231 mmol), tricyclohexylphosphine (1.85 g, 6.6 mmol) and Pd(OAc)2(1.5 g, 6.6 mmol) under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 100oC for 5 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~40% EtOAc in PE) to give the title compound (12 g) as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.27 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 1.9 Hz, 1H), 6.70 (dd, J = 8.2, 1.8 Hz, 1H), 5.27 (s, 2H), 3.41 (s, 3H), 1.93 – 1.86 (m, 1H), 0.99 – 0.92 (m, 2H), 0.69 – 0.64 (m, 2H). Step 3: 2-(4-Dyclopropyl-2-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane To a solution of 1-chloro-4-cyclopropyl-2-(methoxymethoxy)benzene (1.2 g, 5.66 mmol) in 1,4-dioxane (12 mL) was added B2Pin2(2.16 g, 8.49 mmol), KOAc (1.1 g, 11.3 mmol) and XPhos Pd G4 (486 mg, 0.57 mmol) under N2atmosphere, the mixture was degassed with N2 three times and stirred under N2atmosphere at 100oC for 3 hrs. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~20% EtOAc in PE) to give the title compound (250 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 7.7 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J = 7.7, 1.0 Hz, 1H), 5.14 (s, 2H), 3.40 (s, 3H), 1.96 – 1.82 (m, 1H), 1.26 (s, 12H), 0.99 – 0.90 (m, 2H), 0.73 – 0.63 (m, 2H). Intermediate 15 2-(2-(Benzyloxy)-4-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: 2-(Benzyloxy)-1-bromo-4-(trifluoromethoxy)benzene To a mixture of 2-bromo-5-(trifluoromethoxy)phenol (15 g, 58.4 mmol) in DMF (150 mL) was added K2CO3(16 g, 117 mmol) followed by drop-wise addition of (bromomethyl)benzene (10.4 mL, 87.55 mmol) at 0 °C and the mixture was stirred under N2atmosphere at 20oC for 2 hrs. The mixture was diluted with ice-water and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0~5% EtOAc in PE) to give the title compound (18.9 g) as an oil.1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 7.3 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 6.80 (s, 1H), 6.75 (d, J = 8.7 Hz, 1H), 5.15 (s, 2H). Step 2: 2-(2-(Benzyloxy)-4-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane To a mixture of 2-(benzyloxy)-1-bromo-4-(trifluoromethoxy)benzene (6 g, 17.3 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (8.78 g, 34.6 mmol) in 1,4-dioxane (60 mL) were added KOAc (2.54 g, 25.9 mmol) and Pd(dppf)Cl2(1.26 g, 1.73 mmol) under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 100 °C overnight. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~5% EtOAc in PE) to give the title compound (2.8 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 7.3 Hz, 2H), 7.39 – 7.36 (m, 2H), 7.32 – 7.30 (m, 1H), 6.83 (d, J = 7.1 Hz, 1H), 6.76 (s, 1H), 5.11 (s, 2H), 1.36 (s, 12H). Intermediate 16 2-(2-(Benzyloxy)-4-(difluoromethoxy)-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane Step 1: 3-(Difluoromethoxy)-5-methylphenol To a solution 5-methylbenzene-1,3-diol (40 g, 322 mmol) and sodium 2-chloro-2,2- difluoroacetate (74 g, 483 mmol) in DMF (200 mL) and water (200 mL) was added Cs2CO3(210 g, 644 mmol) and the mixture was stirred at 100 ℃ for 16 hrs. After cooling to RT, the reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~20% EtOAc in PE) to give the title compound (3 g) as a solid.1H NMR (400 MHz, CDCl3) δ 6.50 – 6.50 (m, 2H), 6.47 (t, J = 74 Hz, 1 H), 6.44 – 6.43 (m, 1H), 2.29 (s, 3H). Step 2: 5-(Difluoromethoxy)-2-iodo-3-methylphenol To a solution of 3-(difluoromethoxy)-5-methylphenol (3 g, 17.2 mmol) in toluene (40 mL) was added NaH (1.03 g, 25.8 mmol, 60% dispersion in mineral oil) portion-wisely at 0 ℃ and the mixture was stirred at 0 ℃ for 30 mins. Then iodine (8.41 g, 18.9 mmol) was added to the above mixture in portions at 0 ℃ and the mixture was stirred at RT for 3 hrs. The mixture was quenched with sat. aq. NH4Cl solution at 0 ℃, acidified with 2 N aq. HCl to pH = 5 and extracted with EtOAc twice. The combined organic layers were washed with sat. aq. Na2SO3solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~15% EtOAc in PE) to give the title compound (3.1 g) as a solid.1H NMR (400 MHz, CDCl3) δ 6.70 (s, 1H), 6.51 (t, J = 73.1 Hz, 1H), 6.07 (s, 1H), 2.47 (s, 3H). Step 3: 1-(Benzyloxy)-5-(difluoromethoxy)-2-iodo-3-methylbenzene To a solution of 5-(difluoromethoxy)-2-iodo-3-methylphenol (3.1 g, 10.3 mmol) in DMF (30 mL) were added and benzyl bromide (2.65 g, 15.5 mmol) and K2CO3(2.86 g, 20.7 mmol). The resulting mixture was stirred at RT for 16 hrs. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~20 % EtOAc in PE) to give the title compound (3.2 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.52 – 7.50 (m, 2H), 7.42 – 7.38 (m, 2H), 7.35 – 7.32 (m, 1H), 6.70 (d, J = 2.3 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.46 (t, J = 73.8 Hz, 1H), 5.13 (s, 2H), 2.48 (s, 3H). Step 4: 2-(2-(Benzyloxy)-4-(difluoromethoxy)-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane To a mixture of 1-(benzyloxy)-5-(difluoromethoxy)-2-iodo-3-methylbenzene (3.2 g, 8.20 mmol) and HBpin (5.25 g, 41.0 mmol)) in 1,4-dioxane (30 mL) were added TEA (5.7 mL, 41 mmol), CyJohnPhos (0.29 g, 0.82 mmol) and Pd(OAc)2(0.18 g, 0.82 mmol) successively under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 95 °C overnight. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~8% EtOAc in PE) to give the title compound (2.6 g) as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.48 – 7.46 (m, 2H), 7.40 – 7.36 (m, 2H), 7.33 – 7.29 (m, 1H), 7.25 (t, J = 74.2 Hz, 1H), 6.68 (d, J = 1.8 Hz, 1H), 6.58 (d, J = 1.3 Hz, 1H), 5.05 (s, 2H), 2.27 (s, 3H), 1.23 (s, 12H). Intermediate 17 2-(2-(Benzyloxy)-4-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: 2-Bromo-5-methoxy-3-methylphenol To a solution of 3-methoxy-5-methylphenol (4.5 g, 32.61 mmol) in CCl4(50 mL) was added NBS (6.96 g, 39.1 mmol) under N2 atmosphere and the reaction mixture was stirred at 25oC for 18 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~10% EtOAc in PE) to give the title compound (4.0 g) as an oil.1H NMR (400 MHz, CDCl3) δ 6.46 (d, J = 2.8 Hz, 1H), 6.42 (d, J = 2.8 Hz, 1H), 3.76 (s, 3H), 2.36 (s, 3H). Step 2: 1-(Benzyloxy)-2-bromo-5-methoxy-3-methylbenzene To a solution of 2-bromo-5-methoxy-3-methylphenol (4.4 g, 20.4 mmol) in MeCN (50 mL) were added benzyl bromide (4.18 g, 24.4 mmol) and K2CO3(5.62 g, 40.7 mmol). The resulting mixture was stirred at RT for 16 hrs. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~5% EtOAc in PE) to give the title compound (4.0 g) as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.51 – 7.44 (m, 2H), 7.44 – 7.37 (m, 2H), 7.37 – 7.28 (m, 1H), 6.61 (d, J = 2.7 Hz, 1H), 6.59 (d, J = 2.6 Hz, 1H), 5.18 (s, 2H), 3.74 (s, 3H), 2.32 (s, 3H). Step 3: 2-(2-(Benzyloxy)-4-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane To a mixture of 1-(benzyloxy)-2-bromo-5-methoxy-3-methylbenzene (3.0 g, 9.80 mmol) and HBpin (6.27 g, 49.0 mmol)) in 1,4-dioxane (30 mL) were added TEA (6.8 mL, 49 mmol), CyJohnPhos (745 mg, 1.96 mmol) and Pd(OAc)2(439 mg, 1.96 mmol) successively under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 95 °C overnight. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~8% EtOAc in PE) to give the title compound (3.0 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.50 – 7.45 (m, 2H), 7.37 – 7.31 (m, 2H), 7.31 – 7.27 (m, 1H), 6.31 (s, 1H), 6.29 (s, 1H), 5.00 (s, 2H), 3.77 (s, 3H), 2.36 (s, 3H), 1.29 (s, 12H). Intermediate 18 2-(4-(Difluoromethoxy)-2-(methoxymethoxy)-6-(methoxymethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane

[0008] Step 1: (5-(Benzyloxy)-2-bromo-3-(methoxymethoxy)phenyl)methanol To a solution of methyl 5-(benzyloxy)-2-bromo-3-(methoxymethoxy)benzoate (15 g, 39.4 mmol) in THF (100 mL) was added LAH (98 mL, 98 mmol, 1M in THF) drop-wisely at -20 ℃ under N2atmosphere and the mixture was stirred at -20 ℃ for 2 hrs. The mixture was quenched with water (3.7 mL), aq. NaOH (3.7 mL, 15% wt.) and water (11.2 mL) successively at 0oC and the mixture was stirred at 0oC for 30 mins. The mixture was filtered and the filter cake was washed with EtOAc twice. The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in PE) to give the title compound (8 g) as an oil.1 H NMR (400 MHz, CDCl3) δ 7.44 – 7.31 (m, 5H), 6.85 (d, J = 2.7 Hz, 1H), 6.79 (d, J = 2.8 Hz, 1H), 5.21 (s, 2H), 5.06 (s, 2H), 4.73 (d, J = 6.4 Hz, 2H), 3.50 (s, 3H). Step 2: 5-(Benzyloxy)-2-bromo-1-(methoxymethoxy)-3-(methoxymethyl)benzene To a mixture of (5-(benzyloxy)-2-bromo-3-(methoxymethoxy)phenyl)methanol (4 g, 11.4 mmol) in THF (40 mL) was added NaH (911 mg, 22.8 mmol, 60% dispersion in mineral oil) at 0 °C and the mixture was stirred at 0 °C for 20 mins. MeI (3.2 g, 22.8 mmol) was added to the above mixture at 0 °C and the resulting mixture was stirred at 25oC for 5 hrs. The mixture was poured into ice-water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~40% EtOAc in PE) to give the title compound (3.5 g) as an oil.1H NMR (400 MHz, CDCl3) δ 7.46 – 7.29 (m, 5H), 6.83 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 5.21 (s, 2H), 5.05 (s, 2H), 4.51 (s, 2H), 3.50 (s, 3H), 3.45 (s, 3H). Step 3: 4-Bromo-3-(methoxymethoxy)-5-(methoxymethyl)phenol To a solution of 5-(benzyloxy)-2-bromo-1-(methoxymethoxy)-3-(methoxymethyl)benzene (3.5 g, 9.56 mmol) in MeOH (35 mL) was added PtO2(250 mg, 0.96 mmol) under N2 temperature and the mixture was stirred with a H2balloon at RT for 5 hrs. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (1.7 g) as an oil.1H NMR (400 MHz, CDCl3) δ 6.67 (d, J = 2.8 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 5.21 (s, 2H), 4.52 (s, 2H), 3.51 (s, 3H), 3.48 (s, 3H). Step 4: 2-Bromo-5-(difluoromethoxy)-1-(methoxymethoxy)-3-(methoxymethyl)benzene To a solution of 4-bromo-3-(methoxymethoxy)-5-(methoxymethyl)phenol (1.7 g, 6.16 mmol) in MeCN (33 mL) and water (20 mL) was added KOH (6.8 g, 123 mmol) and diethyl (bromodifluoromethyl)phosphonate (3.3 g, 12.3 mmol). The mixture was stirred at 0 °C for 16 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~40% EtOAc in PE) to give the title compound (1.5 g) as an oil.1H NMR (400 MHz, CDCl3) δ 6.96 (s, 1H), 6.89 (s, 1H), 6.51 (t, J = 73.7, 1H), 5.24 (s, 2H), 4.51 (s, 2H), 3.51 (s, 3H), 3.49 (s, 3H). Step 5: 2-(4-(Difluoromethoxy)-2-(methoxymethoxy)-6-(methoxymethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane To a solution of 2-bromo-5-(difluoromethoxy)-1-(methoxymethoxy)-3- (methoxymethyl)benzene (600 mg, 1.83 mmol) in 1,4-dioxane (10 mL) was added B2Pin2(463 mg, 1.83 mmol), KOAc (545 mg, 5.49 mmol) and Pd(t-Bu3P)2(85 mg, 0.18 mmol) under N2atmosphere. The mixture was degassed with N2three times and stirred under N2atmosphere at 115 ℃ for 2 hrs. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~40% EtOAc in PE) to give the title compound (160 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 6.72 (s, 1H), 6.67 (s, 1H), 6.48 (t, J = 73.5 Hz, 1H), 5.13 (s, 2H), 4.46 (s, 2H), 3.46 (s, 3H), 3.32 (s, 3H), 1.37 (s, 12H). Intermediate 19 2-(4-Methoxy-2-(methoxymethoxy)-6-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane Step 1: (2-Bromo-5-methoxy-3-(methoxymethoxy)phenyl)methanol To a solution of methyl 2-bromo-5-methoxy-3-(methoxymethoxy)benzoate (25 g, 82.2 mmol) in THF (250 mL) was added LiAlH4(3.44 g, 90.5 mmol) at 0oC under N2atmosphere and the mixture was stirred at RT for 2 hrs. The reaction mixture was quenched with water (3.4 mL), 15% aq. NaOH solution (3.4 mL) and water (10.3 mL) at 0oC and the suspension was stirred at this temperature for 30 mins. The mixture was filtered and the filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by chromatography (silica gel, 0~40% EtOAc in PE) to give the title compound (15.5 g) as a solid.1H NMR (400 MHz, CDCl3) δ 6.76 (d, J = 2.8 Hz, 1H), 6.69 (d, J = 2.8 Hz, 1H), 5.23 (s, 2H), 4.73 (d, J = 5.5 Hz, 2H), 3.80 (s, 3H), 3.52 (s, 3H). LC / MS (ESI) (m / z): 277.0 (M+H)+. Step 2: 2-Bromo-5-methoxy-1-(methoxymethoxy)-3-(methoxymethyl)benzene To a solution of methyl (2-bromo-5-methoxy-3-(methoxymethoxy)phenyl)methanol (14 g, 50.7 mmol) in THF (150 mL) was added NaH (3.04 g, 76.0 mmol, 60% dispersion in mineral oil) in portions at 0oC and the mixture was stirred at 0oC for 1 hr. MeI (10.8 g, 76.1 mmol) was added at 0oC and the resulting mixture was stirred at 0oC for 2 hrs. The mixture was quenched with sat. aq. NH4Cl solution at 0 ℃ and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in PE) to give the title compound (9.8 g) as a solid.1H NMR (400 MHz, CDCl3) δ 6.75 (d, J = 2.9 Hz, 1H), 6.69 (d, J = 2.9 Hz, 1H), 5.22 (s, 2H), 4.51 (s, 2H), 3.80 (s, 3H), 3.51 (s, 3H), 3.48 (s, 3H). Step 3: 2-(4-Methoxy-2-(methoxymethoxy)-6-(methoxymethyl)phenyl)-4,4,5,5- tetramethyl- 1,3,2-dioxaborolane To a solution of 2-bromo-5-methoxy-1-(methoxymethoxy)-3-(methoxymethyl)benzene (4 g, 13.8 mmol) in 1,4-dioxane (50 mL) were added HBpin (17.7 g, 138 mmol), CyJohnPhos (966 mg, 2.76 mmol), TEA (13.9 g, 138 mmol) and Pd(OAc)2(310 mg, 1.38 mmol) under N2atmosphere. The mixture was degassed with N2three times and stirred under N2at 80 ℃ overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in PE) to give the title compound (4.15 g) as a solid.1H NMR (400 MHz, CDCl3) δ 6.52 (d, J = 2.1 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 5.13 (s, 2H), 4.47 (s, 2H), 3.78 (s, 3H), 3.47 (s, 3H), 3.31 (s, 3H), 1.37 (s, 12H). Intermediate 20 2-(2-(Methoxymethoxy)-6-(methoxymethyl)-4-(trifluoromethoxy)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane Step 1: (2-Bromo-3-(methoxymethoxy)-5-(trifluoromethoxy)phenyl)methanol To a solution of methyl 2-bromo-3-(methoxymethoxy)-5-(trifluoromethoxy)benzoate (3.17 g, 9.21 mmol) in THF (45 mL) was added LiBH4(6 mL, 12 mmol, 2 M in THF) drop-wisely at 0 °C under N2atmosphere and the mixture was stirred at RT for 5 hrs. The mixture was quenched with sat. aq. NH4Cl solution at 0 °C and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in PE) to give the title compound (2.7 g) as an oil.1H NMR (400 MHz, CDCl3) δ 7.12 (s, 1H), 6.99 (s, 1H), 5.25 (s, 2H), 4.77 (d, J = 6.2 Hz, 2H), 3.52 (s, 3H). Step 2: 2-Bromo-1-(methoxymethoxy)-3-(methoxymethyl)-5-(trifluoromethoxy)benzene To a solution of (2-bromo-3-(methoxymethoxy)-5-(trifluoromethoxy)phenyl)methanol (2.7 g, 8.13 mmol) in THF (27 mL) was added NaH (0.65 g, 16.3 mmol, 60% dispersion in mineral oil) in portions at 0 °C under N2atmosphere and the mixture was stirred at 0 °C for 30 mins. MeI (1.73 g, 12.2 mol) was added to the above mixture and the resulting mixture was stirred at RT for 2 hrs. The mixture was quenched with sat. aq. NH4Cl solution at 0 °C and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in PE) to give the title compound (2.3 g) as an oil.1H NMR (400 MHz, CDCl3) δ 7.07 (s, 1H), 6.98 (s, 1H), 5.25 (s, 2H), 4.52 (s, 2H), 3.52 (s, 3H), 3.49 (s, 3H). Step 3: 2-(2-(Methoxymethoxy)-6-(methoxymethyl)-4-(trifluoromethoxy)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane To a mixture of 2-bromo-1-(methoxymethoxy)-3-(methoxymethyl)-5- (trifluoromethoxy)benzene (950 mg, 2.76 mmol) and potassium acetate (600 mg, 6.12 mmol) in 1,4-dioxane (500 mL) was added bis(pinacolato)diboron (701 mg,2.76 mmol) and Pd(t- Bu3P)2(150 mg, 0.27 mmol) under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 115oC for 2 hrs. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, fitered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in PE) to give the title compound (300 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 6.79 (s, 1H), 5.14 (s, 2H), 4.48 (s, 2H), 3.47 (s, 3H), 3.33 (s, 3H) ,1.38 (s, 12H). Intermediate 21 3-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole Step 1: 6-Bromo-3-fluoro-1H-indole To a solution of 6-bromo-1H-indole-3-carboxylic acid (2.9 g, 12.1 mmol) in DCE (24 mL) and water (12 mL) was added Na2CO3(5.12 g, 48.3 mmol) followed by portion-wise addition of Selectfluor (8.56 g, 24.2 mmol) at 0 ℃ and the mixture was stirred under N2atmosphere at RT for 16 hrs. The reaction was diluted with water and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~10% EtOAc in PE) to give the title compound (1.8 g) as a solid.1H NMR (400 MHz, CDCl3) δ 7.53 (bs, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.37 – 7.34 (m, 1H), 7.14 (dd, J = 8.5 and 2.5 Hz, 1H), 6.85 – 6.82 (m, 1H). LC / MS (ESI) (m / z): 214.2 (M+H)+. Step 2: 3-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole To a mixture of 6-bromo-3-fluoro-1H-indole (200 mg, 0.93 mmol) and 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (284 mg, 1.12 mmol) in 1,4-dioxane (5 mL) was added Pd(dppf)Cl2DCM complex (76.5 mg, 0.09 mmol) and KOAc (275 mg, 2.81 mmol) under N2atmosphere at RT, the mixture was degassed with N2three times and stirred at 90 °C for 16 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~20% EtOAc in PE) to give the title compound (200 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 6.95 (t, J = 2.8 Hz, 1H), 1.29 (s, 12H). LC-MS (ESI) (m / z): 260.0 (M-H)-. Intermediate 22 Ethyl 3-((R)-3-((6-bromo-5-methylpyridazin-3-yl)amino)piperidin-1-yl)butanoate Step 1: (R)-6-bromo-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine hydrochloride To a solution of tert-butyl (R)-3-((6-bromo-5-methylpyridazin-3-yl)amino)piperidine- 1- carboxylate (Intermediate 6, 1.5 g, 4.05 mmol) in 1,4-dioxane (15 mL) was added HCl in 1,4- dioxane (5 mL, 4 M) and the mixture was stirred at RT for 1 hr. The mixture was concentrated under reduced pressure to give the title compound (1.3 g) as a solid. LC-MS (ESI) m / z: 271.1 (M+H)+. Step 2: Ethyl 3-((R)-3-((6-bromo-5-methylpyridazin-3-yl)amino)piperidin-1-yl)butanoate To a solution of (R)-6-bromo-5-methyl-N-(piperidin-3-yl)pyridazin-3-amine (1.3 g, 4.81 mmol) and ethyl 3-oxobutanoate (1.25 g, 9.62 mmol) in EtOH (13 mL) was added AcOH (0.23 mL, 4.81 mmol) and NaBH3CN (0.91 g, 14.43 mmol) at 0 °C under N2atmosphere and the mixture was stirred at RT for 1 hour. The mixture was quenched with sat. aq. NaHCO3solution and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (2.7 g) as a solid. LC-MS (ESI) (m / z): 387.3 (M+H)+. Example 1 2-(6-((3-Hydroxybenzyl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol Step 1: S-(3-methoxybenzyl) ethanethioate To a solution of 1-(bromomethyl)-3-methoxybenzene (2.0 g, 9.95 mmol) in DMF (20 mL) was added potassium thioacetate (2.86 g, 24.9 mmol) and the reaction mixture was stirred under N2atmosphere at 100 ℃ for 1 hour. The mixture was diluted with sat. aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~20% EtOAc in PE) to give the title compound (1.5 g) as an oil.1H NMR (400 MHz, DMSO-d6) δ 7.25 – 7.17 (m, 1H), 6.87 (s, 1H), 6.86 – 6.79 (m, 2H), 4.08 (s, 2H), 3.73 (s, 3H), 2.35 (s, 3H). Step 2: (3-Methoxyphenyl)methanethiol To the solution of S-(3-methoxybenzyl) ethanethioate (200 mg, 1.02 mmol) in MeOH (5 mL) was added K2CO3(211 mg, 1.53 mmol) and the mixture was stirred at RT for 1 hr. The reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (150 mg) as an oil. LC-MS (ESI) m / z: 155.1 (M+H)+. Step 3: 3-(2-Methoxy-4-(trifluoromethyl)phenyl)-6-((3-methoxybenzyl)thio)-4- methylpyidazine To the mixture of (3-methoxyphenyl)methanethiol (195 mg, 1.26 mmol) and 6-chloro-3-(2- methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (383 mg, 1.26 mmol) in DMF (5 mL) was added Cs2CO3 (1.23 g, 3.79 mmol) and the reaction mixture was stirred under N2 atmosphere at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~55% EtOAc in PE) to give the title compound (490 mg) as a solid. LC-MS (ESI) m / z: 421.1 (M+H)+. Step 4: 2-(6-((3-Hydroxybenzyl)thio)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol To a solution of 3-(2-methoxy-4-(trifluoromethyl)phenyl)-6-((3-methoxybenzyl)thio)-4- methylpyridazine (490 mg, 1.16 mmol) in DCM (5 mL) was added BBr3(3.5 mL, 3.50 mmol, 1M in DCM) drop-wisely at -78 ℃ under N2atmosphere and the mixture was stirred at RT for 3 hrs. The reaction mixture was quenched with sat. aq. NaHCO3solution at 0 ℃ and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 40~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (129.6 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.25 (s, 1H), 7.12 (dd, J = 8.0 Hz, 1H), 6.90 – 6.86 (m, 2H), 6.66 (d, J = 9.0 Hz, 1H), 4.49 (s, 2H), 2.12 (s, 3H). LC-MS (ESI) m / z: 393.0 (M+H)+. Example 2 (R)-2-(5-(aminomethyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5- (trifluoromethyl)phenol formic acid S yl)-6-(2-methoxy-4- (trfluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin- 3-yl)amino)piperidine-1-carboxylate (1.5 g, 3.21 mmol) in MeCN (15 mL) and water (15 mL) were added ((benzyloxy)carbonyl)glycine (1 g, 4.82 mmol), K2S2O8 (1.3 g, 4.82 mmol) and AgNO3(109 mg, 0.642 mmol) under N2atmosphere at RT. The mixture was degassed with N2three times and stirred under N2atmosphere at 60 ℃ overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~40% EtOAc in PE) to give the title compound (900 mg) as a solid. LC-MS (ESI) (m / z): 630 (M+H)+. Step 2: Benzyl (R)-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin- 3- ylamino)pyridazin-4-yl)methyl)carbamate hydrochloride To a solution of tert-butyl (R)-3-((4-((((benzyloxy)carbonyl)amino)methyl)-6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (900 mg, 1.43 mmol) in DCM (10 mL) was added HCl / 1,4-dioxane (5 mL, 4 M) and the mixture was stirred at RT for 2 hrs. The mixture was concentrated under reduced pressure to dryness to give the title compound (750 mg) as a solid, which was directly used in the next reaction without purification. LC-MS (ESI) m / z: 530 (M+H)+. Step 3: Benzyl (R)-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin-3-yl)amino)pyridazin-4-yl)methyl)carbamate To a mixture of benzyl (R)-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3- (piperidin- 3-ylamino)pyridazin-4-yl)methyl)carbamate hydrochloride (430 mg, 0.76 mmol), 37% aq. HCHO solution (2 mL) and AcOH (0.01 mL, 0.18 mmol) in MeOH (5 mL) was added NaBH3CN (143 mg, 2.3 mmol) at 0oC and the mixture was stirred at 25oC for 20 mins. The mixture was quenched with sat. aq. NH4Cl solution and extracted with CHCl3 / i-PrOH (v / v= 3 / 1) three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (350 mg) as a solid, which was used directly in the next reaction without purification. LC / MS (ESI) m / z: 544.2 (M+H)+. Step 4: (R)-2-(5-(aminomethyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3- yl)- 5-(trifluoromethyl)phenol To a solution of benzyl (R)-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin-3-yl)amino)pyridazin-4-yl)methyl)carbamate (20 mg, 0.04 mmol) in DCM (1 mL) was added BBr3(37 mg, 0.15 mmol) drop-wisely at -78oC and the mixture was stirred at RT for 1 hr. The reaction mixture was quenched with MeOH at -78oC and the mixture was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% FA) to give the title compound (3 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.40 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 4.58 – 4.54 (m, 1H), 4.31 – 4.17 (m, 2H), 3.69 – 3.50 (m, 1H), 3.28 – 3.13 (m, 2H), 2.84 (s, 3H), 2.24 (s, 3H), 2.19 – 2.08 (m, 3H), 1.96 – 1.86 (m, 2H). LC / MS (ESI) m / z: 396.0 (M+H)+. Example 3 (R)-1-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3- yl)amino)pyridazin-4-yl)methyl)guanidine, FA salt To a mixture of (R)-2-(5-(aminomethyl)-4-methyl-6-((1-methylpiperidin-3- yl)amino)pyridazin- 3-yl)-5-(trifluoromethyl)phenol (20 mg, 0.051 mmol) and DIPEA (19.6 mg, 0.152 mmol) in MeCN (1 mL) was added 1H-pyrazole-1-carboximidamide hydrochloride (11 mg, 0.076 mmol) at RT and the mixture stirred at RT for 3 hrs. The mixture was filtered and the filtrate was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 5~95% MeCN in H2O with 0.1% FA) to give the title compound (2 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.40 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.19 (s, 1H), 4.54 – 4.48 (m, 1H), 4.44 (s, 2H), 3.27 – 3.16 (m, 1H), 2.96 – 2.84 (m, 1H), 2.80 – 2.64 (m, 2H), 2.57 (s, 3H), 2.18 (s, 3H), 2.04 – 1.93 (m, 2H), 1.86 – 1.69 (m, 2H). LC / MS (ESI) (m / z): 438.3 (M+H)+. Example 4 (R)-1-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3- yl)amino)pyridazin-4-yl)methyl)urea, FA salt (partial) To a mixture of (R)-2-(5-(aminomethyl)-4-methyl-6-((1-methylpiperidin-3- yl)amino)pyridazin- 3-yl)-5-(trifluoromethyl)phenol (50 mg, 0.126 mmol) and TEA (25.6 mg, 0.253 mmol) in DCM (1 mL) was added TMSNCO (29.1 mg, 0.253 mmol) at RT and the reaction mixture stirred at RT for 6 hrs. The mixture was concentrated under reduced pressure to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% FA) to give the title compound (18 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.18 (s, 1H), 4.44 – 4.30 (m, 3H), 3.52 – 3.43 (m, 1H), 3.17 – 3.08 (m, 1H), 2.90 – 2.72 (m, 2H), 2.68 (s, 3H), 2.19 (s, 3H), 2.15 – 2.03 (m, 2H), 1.90 – 1.81 (m, 1H), 1.75 – 1.62 (m, 1H). LC / MS (ESI) (m / z): 439.1 (M+H)+. Example 5 (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-8-(1-methylpiperidin-3-yl)-5,8- dihydropyrimido[4,5-c]pyridazin-7(6H)-one To a solution of (R)-2-(5-(aminomethyl)-4-methyl-6-((1-methylpiperidin-3- yl)amino)pyridazin-3-yl)-5-(trifluoromethyl)phenol (20 mg, 0.051 mmol) in THF (1 mL) was added CDI (16.4 mg, 0.101 mmol) at RT and the reaction mixture was stirred at 50oC overnight. The mixture was concentrated under reduced pressure to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% FA) to give the title compound (3 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.22 (s, 1H), 5.37 – 5.26 (m, 1H), 4.52 (s, 2H), 4.14 (t, J = 11.6 Hz, 1H), 3.63 – 3.52 (m, 2H), 3.05 (t, J = 12.7 Hz, 1H), 2.95 (s, 3H), 2.82 – 2.70 (m, 1H), 2.13 (s, 3H), 2.03 – 1.89 (m, 2H), 1.34 – 1.28 (m, 1H). LC / MS (ESI) (m / z): 422.2 (M+H)+. Example 6 (R)-N-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3-yl) amino)pyridazin-4-yl)methyl)acetamide, partial FA salt To a mixture of (R)-2-(5-(aminomethyl)-4-methyl-6-((1-methylpiperidin-3- yl)amino)pyridazin- 3-yl)-5-(trifluoromethyl)phenol (10 mg, 0.025 mmol) and TEA (5.1 mg, 0.051 mmol) in THF (1 mL) was added Ac2O (3.1 mg, 0.030 mmol) at 0oC. The reaction mixture was stirred at 0oC for 2 hrs. Then the mixture was concentrated under reduced pressure to dryness. The residue was dissolved in MeOH (1 mL) and K2CO3(10 mg) was added. The mixture was stirred at RT for 1 hr. The mixture was filtered and the filtrate was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% FA) to give the title compound (3 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.54 (t, J = 6.0 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.25 – 7.20 (m, 2H), 6.61 (d, J = 7.1 Hz, 1H), 4.22 – 4.21 (m, 2H), 4.18 – 4.10 (m, 1H), 3.00 – 2.95 (m, 1H), 2.71 – 2.58 (m, 1H), 2.20 (s, 3H), 2.08 (s, 3H), 2.01 – 1.89 (m, 2H), 1.88 (s, 3H), 1.86 – 1.80 (m, 1H), 1.76 – 1.70 (m, 1H), 1.60 – 1.51 (m, 1H), 1.30 – 1.22 (m, 1H). LC / MS (ESI) (m / z): 438.2 (M+H)+. Example 7 Methyl (R)-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin- 3-yl)amino)pyridazin-4-yl)methyl)carbamate, partial FA salt To a solution of (R)-2-(5-(aminomethyl)-4-methyl-6-((1-methylpiperidin-3- yl)amino)pyridazin-3- yl)-5-(trifluoromethyl)phenol (20 mg, 0.051 mmol) in THF (1 mL) was added methyl chloroformate (7.3 mg, 0.077 mmol) and TEA (10 mg, 0.10 mmol) at 0oC. The reaction mixture was stirred at 0oC for 2 hrs. The mixture was concentrated under reduced pressure to dryness and the residue was dissolved in MeOH (1 mL). K2CO3(10 mg) was added and the resulting mixture was stirred at 0oC for 1 hr. The mixture was filtered and the filtrate was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% FA) to give the title compound (5 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.17 (s, 1H), 4.46 – 4.31 (m, 3H), 3.70 (s, 3H), 3.61 – 3.46 (m, 1H), 3.30 – 3.25 (m, 1H), 3.23 – 3.13 (m, 1H), 2.97 – 2.84 (m, 1H), 2.73 (s, 3H), 2.20 (s, 3H), 2.17 – 2.07 (m, 2H), 1.95 – 1.82 (m, 1H), 1.81 – 1.65 (m, 1H). LC / MS (ESI) (m / z): 454.4 (M+H)+. Example 8 Methyl (R)-3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin- 3-yl)amino)pyridazin-4-yl)propanoate, partial FA salt Step 1: Tert-butyl (R)-3-((4-(3-methoxy-3-oxopropyl)-6-(2-methoxy-4-(trifluoromethyl) phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a mixture of tert-butyl (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin- 3-yl)amino)piperidine-1-carboxylate (1 g, 2.15 mmol) and 4-methoxy-4- oxobutanoic acid (425 mg, 3.22 mmol) in DMSO (6 mL) were added BPO (1.04 g, 4.29 mmol), 4CzIPN (17 mg, 0.021 mmol) and 4A MS (50 mg) under N2atmosphere. The reaction mixture was degassed with N2three times and stirred under 18W white LED irradiation overnight. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in PE) to give the title compound (86 mg) as a solid. LC / MS (ESI) m / z: 553.3 (M+H)+. Step 2: Methyl (R)-3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin- 3- ylamino)pyridazin-4-yl)propanoate hydrochloride To a solution of tert-butyl (R)-3-((4-(3-methoxy-3-oxopropyl)-6-(2-methoxy-4- (trifluoromethyl) phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (85mg, 0.154 mmol) in DCM (1 mL) was added HCl / 1,4-dioxane (1 mL, 4 M) and the mixture was stirred at RT for 1 hr. The mixture was concentrated under reduced pressure to give the title compound (60 mg) as a solid. LC / MS (ESI) m / z: 453.4 (M+H)+. Step 3: Methyl (R)-3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin-3-yl)amino)pyridazin-4-yl)propanoate To the solution of methyl (R)-3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3- (piperidine-3-ylamino)pyridazin-4-yl)propanoate (60 mg, 0.13 mmol) in MeOH (1 mL) were added 37% aq. HCHO (0.1 mL), AcOH (16 mg, 0.27 mmol) and NaBH3CN (25 mg, 0.40 mmol) and the mixture was stirred under N2 atmosphere at RT for 30 mins. The reaction mixture was quenched with sat. aq. NaHCO3solution and extracted with CHCl3 / i-PrOH (v / v= 3 / 1) twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (50 mg) as a solid. LC / MS (ESI) m / z: 467 (M+H)+. Step 4: Methyl (R)-3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methyl piperidin-3-yl)amino)pyridazin-4-yl)propanoate To the solution of methyl (R)-3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3- ((1- methylpiperidin-3-yl)amino)pyridazin-4-yl)propanoate (50 mg, 0.107 mmol) in DCM (1 mL) was added BBr3(53.7 mg, 0.21 mmol) at -78 ℃ under N2atmosphere and the mixture was stirred at RT for 2 hrs. The reaction mixture was quenched with MeOH at -78 ℃ and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 20~95% MeCN in H2O with 0.1% FA) to give the title compound (15 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.24 – 7.18 (m, 2H), 5.90 (d, J = 7.8 Hz, 1H), 4.34 – 4.20 (m, 1H), 3.62 (s, 3H), 2.96 – 2.92 (m, 1H), 2.88 – 2.80 (m, 2H), 2.68 – 2.63 (m, 1H), 2.50 – 2.46 (m, 2H), 2.19 (s, 3H), 1.98 (s, 3H), 1.95 – 1.81 (m, 3H), 1.74 – 1.67 (m, 1H), 1.60 – 1.54 (m, 1H), 1.44 – 1.34 (m, 1H). LC / MS (ESI) m / z: 453.1 (M+H)+. Example 9 (R)-3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3- yl)amino)pyridazin-4-yl)propanoic acid To a solution of methyl (R)-3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methyl piperidin-3-yl)amino)pyridazin-4-yl)propanoate (15 mg, 0.033 mmol) in MeOH (1 mL) and water (0.2 mL) was added LiOH (4 mg, 0.167 mmol) and the mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% FA) to give the title compound (3 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 4.64 – 4.52 (m, 1H), 3.77 – 3.34 (m, 2H), 3.28 – 3.05 (m, 2H), 3.04 – 2.97 (m, 2H), 2.84 (s, 3H), 2.63 – 2.51 (m, 1H), 2.45 – 2.35 (m, 1H), 2.32 – 2.18 (m, 1H), 2.13 (s, 3H), 2.10 – 1.99 (m, 1H), 1.99 – 1.73 (m, 2H). LC / MS (ESI) m / z: 439.2 (M+H)+. Example 10 (R)-3-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-methyl-8-(1-methylpiperidin-3-yl)-5,8- dihydropyrido[2,3-c]pyridazin-7(6H)-one 3 To a solution of (R)-3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin- 3-yl)amino)pyridazin-4-yl)propanoic acid (50 mg, 0.11 mmol) in MeCN (3 mL) was added NMI (37 mg, 0.46 mmol) and the mixture was stirred at 70 ℃ for 5 mins. TCFH (48 mg, 0.17 mmol) was added to the reaction mixture the resulting mixture was stirred

[0009] at 70 ℃ for 3 hrs. The mixture was concentrated to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 20~90% MeCN in H2O with 0.1% NH3H2O) to give the title compound (3 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.31 – 7.24 (m, 2H), 5.14 – 5.07 (m, 1H), 2.97 – 2.90 (m, 3H), 2.76 – 2.70 (m, 3H), 2.65 – 2.61 (m, 2H), 2.20 (s, 3H), 2.09 (s, 3H), 1.90 – 1.83 (m, 1H), 1.76 – 1.70 (m, 1H), 1.67 – 1.55 (m, 2H). LC / MS (ESI) m / z: 421.3 (M+H)+. Example 11 (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3- yl)amino)pyridazine-4-carboxylic acid Step 1: Methyl 3,6-dichloropyridazine-4-carboxylate To a mixture of 3,6-dichloropyridazine-4-carboxylic acid (5 g, 25.9 mmol) in MeOH (25 mL) and DCM (8 mL) was added TMSCHN2(19.43 mL, 38.9 mmol, 2 M in hexane) drop-wisely at 0oC and the mixture was stirred at RT overnight. The reaction mixture was quenched with ice-water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~10% EtOAc in PE) to give the title compound (2.7 g) as an oil.1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 4.02 (s, 3H). LC- MS (ESI) (m / z): 207.1 (M+H)+. Step 2: Methyl 3,6-dichloro-5-methylpyridazine-4-carboxylate To a mixture of methyl 3,6-dichloropyridazine-4-carboxylate (2.5 g, 12.1 mmol) in DMSO (20 104 mL) was added MeNO2(3.68 g, 60.4 mmol) and the mixture was stirred at RT for 30 mins. Then TEA (1.83 g, 18.1 mmol) was added drop-wisely to the above mixture at 0oC and the resulting mixture was stirred at RT for 3 hrs. The reaction mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~10% EtOAc in PE) to give the title compound (1.5 g) as a solid.1H NMR (400 MHz, CDCl3) δ 4.02 (s, 3H), 2.39 (s, 3H). LC-MS (ESI) (m / z): 221.1 (M+H)+. Step 3: Methyl 3-chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl pyridazine-4- carboxylate To a mixture of methyl 3,6-dichloro-5-methylpyridazine-4-carboxylate (1.4 g, 6.33 mmol) and (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (550 mg, 4.22 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added Pd(dtbpf)Cl2(415 mg, 4.22 mmol) and K2CO3(1.75 g, 12.7 mmol) under N2atmosphere. The reaction mixture was degassed with N2three times and stirred at RT for 3 hrs. The reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in PE) and further purified by chiral SFC to give the title compound (700 mg) as a solid. The structure was confirmed by the nuclear Overhauser effect. Chiral SFC condition: ChiralPak C-IG, 250×30 mm I.D., 5µm Mobile phase: A for CO2and B for MeOH (0.1% 7 M NH3in MeOH) Gradient: B 20%; Flow rate: 60 mL / min.1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.14 (s, 1H), 3.79 (s, 3H), 3.69 (s, 3H), 2.54 (s, 3H). LC-MS (ESI) (m / z): 361.2 (M+H)+. Step 4: (R)-3-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazine-4-carboxylic acid To a mixture of methyl 3-chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazine- 4-carboxylate (700 mg, 1.94 mmol) and tert-butyl (R)-3-aminopiperidine- 1-carboxylate (971.6 mg, 4.85 mmol) in DMSO (15 mL) was added CsF (491 mg, 0.753 mmol) at RT and the mixture was stirred under N2atmosphere at 120oC for 6 hrs. After cooling to RT, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in PE) to give the title compound (600 mg) as a solid. LC-MS (ESI) (m / z): 511.4 (M+H)+. Step 5: (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3-ylamino) pyridazine-4-carboxylic acid To a solution of (R)-3-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazine-4-carboxylic acid (200 mg, 0.39 mmol) in DCM (2 mL) was added BBr3(489 mg, 1.96 mmol) at -78oC and the mixture was stirred at RT for 2 hrs. The reaction mixture was quenched with MeOH at -50oC and concentrated under reduced pressure to dryness to give the title compound (160 mg) as an oil, which was directly used in the next reaction without purification. LC-MS (ESI) (m / z): 397.4 (M+H)+. Step 6: (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3- yl)amino)pyridazine-4-carboxylic acid, FA salt To a mixture of ((R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3- ylamino)pyridazine-4-carboxylic acid (80 mg, 0.252 mmol), 37% aq. HCHO (0.1 mL) in MeOH (1 mL) was added AcOH (30.3 mg, 0.505 mmol) and NaBH3CN (47.6 mg, 0.757 mmol) at 0oC and the mixture was stirred at RT for 30 mins. The reaction mixture was concentrated under reduced pressure to dryness. The residue was purified by pre-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% FA) to give the title compound (10 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 4.52 – 4.37 (m, 1H), 4.12 – 3.85 (m, 1H), 3.57 – 3.45 (m, 1H), 3.15 – 2.75 (m, 2H), 2.88 (s, 3H), 2.22 (s, 3H), 2.16 – 2.08 (m, 2H), 2.02 – 1.50 (m, 2H). LC-MS (ESI) (m / z): 411.4 (M+H)+. Example 12 (R)-N-carbamimidoyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methyl piperidin-3-yl)amino)pyridazine-4-carboxamide, FA salt Step 1: Tert-butyl (R)-N-carbamimidoyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methyl-3-((1-methylpiperidin-3-yl)amino)pyridazine-4-yl)propanoyl)carbamate To a solution of (R)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin- 3-yl)amino)pyridazine-4-carboxylic acid (10 mg, 0.024 mmol) and 1-(tert- butoxycarbonyl)guanidine (5.8 mg, 0.037 mmol) in MeCN (1 mL) was added NMI (8 mg, 0.097 mmol) and the mixture was stirred at 70oC for 5 mins. TCFH (10.3 mg, 0.037 mmol) was added and the resulting mixture was stirred at 70oC for 1 hr. The mixture was concentrated under reduced pressure to give the title compound (12 mg) as an oil, which was directly used in the next reaction without purification. LC / MS (ESI) (m / z): 552.5 (M+H)+. Step 2: (R)-N-carbamimidoyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin-3-yl)amino)pyridazine-4-carboxamide, FA salt To a solution of tert-butyl (R)-N-carbamimidoyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methyl-3-((1-methylpiperidin-3-yl)amino)pyridazine-4-yl)propanoyl)carbamate (12 mg, 0.024 mmol) in DCM (1 mL) was added TFA (0.5 mL) and the mixture was stirred at RT for 3 hr. The mixture was concentrated to dryness and the residue was purified by pre-HPLC (YMC- Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% FA) to give the title compound (1 mg) as a solid. LC / MS (ESI) (m / z): 452.3 (M+H)+. Example 13 (R)-N-carbamoyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin-3-yl)amino)pyridazine-4-carboxamide Step 1: (R)-N-carbamoyl-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3- (piperidin-3- ylamino)pyridazine-4-carboxamide To a mixture of (R)-3-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)-6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazine-4-carboxylic acid (120 mg, 0.235 mmol) and cyanamide (15 mg, 0.353 mmol) in DMF (3 mL) were added BOP (156 mg, 0.353 mmol) and DIEA (91 mg, 0.705 mmol) at RT and the mixture was stirred under N2 atmosphere at RT overnight. To the mixture was added aq. HCl (3 mL, 3 M) and the resulting mixture was stirred at 50 ℃ for 3 hrs. The mixture was neutralized with sat. aq. NaHCO3 solution and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (200 mg) as a solid. LC-MS (ESI) m / z: 453.3 (M+H)+. Step 2: (R)-N-carbamoyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3- (piperidin-3- ylamino)pyridazine-4-carboxamide To the solution of (R)-N-carbamoyl-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3- (piperidin-3-ylamino)pyridazine-4-carboxamide (200 mg, 0.442 mmol) in DCM (3 mL) was added BBr3 (1 mL, 1 mmol, 1 M in DCM) at -78 ℃ under N2 atmosphere and the mixture was stirred at RT for 3 hrs. The mixture was poured into ice-cold sat. aq. NaHCO3solution and extracted with DCM twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (YMC-Actus Triart C18250*20 mm, 40~65% MeCN in H2O with 0.1% NH3.H2O) to give the title compound (60 mg) as a solid. LC-MS (ESI) m / z: 439.3 (M+H)+. Step 3: (R)-N-carbamoyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methyl piperidin-3-yl)amino)pyridazine-4-carboxamide (ZAZ-N221938-452) To a mixture of (R)-N-carbamoyl-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3- (piperidin-3-ylamino)pyridazine-4-carboxamide (50 mg, 0.114 mmol) and 37% aq. HCHO (18 mg, 0.228 mmol) in MeOH (2 mL) was added NaBH3CN (22 mg, 0.342 mmol) at 0 ℃ and the mixture was stirred at RT for 30 mins. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus TriartC18250*20 mm, 30~95% MeCN in H2O with 0.1% NH3.H2O) to give the title compound (23 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 4.46 – 4.39 (m, 1H), 3.11 – 2.84 (m, 2H), 2.60 – 2.57 (m, 1H), 2.30 (s, 3H), 2.28 – 2.23 (m, 1H), 2.11 (s, 3H), 1.97 – 1.87 (m, 1H), 1.84 – 1.77 (m, 1H), 1.72 – 1.64 (m, 1H), 1.62 – 1.49 (m, 1H). LC-MS (ESI) m / z: 453.1 (M+H)+. Example 14 (R)-2-(5-(hydroxymethyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin-3-yl)-5- (trifluoromethyl)phenol, FA salt (partial)

[0010] Step 1: Tert-butyl (R)-3-((4-((benzyloxy)methyl)-6-(2-methoxy-4- (trifluoromethyl)phenyl)- 5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a mixture of tert-butyl (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin- 3-yl)amino)piperidine-1-carboxylate (1.0 g, 2.15 mmol) in MeCN (6 mL) and water (6 mL) was added 2-(benzyloxy)acetic acid (534 mg, 3.22 mmol), AgNO3(0.36 g, 0.429 mmol) and K2S2O8(0.71 g, 3.22 mmol) successively under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 60oC overnight. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate and wash were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 50~80% EtOAc in PE) to give the title compound (200 mg, 15.9% yield) as a solid. LC / MS (ESI) (m / z): 587 (M+H)+. Step 2: (R)-4-((benzyloxy)methyl)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-N- (piperidin-3-yl)pyridazin-3-amine To a solution of tert-butyl (R)-3-((4-((benzyloxy)methyl)-6-(2-methoxy-4-(trifluoromethyl) phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (40 mg, 0.068 mmol) in 1,4- dioxane (1 mL) was added HCl / 1,4-dioxane (1 mL, 4 M) and the mixture was stirred at RT for 1 hr. The mixture was basified with sat. aq. NaHCO3solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (30 mg) as a solid. LC / MS (ESI) (m / z): 487 (M+H)+. Step 3: (R)-4-((benzyloxy)methyl)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-N- (1- methylpiperidin-3-yl)pyridazin-3-amine To a solution of (R)-4-((benzyloxy)methyl)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methyl- N-(piperidin-3-yl)pyridazin-3-amine (30 mg, 0.062 mmol) and aq. HCHO (25 mg, 0.31 mmol, 37% wt. in water) in MeOH (2 mL) was added NaBH3CN (11 mg, 0.19 mmol) and the mixture was stirred at RT for 30 mins. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (23 mg) as a solid. LC / MS (ESI) (m / z): 501 (M+H)+. Step 4: (R)-2-(5-(hydroxymethyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)pyridazin- 3- yl)-5-(trifluoromethyl)phenol To a solution of (R)-4-((benzyloxy)methyl)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methyl-N-(1-methylpiperidin-3-yl)pyridazin-3-amine (15 mg, 0.030 mmol) in DCM (5 mL) was added BBr3(1.5 mL, 0.15 mmol, 1 M in DCM) drop-wisely at -20oC and the mixture was stirred at -20oC for 5 hrs. The reaction mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% FA) to give the title compound (2 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.32 – 7.24 (m, 2H), 7.22 (s, 1H), 6.33 (d, J = 7.4 Hz, 1H), 5.49 (bs, 1H), 4.57 (s, 2H), 4.50 – 4.46 (m, 1H), 3.75 – 3.66 (m, 1H), 3.48 – 3.40 (m, 1H), 2.96 – 2.87 (m, 1H), 2.83 (s, 3H), 2.80 – 2.72 (m, 1H), 2.04 (s, 3H), 2.01 – 1.95 (m, 1H), 1.81 – 1.68 (m, 1H), 1.65 – 1.47 (m, 1H). LC / MS (ESI) (m / z): 397 (M+H)+. Example 15 (R)-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3- yl)amino) pyridazin-4-yl)methyl carbamate To a mixture of (R)-2-(5-(hydroxymethyl)-4-methyl-6-((1-methylpiperidin-3- yl)amino)pyridazin- 3-yl)-5-(trifluoromethyl)phenol (20 mg, 0.076 mmol) and TEA (22.9 mg, 0.227 mmol) in DCM (1 mL) was added trichloroacetyl isocyanate (21.3 mg, 0.114 mmol) at 0oC. The reaction mixture was stirred at RT for 3 hrs. Then the mixture was concentrated under reduced pressure to dryness. The residue was dissolved in MeOH (1 mL) and the resulting

[0011] mixture was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% FA) to give the title compound (6 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.17 (s, 1H), 5.19 (s, 2H), 4.42 – 4.30 (m, 1H), 3.15 – 3.06 (m, 1H), 2.79 – 2.65 (m, 1H), 2.36 (s, 3H), 2.34 – 2.24 (m, 2H), 2.21 (s, 3H), 2.07 – 1.98 (m, 1H), 1.92 – 1.83 (m, 1H), 1.78 – 1.68 (m, 1H), 1.60 – 1.47 (m, 1H). LC / MS (ESI) (m / z): 440.1 (M+H)+. Example 16 (R)-3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3-yl) amino)pyridazin-4-yl)propanamide, FA salt (partial) Step 1: Tert-butyl (R)-3-((4-formyl-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl pyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (R)-3-((4-(hydroxymethyl)-6-(2-methoxy-4- (trifluoromethyl)phenyl)- 5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (300 mg, 0.60 mmol) in DCM (3 mL) was added Dess-Martin reagent (330 mg, 0.78 mmol) at 0oC and the mixture was stirred at 30oC for 1 hour. The mixture was quenched with saturated aq. NaHCO3solution and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~20% EtOAc in PE) to give the title compound (252 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 10.63 (s, 1H), 8.53 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.19 (s, 1H), 3.84 (s, 3H), 3.70 – 3.51 (m, 3H), 3.39 – 3.30 (m, 1H), 2.39 (s, 3H), 2.03 – 1.95 (m, 1H), 1.86 – 1.77 (m, 2H), 1.70 – 1.56 (m, 2H), 1.42 (s, 9H). LC / MS (ESI) m / z: 495.3 (M+H)+. Step 2: Tert-butyl (R,E)-3-((4-(3-amino-3-oxoprop-1-en-1-yl)-6-(2-methoxy-4-(trifluoro methyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of diethyl (2-amino-2-oxoethyl)phosphonate (67 mg, 0.368 mmol) in THF (1 mL) 111 was added NaH (15 mg, 0.375 mmol, 60% dispersion in mineral oil) at 0oC and the mixture was stirred at 0 ℃ for 1 hour. Then a solution of tert-butyl (R)-3-((4-formyl-6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate(130 mg, 0.263 mmol) in THF (2 mL) was added to the above mixture and the resulting mixture was stirred at RT for 1 hr. The reaction mixture was quenched with sat. aq. NH4Cl solution with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in PE) to give the title compound (80 mg) as a solid. LC-MS (ESI) m / z: 536.5 (M+H)+. Step 3: Tert-butyl (R)-3-((4-(3-amino-3-oxopropyl)-6-(2-methoxy-4-(trifluoromethyl) phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (R,E)-3-((4-(3-amino-3-oxoprop-1-en-1-yl)-6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (70 mg, 0.131 mmol) in MeOH (1 mL) and EtOAc (1 mL) was added Pd / C (10 mg, 10% wt.) under N2temperature and the mixture was stirred under a H2balloon at RT overnight. 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: 538.6 (M+H)+. Step 4: (R)-3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3-ylamino) pyridazin-4-yl)propanamide To the solution of tert-butyl (R)-3-((4-(3-amino-3-oxopropyl)-6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (55 mg, 0.102 mmol) in DCM (1 mL) was added BBr3(128 mg, 0.512 mmol) at -78 ℃ under N2atmosphere and the mixture was stirred at RT for 2 hrs. The reaction mixture was quenched with MeOH at -78 ℃ and concentrated under reduced pressure to dryness to give the title compound (40 mg) as a solid. LC-MS (ESI) m / z: 424.4 (M+H)+. Step 5: (R)-3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin- 3- yl)amino)pyridazin-4-yl)propanamide, FA salt To the solution of (R)-3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3- ylamino)pyridazin-4-yl)propanamide (35 mg, 0.083 mmol) in MeOH (1 mL) were added 37% aq. HCHO (0.1 mL), AcOH (10 mg, 0.165 mmol) and NaBH3CN (16 mg, 0.248 mmol) and the mixture was stirred under N2atmosphere at RT for 30 minutes. The mixture was concentrated to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% FA) to give the title compound (12 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.18 (s, 1H), 4.51 – 4.41 (m, 1H), 3.80 – 3.55 (m, 1H), 3.43 – 3.33 (m, 1H), 3.15 – 3.04 (m, 1H), 3.01 – 2.96 (m, 2H), 2.86 (s, 3H), 2.60 – 2.50 (m, 2H), 2.22 – 2.15 (m, 2H), 2.15 (s, 3H), 1.99 – 1.80 (m, 2H), 1.42 – 1.22 (m, 1H). LC / MS (ESI) m / z: 438.2 (M+H)+. Example 17 Ethyl (R)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino) piperidin-1-yl)propanoate Step 1: (R)-2-(4-Methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5- (trifluoromethyl)phenol To a solution of tert-butyl (R)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin- 3-yl)amino)piperidine-1-carboxylate (400 mg, 0.857 mmol) in DCM (5 mL) was added BBr3(2.57 mL, 2.57 mmol, 1 M in DCM) drop-wisely at -78 ℃ and the mixture was stirred at -78 ℃ to RT for 2 hrs. The mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (320 mg) as a solid, which was directly used in the next reaction without purification. LC / MS (ESI) (m / z): 353.2 (M+H)+. Step 2: Ethyl (R)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl) amino)piperidin-1-yl)propanoate To a solution of (R)-2-(4-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5- (trifluoromethyl)phenol (60 mg, 0.170 mmol) in EtOH (2 mL) was added Cs2CO3(222 mg, 0.681 mmol) at RT and the mixture was stirred at RT for 5 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (11 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 6.77 (s, 1H), 4.16 – 4.10 (m, 3H), 3.15 – 3.08 (m, 1H), 2.83 – 2.75 (m, 3H), 2.57 (t, J = 7.2 Hz, 2H), 2.40 – 2.31 (m, 1H), 2.30 – 2.21 (m, 1H), 2.13 (s, 3H), 2.02 – 1.95 (m, 1H), 1.87 – 1.80 (m, 1H), 1.73 – 1.65 (m, 1H), 1.52 – 1.43 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m / z): 453.2 (M+H)+. Example 18 (R)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino) piperidin-1-yl)propanoic acid, partial FA salt To a solution of ethyl (R)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin- 3-yl)amino)piperidin-1-yl)propanoate (50 mg, 0.11 mmol) in MeOH (2 mL) and water (0.5 mL) was added LiOH (10.6 mg, 0.44 mmol) and the mixture was stirred at RT for 1 hr. The mixture was concentrated under vacuum to dryness. The residue was purified by prep-HPLC (YMC- Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% FA) to give the title compound (12 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 6.85 (s, 1H), 4.39 – 4.32 (m, 1H), 3.60 – 3.52 (m, 1H), 3.36 – 3.33 (m, 1H), 3.28 – 3.15 (m, 4H), 2.64 – 2.51 (m, 2H), 2.20 – 2.07 (m, 2H), 2.14 (s, 3H), 1.98 – 1.88 (m, 1H), 1.84 – 1.74 (m, 1H). LC / MS (ESI) (m / z): 425.2 (M+H)+. The examples listed in Error! Reference source not found.2 were prepared following similar methods and protocols described for the synthesis of Example 17 Table 2. Examples Prepared Using Procedure for Example 17

[0012] Example 23 Methyl 3-((3R)-3-((6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate Step 1: Tert-butyl (3R)-3-((6-(2-(methoxymethoxy)-6-(methoxymethyl)-4- (trifluoromethyl) phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a mixture of 2-(2-(methoxymethoxy)-6-(methoxymethyl)-4-(trifluoromethyl)phenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (263 mg, 0.700 mmol) and tert-butyl (R)-3-((6- bromo-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (Intermediate 6, 200 mg, 0.539 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was added Pd(dtbpf)Cl2(35 mg, 0.054 mmol) and K2CO3(223 mg, 1.616 mmol) under N2atmosphere. The reaction mixture was degassed with N2 three times and stirred at 70oC for 3 hrs. After cooling to RT, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~40% EtOAc in PE) to give the title compound (130 mg) as a solid. LC-MS (ESI) (m / z): 541.3 (M+H)+. Step 2: 3-(Methoxymethyl)-2-(4-methyl-6-(((R)-piperidin-3-yl)amino)pyridazin-3-yl)-5- (trifluoromethyl)phenol hydrochloride To a solution of tert-butyl (3R)-3-((6-(2-(methoxymethoxy)-6-(methoxymethyl)-4-(trifluoro- methyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (120 mg, 0.22 mmol) in DCM (1 mL) was added HCl / 1,4-dioxane (1 mL, 4 M) and the mixture was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure to dryness to afford the title compound (100 mg) as a solid, which was directly used in the next reaction without purification. LC-MS (ESI) m / z: 397.4 (M+H)+. Step 3: Methyl 3-((3R)-3-((6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl)phenyl)- 5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate The title compound was prepared following methods and protocols described in Example 17 step 2 and purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% NH4HCO3) as a solid.1H NMR (400 MHz, CD3OD) δ 7.30 (s, 1H), 7.11 (s, 1H), 6.79 (s, 1H), 4.27 (dd, J = 12.4, 3.0 Hz, 1H), 4.16 (dd, J = 12.4, 3.3 Hz, 1H), 4.14 – 4.08 (m, 1H), 3.67 & 3.66 (s, 3H), 3.21 & 3.20 (s, 3H), 3.08 – 3.01 (m, 1H), 2.79 – 2.68 (m, 3H), 2.59 -2.53 (m, 2H), 2.32 – 2.15 (m, 2H), 2.01 (s, 3H), 2.00 – 1.92 (m, 1H), 1.84 – 1.76 (m, 1H), 1.71 – 1.63 (m, 1H), 1.50 – 1.41 (m, 1H). LC-MS (ESI) m / z: 483.3 (M+H)+. Example 24 3-((3R)-3-((6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl)phenyl)-5-methyl- pyridazin-3-yl)amino)piperidin-1-yl)propanoic acid The title compound was prepared following methods and protocols described in Example 18 and purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 20~95% MeCN in H2O with 0.1% NH4HCO3) as a solid.1H NMR (400 MHz, CD3OD) δ 7.30 (s, 1H), 7.12 (s, 1H), 6.87 (s, 1H), 4.41 – 4.32 (m, 1H), 4.29 – 4.21 (m, 1H), 4.19 – 4.12 (m, 1H), 3.57 – 3.46 (m, 1H), 3.36 – 3.32 (m, 1H), 3.30 – 3.21 (m, 4H), 3.19 & 3.18 (s, 3H), 2.66 – 2.45 (m, 2H), 2.21 – 2.07 (m, 2H), 2.05 (s, 3H), 1.98 – 1.87 (m, 1H), 1.86 – 1.71 (m, 1H). LC-MS (ESI) m / z: 469.3 (M+H)+. Example 25 Ethyl (R)-3-(3-((6-(2-hydroxy-4-methoxyphenyl)-5-methylpyridazin-3-yl)amino) piperidin- 1-yl)propanoate Step 1: 2-(Benzyloxy)-1-bromo-4-methoxybenzene To a solution of 2-bromo-5-methoxyphenol (25.0 g, 123.13 mmol) in DMF (40 mL) was added BnBr (21.06 g, 123.13 mmol) and K2CO3(34.04 g, 246.27 mmol) at 0 ℃ and the mixture was stirred at RT for 16 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~13% EtOAc in PE) to give the title compound (23.0 g) as an oil.1H NMR (400 MHz, CDCl3) δ 7.52 – 7.35 (m, 5H), 7.35 – 7.28 (m, 1H), 6.52 (d, J = 2.7 Hz, 1H), 6.46 – 6.35 (m, 1H), 5.12 (s, 2H), 3.75 (s, 3H). Step 2: 2-(2-(Benzyloxy)-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0013] To a mixture of 2-(benzyloxy)-1-bromo-4-methoxybenzene (11.6 g, 39.569 mmol) and HBpin (10.13 g, 79.138 mmol) in 1,4-dioxane (120 mL) were added TEA (12.01 g, 118.707 mmol), SPhos (3.25 g, 7.914 mmol) and Pd(MeCN)2Cl2(1.03 g, 3.957 mmol) successively under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 60 °C overnight. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in PE) to give the title compound (10 g) as an oil.1H NMR (400 MHz, CDCl3) δ 7.73 – 7.57 (m, 3H), 7.40 – 7.33 (m, 2H), 7.32 – 7.26 (m, 1H), 6.54 – 6.47 (m, 2H), 5.10 (s, 2H), 3.81 (s, 3H), 1.36 (s, 12H). Step 3: Tert-butyl (R)-3-((6-(2-(benzyloxy)-4-methoxyphenyl)-5-methylpyridazin-3-yl)- amino)piperidine-1-carboxylate To a mixture of 2-(2-(benzyloxy)-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.1 g, 3.23 mmol) and tert-butyl (R)-3-((6-bromo-5-methylpyridazin-3-yl)amino)- piperidine- 1-carboxylate (Intermediate 6, 1.0 g, 3.23 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was added Pd(dtbpf)Cl2(175.3 mg, 0.27 mmol) and K2CO3(744.5 mg, 5.39 mmol) under N2atmosphere. The reaction mixture was degassed with N2three times and stirred at 80oC for 3 hrs. After cooling to RT, the reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in PE) to give the title compound (700 mg) as a solid. LC-MS (ESI) (m / z): 505.3 (M+H)+. Step 4: (R)-6-(2-(benzyloxy)-4-methoxyphenyl)-5-methyl-N-(piperidin-3-yl)pyridazin-3- amine hydrochloride To a solution of tert-butyl (R)-3-((6-(2-(benzyloxy)-4-methoxyphenyl)-5-methylpyridazin-3- yl)-amino)piperidine-1-carboxylate (101 mg, 0.20 mmol) in DCM (2 mL) was added HCl / 1,4- dioxane (1 mL, 4 M) and the mixture was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure to dryness to afford the title compound (75 mg) as a solid, which was directly used in the next reaction without purification. LC-MS (ESI) (m / z): 405.2 (M+H)+. Step 5: Ethyl (R)-3-(3-((6-(2-(benzyloxy)-4-methoxyphenyl)-5-methylpyridazin-3- yl)amino)- piperidin-1-yl)propanoate To a solution of (R)-6-(2-(benzyloxy)-4-methoxyphenyl)-5-methyl-N-(piperidin-3-yl)- pyridazin- 3-amine hydrochloride (75 mg, 0.17 mmol) in EtOH (1 mL) was added , TEA (52 118 mg, 0.52 mmol) and ethyl acrylate (26 mg, 0.30 mmol) at 0oC and the mixture was stirred at 25oC overnight. The mixture was concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~5% MeOH in DCM) to give the title compound (86 mg) as a solid. LC / MS (ESI) m / z: 505.3 (M+H)+. Step 6: Ethyl (R)-3-(3-((6-(2-hydroxy-4-methoxyphenyl)-5-methylpyridazin-3-yl)amino)- piperidin-1-yl)propanoate To a solution of ethyl (R)-3-(3-((6-(2-(benzyloxy)-4-methoxyphenyl)-5-methylpyridazin-3- yl)amino)piperidin-1-yl)propanoate (86 mg, 0.17 mmol) in EtOH (2 mL) was added Pd / C (4 mg, 10% wt.) at RT under N2 atmosphere and the mixture was stirred under a H2 balloon at 30oC for 1 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 10~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (30 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.11 (d, J = 9.1 Hz, 1H), 6.65 (s, 1H), 6.50 – 6.41 (m, 3H), 4.05 (q, J = 7.1 Hz, 2H), 4.01 – 3.92 (m, 1H), 3.74 (s, 3H), 2.98 – 2.89 (m, 1H), 2.69 – 2.56 (m, 3H), 2.45 (t, J = 7.0 Hz, 2H), 2.09 – 2.05 (m, 1H), 2.05 (s, 3H), 1.98 – 1.90 (m, 1H), 1.89 – 1.80 (m, 1H), 1.74 – 1.63 (m, 1H), 1.56 – 1.42 (m, 1H), 1.34 – 1.23 (m, 1H), 1.17 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m / z: 415.3 (M+H)+. Example 26 (R)-3-(3-((6-(2-hydroxy-4-methoxyphenyl)-5-methylpyridazin-3-yl)amino)piperidin-1- yl) propanoic acid The title compound was prepared following methods and protocols described in Example 18 and purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% NH4HCO3) as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J = 8.1 Hz, 1H), 6.72 (s, 1H), 6.58 – 6.50 (m, 3H), 3.80 (s, 3H), 3.04 – 2.99 (m, 1H), 2.78 – 2.72 (m, 1H), 2.65 (t, J = 6.9 Hz, 2H), 2.36 (t, J = 7.2 Hz, 2H), 2.20 – 2.13 (m, 1H), 2.11 (s, 3H), 2.09 – 2.00 (m, 2H), 1.95 – 1.88 (m, 1H), 1.80 – 1.72 (m, 1H), 1.62 – 1.53 (m, 1H), 1.41 – 1.32 (m, 1H). LC-MS (ESI) m / z: 387.3 (M+H)+. Example 27 Tert-butyl (R)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate Step 1: (R)-2-(5-(hydroxymethyl)-4-methyl-6-(piperidin-3-ylamino)pyridazin-3-yl)-5- (trifluoromethyl)phenol To a solution of tert-butyl (R)-3-((4-(hydroxymethyl)-6-(2-methoxy-4- (trifluoromethyl)phenyl)- 5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (200 mg, 0.40 mmol) in DCM (3 mL) was added BBr3(503 mg, 2.03 mmol) drop-wisely at -78oC and the mixture was stirred at 25oC for 1 hour. The reaction mixture was quenched with MeOH at -78oC and concentrated under reduced pressure to give the title compound (120 mg) as an oil, which was directly used in the next reaction without purification. LC / MS (ESI) m / z: 383.1 (M+H)+. Step 2: Tert-butyl (R)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4- (hydroxymethyl)- 5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate The title compound was prepared following methods and protocols described in Example 17 step 2 and purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 20~95% MeCN in H2O with 0.1% NH4HCO3) as a solid.1H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.20 (s, 1H), 4.81 – 4.71 (m, 2H), 4.42 – 4.35 (m, 1H), 3.10 – 2.96 (m, 1H), 2.74 (t, J = 7.2 Hz, 2H), 2.70 – 2.60 (m, 1H), 2.50 (t, J = 7.2 Hz, 2H), 2.46 – 2.30 (m, 2H), 2.18 (s, 3H), 2.03 – 1.94 (m, 1H), 1.90 – 1.83 (m, 1H), 1.73 – 1.58 (m, 2H), 1.49 (s, 9H). LC-MS (ESI) (m / z): 511.3 (M+H)+. Example 28 Ethyl 3-((3R)-3-((4-(aminomethyl)-6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl)- phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate, FA salt The title compound was prepared following methods and protocols described in Example 17 step 2 as a solid.1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.20 (s, 1H), 6.24 (d, J = 8.0 Hz, 1H), 5.44 (bs, 1H), 4.58 (d, J = 13.3 Hz, 1H), 4.48 (d, J = 13.3 Hz, 1H), 4.28 – 4.22 (m, 1H), 4.06 (q, J = 7.1 Hz, 2H), 2.83 – 2.77 (m, 1H), 2.69 – 2.53 (m, 3H), 2.48 – 2.43 (m, 2H), 2.33 – 2.20 (m, 2H), 2.01 (s, 3H), 1.80 – 1.64 (m, 2H), 1.56 – 1.44 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H). LC-MS (ESI) m / z: 483.2 (M+H)+. Example 29 (R)-3-(3-((4-((carbamoyloxy)methyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoic acid Step 1: Tert-butyl (R)-3-(3-((4-((carbamoyloxy)methyl)-6-(2-hydroxy-4-(trifluoromethyl) phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate The title compound was prepared following methods and protocols described in Example 15 as a solid. LCMS (ESI) m / z: 554.3 (M+H)+. Step 2: (R)-3-(3-((4-((carbamoyloxy)methyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoic acid To a solution of tert-butyl (R)-3-(3-((4-((carbamoyloxy)methyl)-6-(2-hydroxy-4-(trifluoro- methyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate (40 mg, 0.072 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) at 0 ℃ and the mixture was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (8 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.18 (s, 1H), 5.27 (d, J = 13.3 Hz, 1H), 5.17 (d, J = 13.3 Hz, 1H), 4.55 – 4.44 (m, 1H), 3.65 – 3.51 (m, 1H), 3.42 – 3.32 (m, 3H), 3.29 – 3.17 (m, 2H), 2.76 – 2.57 (m, 2H), 2.24 (s, 3H), 2.23 – 2.09 (m, 2H), 2.01 – 1.82 (m, 2H). LCMS (ESI) m / z: 498.2 (M+H)+. Example 30 Ethyl (R)-3-(3-((4-((carbamoyloxy)methyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate The title compound was prepared following protocols described in Example 15 as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.16 (s, 1H), 5.23 – 5.11 (m, 2H), 4.38 – 4.32 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.06 – 2.94 (m, 1H), 2.78 (t, J = 7.1 Hz, 2H), 2.69 – 2.60 (m, 1H), 2.57 (t, J = 7.1 Hz, 2H), 2.52 – 2.38 (m, 2H), 2.21 (s, 3H), 1.93 – 1.79 (m, 2H), 1.71 – 1.61 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H). LCMS (ESI) m / z: 526.2 (M+H)+. Example 31 (R)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoic acid Step 1: Ethyl (R)-3-(3-((4-((benzyloxy)methyl)-6-(2-methoxy-4-(trifluoromethyl)phenyl)- 5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate The title compound was prepared following methods and protocols described in Example 17 step 2 as a solid. LC / MS (ESI) (m / z): 587.4 (M+H)+. Step 2: (R)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoic acid To a solution of ethyl (R)-3-(3-((4-((benzyloxy)methyl)-6-(2-methoxy-4-(trifluoro- methyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate (65 mg, 0.111 mmol) in DCM (2 mL) was added BBr3 (0.22 mL, 0.22 mmol, 1M in DCM) drop-wisely at -78oC. The mixture was stirred at -78oC to RT for 1 hr. The mixture was quenched with MeOH at - 78oC and concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (12 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 4.80 (d, J = 13.6 Hz, 1H), 4.75 (d, J = 13.6 Hz, 1H), 4.54 – 4.48 (m, 1H), 3.49 – 3.37 (m, 2H), 3.25 – 3.12 (m, 4H), 2.57 – 2.45 (m, 2H), 2.15 (s, 3H), 2.14 – 2.06 (m, 2H), 1.98 – 1.86 (m, 2H). LC-MS (ESI) (m / z): 455.3 (M+H)+. Example 32 Ethyl 3-((3R)-3-((4-((((benzyloxy)carbonyl)amino)methyl)-6-(2-hydroxy-6-(methoxyme- thyl)- 4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1- yl)propanoate

[0014] Step 1: Tert-butyl (3R)-3-((4-((((benzyloxy)carbonyl)amino)methyl)-6-(2- (methoxymethoxy)-6-(methoxymethyl)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-1-carboxylate The title compound was prepared following methods and protocols described in Example 14 step 1 as a solid. LC-MS (ESI) m / z: 704.3 (M+H)+. Step 2: Benzyl ((6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl)phenyl)-5-methyl- 3- (((R)-piperidin-3-yl)amino)pyridazin-4-yl)methyl)carbamate hydrochloride To a solution of tert-butyl (3R)-3-((6-(2-(methoxymethoxy)-6-(methoxymethyl)-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (90 mg, 0.128 mmol) in DCM (1 mL) was added HCl / 1,4-dioxane (1 mL, 4M) and the mixture was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure to dryness to give the title compound (70 mg) as a solid, which was directly used in the next reaction without purification. LC / MS (ESI) m / z: 560.3 (M+H)+. Step 3: Ethyl 3-((3R)-3-((4-((((benzyloxy)carbonyl)amino)methyl)-6-(2-hydroxy-6- (methoxymethyl)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1- yl)propanoate The title compound was prepared following methods and protocols described in Example 17 step 2 and purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% NH4HCO3) as a solid.1H NMR (400 MHz, CD3OD) δ 10.12 (bs, 1H), 7.97 (bs, 1H), 7.38 – 7.31 (m, 5H), 7.25 (s, 1H), 7.14 (s, 1H), 6.19 – 6.07 (m, 1H), 5.13 – 5.05 (m, 2H), 4.26 – 4.12 (m, 4H), 4.09 – 3.94 (m, 3H), 3.14 (s, 3H), 3.00 – 2.90 (m, 1H), 2.69 – 2.56 (m, 3H), 1.96 (s, 3H), 2.14 – 1.92 (m, 2H), 1.91 – 1.63 (m, 3H), 1.50 – 1.44 (m, 1H), 1.29 – 1.23 (m, 2H), 1.21 – 1.09 (m, 3H). LC-MS (ESI) m / z: 660.4 (M+H)+. Example 33 Ethyl 3-((3R)-3-((4-(aminomethyl)-6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl)- phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate, FA salt To a solution of ethyl 3-((3R)-3-((4-((((benzyloxy)carbonyl)amino)methyl)-6-(2-hydroxy-6- (methoxymethyl)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1- yl)propanoate (30 mg, 0.045 mmol) in MeOH (2 mL) was added Pd / C (5 mg, 10% wt.) at RT under N2 atmosphere, the mixture was degassed with N2 three times and stirred under a H2 balloon at 30oC for 1 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 20~95% MeCN in H2O with 0.1% FA) to give the title compound (25 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.32 (s, 1H), 7.14 (s, 1H), 4.50 – 4.45 (m, 1H), 4.27 – 4.11 (m, 6H), 3.39 – 3.32 (m, 1H), 3.21 & 3.20 (s, 3H), 3.15 – 3.05 (m, 2H), 3.04 – 2.94 (m, 1H), 2.94 – 2.75 (m, 2H), 2.74 – 2.66 (m, 2H), 2.14 (s, 3H), 2.08 – 1.98 (m, 2H), 1.89 – 1.73 (m, 2H), 1.31 – 1.20 (m, 3H). LC-MS (ESI) m / z: 526.3 (M+H)+. Example 34 Ethyl (R)-3-(3-((4-(aminomethyl)-6-(2-hydroxy-4-methoxyphenyl)-5-methylpyridazin- 3- yl)amino)piperidin-1-yl)propanoate, bis FA salt The title compound was prepared following methods and protocols described in Example 32 & Example 33 as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.06 – 7.04 (m, 1H), 6.49 – 6.47 (m, 2H), 4.22 – 4.17 (m, 1H), 4.09 – 4.04 (m, 2H), 3.91 – 3.81 (m, 2H), 3.75 (s, 3H), 2.98 – 2.96 (m, 1H), 2.67 – 2.61 (m, 3H), 2.48 – 2.45 (m, 2H), 2.15 – 2.08 (m, 2H), 2.06 (s, 3H), 1.89 -1.87 (m, 1H), 1.73 – 1.70 (m, 1H), 1.53 – 1.40 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H). LC / MS (ESI) (m / z): 444.2 (M+H)+. Example 35 Ethyl (R)-3-(3-((4-(aminomethyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate Step 1: Ethyl (R)-3-(3-((4-((((benzyloxy)carbonyl)amino)methyl)-6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate The title compound was prepared following methods and protocols described in Example 17 step 2 as a solid. LC / MS (ESI) (m / z): 630 (M+H)+. Step 2: Ethyl (R)-3-(3-((4-(aminomethyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate To a solution of ethyl (R)-3-(3-((4-((((benzyloxy)carbonyl)amino)methyl)-6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate (100 mg, 0.159 mmol) in DCM (3 mL) was added BBr3(120 mg, 0.476 mmol) drop-wisely at -78oC and the mixture was stirred at RT for 3 hrs. The mixture was quenched with EtOH at -78oC and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 15~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (22 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.16 (s, 1H), 4.42 – 4.29 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 4.03 – 3.91 (m, 2H), 3.09 – 2.96 (m, 1H), 2.83 – 2.74 (m, 2H), 2.73 – 2.61 (m, 1H), 2.59 – 2.55 (m, 2H), 2.47 – 2.42 (m, 1H), 2.16 (s, 3H), 2.05 – 1.83 (m, 3H), 1.74 – 1.55 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). LC / MS (ESI) (m / z): 482.4 (M+H)+. Example 35a Ethyl (R)-3-(3-((4-((((benzyloxy)carbonyl)amino)methyl)-6-(2-hydroxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate To a solution of ethyl (R)-3-(3-((4-(aminomethyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate (50 mg, 0.10 mmol) in MeCN (2 mL) was added TEA (44 uL, 0.32 mmol) followed by CbzOSu (37.4 mg, 0.15 mmol) at RT and the mixture was stirred at RT for 2 hrs. The mixture was diluted with EtOAc, washed with saturated aq. NaHCO3solution and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 21.2*250 mm, 10~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (5.8 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.08 – 7.83 (m, 1H), 7.38 – 7.30 (m, 6H), 7.25 – 7.19 (m, 2H), 6.27 – 6.01 (m, 1H), 5.09 (s, 2H), 4.21 – 4.17 (m, 2H), 4.05 (q, J = 7.1 Hz, 2H), 3.03 – 2.87 (m, 1H), 2.70 – 2.55 (m, 3H), 2.48 – 2.43 (m, 2H), 2.07 (s, 3H), 1.95 – 1.88 (m, 1H), 1.86 – 1.79 (m, 1H), 1.74 – 1.66 (m, 1H), 1.52 – 1.44 (m, 1H), 1.36 – 1.21 (m, 3H), 1.16 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m / z): 616.3 (M+H)+. Example 36 Methyl (R)-3-(3-((4-(aminomethyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate The title compound was prepared following methods and protocols described in Example 34 as a solid.1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.16 (s, 1H), 4.38 – 4.32 (m, 1H), 3.94 – 3.86 (m, 2H), 3.67 (s, 3H), 3.00 – 2.89 (m, 1H), 2.75 – 2.70 (m, 2H), 2.65 – 2.55 (m, 3H), 2.41 – 2.36 (m, 1H), 2.15 (s, 3H), 2.02 – 2.01 (m, 1H), 1.93 – 1.80 (m, 2H), 1.70 – 1.59 (m, 2H). LC-MS (ESI) (m / z): 468.3 (M+H)+. Example 37 (R)-3-(3-((4-(aminomethyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin- 3-yl)amino)piperidin-1-yl)propanoic acid The title compound was prepared following methods and protocols described in Example 18 and purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% NH4HCO3) as a solid.1H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.16 (s, 1H), 4.50 – 4.47 (m, 1H), 4.09 (s, 2H), 3.11 – 3.03 (m, 2H), 2.96 – 2.87 (m, 1H), 2.61 – 2.41 (m, 3H), 2.18 (s, 3H), 2.13 – 2.06 (m, 2H), 2.04 – 2.02 (m, 1H), 2.00 – 1.93 (m, 2H), 1.88 – 1.82 (m, 1H). LC-MS (ESI) m / z: 454.3 (M+H)+. Example 38 Methyl (R)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4- (((methoxycarbonyl)amino) methyl)-5-methylpyridazin-3-yl)amino)piperidin-1- yl)propanoate Step 1: Methyl (R)-3-(3-((4-(((methoxycarbonyl)amino)methyl)-6-(2- ((methoxycarbonyl)- oxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidin-1-yl)propanoate To a solution of methyl (R)-3-(3-((4-(aminomethyl)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)- 5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate (100 mg, 0.214 mmol) in THF (5 mL) was added TEA (65 mg, 0.644 mmol) followed by drop-wise addition of methyl chloroformate (40 mg, 0.426 mmol) at 0oC and the mixture was stirred at 0oC for 1.5 hrs. The mixture was quenched with ice-water and extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (110 mg) as a solid, which was directly used in the next reaction without purification. LC-MS (ESI) m / z: 584.3 (M+H)+. Step 2: Methyl (R)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-(((methoxycarbonyl) amino)methyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate To a solution of methyl (R)-3-(3-((4-(((methoxycarbonyl)amino)methyl)-6-(2-((methoxy- carbonyl)oxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidin-1- yl)propanoate (110 mg, 0.188 mmol) in MeOH (3 mL) was added K2CO3(118 mg, 0.855 mmol) at RT and the mixture was stirred at RT for 2 hrs. The mixture was filtered and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% NH4OAc) to give the title compound (35 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.16 (s, 1H), 4.34 – 4.27 (m, 3H), 3.70 (s, 3H), 3.67 (s, 3H), 3.18 – 3.11 (m, 1H), 2.88 – 2.75 (m, 3H), 2.61 (t, J = 7.2 Hz, 2H), 2.46 – 2.28 (m, 2H), 2.18 (s, 3H), 2.05 – 1.96 (m, 1H), 1.93 – 1.85 (m, 1H), 1.77 – 1.67 (m, 1H), 1.63 – 1.54 (m, 1H). LC-MS (ESI) m / z: 526.3 (M+H)+. Example 39 Ethyl (R)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4-(((methoxycarbonyl)amino)- methyl)-5-methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate The title compound was prepared following methods and protocols described in Example 38 as a solid.1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.15 (s, 1H), 4.33 (s, 2H), 4.32 – 4.27 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.69 (s, 3H), 3.10 – 2.99 (m, 1H), 2.75 – 2.71 (m, 2H), 2.71 – 2.63 (m, 1H), 2.57 – 2.53 (m, 2H), 2.34 – 2.19 (m, 2H), 2.17 (s, 3H), 2.01 – 1.93 (m, 1H), 1.88 – 1.79 (m, 1H), 1.71 – 1.62 (m, 1H), 1.58 – 1.47 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m / z): 540.3 (M+H)+. Example 40 (R)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4- (((methoxycarbonyl)amino)methyl)-5-methylpyridazin-3-yl)amino)piperidin-1- yl)propanoic acid The title compound was prepared following methods and protocols described in Example 18 and purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% NH4OAc) as a solid.1H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 7.6 Hz, 1H), 7.23 (d, J

[0015] = 7.9 Hz, 1H), 7.16 (s, 1H), 4.52 – 4.40 (m, 2H), 4.37 – 4.29 (m, 1H), 3.69 (s, 3H), 3.27 – 3.20 (m, 5H), 2.59 – 2.46 (m, 2H), 2.38 – 2.27 (m, 1H), 2.19 (s, 3H), 2.16 – 2.08 (m, 2H), 2.01 – 1.90 (m, 2H). LC-MS (ESI) m / z: 512.2 (M+H)+. Example 41 Ethyl (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxylate Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a mixture of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (500 mg, 1.65 mmol) and 1-(tert-butyl) 2-ethyl (2S,5R)-5-aminopiperidine-1,2-dicarboxylate (540 mg, 1.98 mmol) in 1,4-dioxane (6 mL) were added Cs2CO3(1.61 g, 4.96 mmol), Pd2(dba)3(152 mg, 0.165 mmol) and BINAP (206 mg, 0.33 mmol) under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 100oC for 5 hrs. The mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The filtrate and wash were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~60% EtOAc in PE) to give the title compound (610 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.16 (s, 1H), 6.49 (s, 1H), 4.96 – 4.74 (m, 2H), 4.29 – 4.15 (m, 4H), 3.82 (s, 3H), 3.33 – 3.26 (m, 1H), 2.06 – 2.00 (m, 5H), 1.61 – 1.57 (m, 1H), 1.47 – 1.43 (m, 9H), 1.30 (t, J = 7.1 Hz, 3H). LC / MS (ESI) m / z: 539.2 (M+H)+. Step 2: Ethyl (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- 129

[0016] methylpyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (130 mg, 0.156 mmol) in DCM (1 mL) was added BBr3(278 mg, 1.11 mmol) drop-wisely at -78oC and the mixture was stirred at RT for 3 hrs. The reaction mixture was quenched with MeOH at -50oC and concentrated under reduced pressure to dryness. The residue was purified by pre-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (14 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.40 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.17 (s, 1H), 6.76 (s, 1H), 4.26 – 4.15 (m, 2H), 3.99 – 3.89 (m, 1H), 3.49 – 3.41 (m, 1H), 3.39 – 3.34 (m, 1H), 2.50 – 2.40 (m, 1H), 2.29 – 2.20 (m, 1H), 2.19 – 2.14 (m, 1H), 2.13 (s, 3H), 1.70 – 1.59 (m, 1H), 1.59 – 1.47 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H). LC / MS (ESI) (m / z): 425.2 (M+H)+. The examples listed in Error! Reference source not found.3 below were prepared following the methods and protocols described for the synthesis of Example 41 from appropriate starting materials. Table 3. Examples Prepared Using Procedure for Example 41 130 Example 45 Ethyl (2S,5R)-5-((4-cyano-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin- 3- yl)amino)piperidine-2-carboxylate Step 1: 3,6-Dichloro-5-methylpyridazine-4-carbonitrile To a mixture of 3,6-dichloropyridazine-4-carbonitrile (10 g, 57.5 mmol) and acetic acid (6.90 g, 115 mmol) in MeCN (100 mL) and water (100 mL) was added K2S2O8(23.3 g, 86.3 mmol) and AgNO3(1.96 g, 11.5 mmol) under N2atmosphere at RT, the mixture was degassed with N2three times and stirred at 70 °C overnight. The mixture was diluted with EtOAc and the layers were separated. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~20% EtOAc in PE) to afford the title compound (6.4 g) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 3H). LC-MS (ESI) m / z: 188 (M+H)+. Step 2: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((6-chloro-4-cyano-5-methylpyridazin-3- yl)amino)piperidine-1,2-dicarboxylate To a mixture of 3,6-dichloro-5-methylpyridazine-4-carbonitrile (3 g, 15.9 mmol) and 1-(tert- butyl) 2-ethyl (2S,5R)-5-aminopiperidine-1,2-dicarboxylate (5.22 g, 19.1 mmol) in EtOH (15 mL) was added DIEA (3.09 g, 23.9 mmol) under N2atmosphere at RT, the mixture was degassed with N2three times and stirred at 70 °C for 2 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in PE) to afford the title compound (1.4 g) as a solid. LC-MS (ESI) m / z: 424 (M+H)+. Step 3: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-cyano-6-(2-hydroxy-4- (trifluoromethyl)phenyl)- 5-methylpyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a mixture of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-chloro-4-cyano-5-methylpyridazin-3-yl) amino)piperidine-1,2-dicarboxylate (1.4 g, 3.30 mmol) and (2-hydroxy-4- (trifluoromethyl)phenyl)boronic acid (0.88 g, 4.29 mmol) in 1,4-dioxane (14 mL) and water (2 mL) was added SPhos Pd G2 (0.48 g, 0.661 mmol), K3PO4(2.10 g, 9.91 mmol) under N2atmosphere at RT, the mixture was degassed with N2three times and stirred at 100 °C for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in PE) to afford the title compound (1 g) as a solid. LC-MS (ESI) m / z: 550 (M+H)+. Step 4: Ethyl (2S,5R)-5-((4-cyano-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-2-carboxylate A solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-cyano-6-(2-hydroxy-4-(trifluoromethyl)- phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (60 mg, 0.109 mmol) in HCl / 1,4-dioxane (1 mL, 4 M) was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (6 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.44 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 4.35 – 4.25 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.47 – 3.36 (m, 2H), 2.63 (t, J = 11.3 Hz, 1H), 2.32 (s, 3H), 2.28 – 2.11 (m, 2H), 1.78 – 1.59 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m / z): 450.1 (M+H)+. Example 46 Ethyl (2S,5R)-5-((4-cyano-6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl)phenyl) pyridazin-3-yl)amino)piperidine-2-carboxylate partial FA salt

[0017] The title compound was prepared following methods and protocols described in Example 45 as a solid.1H NMR (400 MHz, CD3OD) δ 7.82 (s, 1H), 7.32 (s, 1H), 7.14 (s, 1H), 4.62 – 4.54 (m, 1H), 4.38 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.55 – 3.48 (m, 2H), 3.24 (s, 3H), 2.72 (t, J = 11.3 Hz, 1H), 2.30 – 2.21 (m, 2H), 1.80 – 1.68 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m / z): 479.9 (M+H)+. Example 47 (2S,5R)-5-((4-carbamoyl-6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl)phenyl) pyridazin-3-yl)amino)piperidine-2-carboxylic acid Step 1: (2S,5R)-1-(tert-butoxycarbonyl)-5-((4-carbamoyl-6-(2-(methoxymethoxy)-6-(me- thoxymethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-2-carboxylic acid To a mixture of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-cyano-6-(2-(methoxymethoxy)-6- (methoxymethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate (50 mg, 0.080 mmol) in THF (2 mL) and water (0.5 mL) was added LiOH (10 mg, 0.240 mmol) at 0 ℃ and the mixture was stirred at RT for 30 mins. The mixture was acidified with 1 N aq. HCl and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (35 mg) as a solid. LC / MS (ESI) (m / z): 614.3 (M+H)+. Step 2: (2S,5R)-5-((4-carbamoyl-6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl) phenyl)pyridazin-3-yl)amino)piperidine-2-carboxylic acid To a solution of (2S,5R)-1-(tert-butoxycarbonyl)-5-((4-carbamoyl-6-(2-(methoxymethoxy)- 6- (methoxymethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-2-carboxylic acid (30 mg, 0.049 mmol) in DCM (0.5 mL) was added HCl in 1,4-dioxane (0.5 mL, 4 M) at RT and the mixture was stirred at RT for 2 hrs. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 15~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (5 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.33 (s, 1H), 7.15 (s, 1H), 4.57 – 4.48 (m, 1H), 4.36 (s, 2H), 3.82 – 3.76 (m, 1H), 3.56 – 3.51 (m, 1H), 3.24 (s, 3H), 2.88 (t, J = 11.5 Hz, 1H), 2.50 – 2.44 (m, 1H), 2.33 – 2.27 (m, 1H), 1.90 – 1.76 (m, 2H). LC-MS (ESI) (m / z): 469.7 (M+H)+. Example 48 Ethyl (2S,5R)-5-((4-(aminomethyl)-6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl) phenyl)pyridazin-3-yl)amino)piperidine-2-carboxylate Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((4-(aminomethyl)-6-(2-(methoxymethoxy)-6- (me- thoxymethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-cyano-6-(2-(methoxymethoxy)-6- (methoxymethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate (50 mg, 0.080 mmol) in MeOH (3 mL) were added one drop of FA and Raney Ni (20 mg) under N2atmosphere and the mixture was stirred under a H2balloon at RT for 6 hrs. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (40 mg) as a solid. LC-MS (ESI) m / z: 628.3 (M+H)+. Step 2: Ethyl (2S,5R)-5-((4-(aminomethyl)-6-(2-hydroxy-6-(methoxymethyl)-4- (trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((4-(aminomethyl)-6-(2-(methoxy-methoxy)- 6-(methoxymethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)amino)piperidine-1,2- dicarboxylate (40 mg, 0.064 mmol) in DCM (0.5 mL) was added HCl in 1,4-dioxane (0.5 mL, 4 M) at RT and the mixture was stirred at RT for 2 hrs. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 15~95% MeCN in H2O with 0.1% FA) to give the title compound (5 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.41 (s, 1H), 7.32 (s, 1H), 7.13 (s, 1H), 4.34 (s, 2H), 4.33 – 4.30 (m, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.90 (s, 2H), 3.67 – 3.59 (m, 2H), 3.25 (s, 3H), 2.73 – 2.61 (m, 1H), 2.32 – 2.26 (m, 2H), 1.80 – 1.72 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H). LC-MS (ESI) (m / z): 483.8 (M+H)+. Example 49 Ethyl (2S,5R)-5-((6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-2-carboxylate Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((6-chloro-5-methylpyridazin-3-yl)amino)- piperidine-1,2-dicarboxylate (2) & 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-chloro-4- methylpyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (2-1) To a solution of 3,6-dichloro-4-methylpyridazine (1 g, 6.17 mmol) in DMSO (10 mL) were added CsF (2.81 g, 18.51 mmol) and 1-(tert-butyl) 2-ethyl (2S,5R)-5-aminopiperidine-1,2- dicarboxylate (2.52 g, 9.26 mmol), the mixture was degassed with N2three times and stirred under N2atmosphere at 120 °C overnight. The mixture was diluted with EtOAc, washed with sat. aq. NH4Cl solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~60% EtOAc in PE) to give the title compounds (1.3 g, mixture of regio-isomers) as a

[0018] solid. LC-MS (ESI) (m / z): 399.2 (M+H)+. Step 2: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-(methoxymethoxy)-6-(methoxymethyl)-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a mixture of 2-(2-(methoxymethoxy)-6-(methoxymethyl)-4-(trifluoromethyl)phenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (400 mg, 1.06 mmol) and 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1,2-dicarboxylate & 1-(tert- butyl) 2-ethyl (2S,5R)-5-((6-chloro-4-methylpyridazin-3-yl)amino)piperidine-1,2- dicarboxylate (325 mg, 0.815 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added Ruphos (38 mg, 0.081 mmol), Ruphos Pd G3 (68 mg, 0.081 mmol) and Na2CO3 (259 mg, 2.444 mmol) under N2atmosphere. The reaction mixture was degassed with N2three times and stirred at 80oC overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in PE) to give the title compound (110 mg) as a solid, which was the second eluting isomer from silica gel column.1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.37 (s, 1H), 7.11 & 7.07 (s, 1H), 5.11 (s, 2H), 4.87 – 4.71 (m, 1H), 4.65 – 4.52 (m, 1H), 4.41 (q, J = 13.6 Hz, 2H), 4.30 – 4.20 (m, 3H), 3.38 (s, 3H), 3.37 – 3.32 (m, 1H), 3.30 (s, 3H), 2.27 – 2.18 (m, 1H), 2.15 (s, 3H), 2.13 – 2.07 (m, 1H), 2.03 – 1.94 (m, 1H), 1.76 – 1.64 (m, 1H), 1.54 – 1.40 (m, 9H), 1.31 (t, J = 7.1 Hz, 3H). LC- MS (ESI) (m / z): 613.3 (M+H)+. Step 3: Ethyl (2S,5R)-5-((6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-(methoxymethoxy)-6- (methoxymethyl)-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1,2- dicarboxylate (110 mg, 0.22 mmol) in DCM (1 mL) was added HCl in 1,4-dioxane (1 mL, 4 M) and the mixture was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 20~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (11 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.29 (s, 1H), 7.11 (s, 1H), 6.78 (s, 1H), 4.33 – 4.08 (m, 5H), 3.96 – 3.89 (m, 1H), 3.45 – 3.41 (m, 1H), 3.20 (s, 3H), 2.50 – 2.39 (m, 1H), 2.29 – 2.21 (m, 1H), 2.18 – 2.11 (m, 1H), 2.01 (s, 3H), 1.67 – 1.51 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H). LC- MS (ESI) (m / z): 469.2 (M+H)+. Example 50 (2S,5R)-5-((6-(2-hydroxy-6-(methoxymethyl)-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid 136 T a solution of ethyl (2S,5R)-5-((6-(2-hydroxy-6-(methoxymethyl)-4- (trifluoromethyl)phenyl)- 5-methylpyridazin-3-yl)amino)piperidine-2-carboxylate (40 mg, 0.085 mmol) in MeOH (0.3 mL), THF (1 mL) and water (0.3 mL) was added LiOH (14.3 mg, 0.342 mmol) and the mixture was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 20~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (15 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.30 (s, 1H), 7.12 (s, 1H), 6.80 (s, 1H), 4.32 – 4.22 (m, 2H), 4.20 – 4.14 (m, 1H), 3.79 – 3.72 (m, 1H), 3.50 – 3.45 (m, 1H), 3.20 (s, 3H), 2.78 – 2.66 (m, 1H), 2.49 – 2.40 (m, 1H), 2.29 – 2.22 (m, 1H), 2.03 (s, 3H), 1.89 – 1.78 (m, 1H), 1.76 – 1.63 (m, 1H). LC-MS (ESI) (m / z): 441.3 (M+H)+. The examples listed in Error! Reference source not found.4 below were prepared following the methods and protocols described for the synthesis of Example 50 from appropriate starting materials. Table 4. Examples Prepared Using Procedure for Example 50 , , Example 54 Ethyl (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)-1-methylpiperidine-2-carboxylate To a mixture of ethyl (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin- 3- yl)amino)piperidine-2-carboxylate (20 mg, 0.047 mmol) and 37% aq. HCHO solution (0.1 mL) in MeOH (1 mL) was added AcOH (0.005 mL) and NaBH3CN (9 mg, 0.141 mmol) at 0oC and the mixture was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% FA) to give the title compound (5 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.40 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.17 (s, 1H), 6.82 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.22 – 4.14 (m, 1H), 3.53 – 3.47 (m, 1H), 3.19 – 3.12 (m, 1H), 2.49 (s, 3H), 2.32 – 2.26 (m, 1H), 2.24 – 2.12 (m, 2H), 2.15 (s, 3H), 1.91 – 1.77 (m, 1H), 1.58 – 1.47 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H). LC / MS (ESI) (m / z): 439.2 (M+H)+. Example 55 Ethyl (2S,5R)-5-((4-cyano-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin- 3- yl)amino)-1-methylpiperidine-2-carboxylate The title compound was prepared following methods and protocols described in Example 54 as a solid.1NMR (400 MHz, CD3OD) δ 7.43 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.18 (s, 1H), 4.53 – 4.45 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.33 – 3.27 (m, 1H), 2.85 – 2.82 (m, 1H), 2.32 (s, 3H), 2.31 (s, 3H), 2.23 – 2.18 (m, 1H), 2.17 – 2.14 (m, 1H), 2.06 – 2.00 (m, 1H), 1.84 – 1.73 (m, 1H), 1.64 – 1.54 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H). LC / MS (ESI) (m / z): 464.2 (M+H)+. Example 56 (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)-1- methylpiperidine-2-carboxylic acid, FA salt (partial) To a mixture of (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxylic acid (20 mg, 0.050 mmol), 37% aq. HCHO solution (0.1 mL) in MeOH (1 mL) was added AcOH (0.006 mL) and NaBH3CN (9.5 mg, 0.151 mmol) at 0oC and the mixture was stirred at RT for 30 mins. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% FA) to give the title compound (4 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.41 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.19 (s, 1H), 6.85 (s, 1H), 4.39 – 4.25 (m, 1H), 3.92 – 3.81 (m, 1H), 3.52 – 3.47 (m, 1H), 2.94 (s, 3H), 2.83 – 2.77 (m, 1H), 2.49 – 2.38 (m, 1H), 2.27 – 2.20 (m, 1H), 2.16 (s, 3H), 2.01 – 1.87 (m, 1H), 1.76 – 1.61 (m, 1H). LC / MS (ESI) (m / z): 411.1 (M+H)+. Example 57 (2S,5R)-5-((4-cyano-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl) amino)-1-methylpiperidine-2-carboxylic acid The title compound was prepared following methods and protocols described in Example 56 as a solid.1H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.20 (s, 1H), 4.68 – 4.62 (m, 1H), 3.77 – 3.73 (m, 1H), 3.36 – 3.33 (m, 1H), 2.92 (s, 3H), 2.89 – 2.87 (m, 1H), 2.43 – 2.39 (m, 1H), 2.35 (s, 3H), 2.25 – 2.22 (m, 1H), 1.93 – 1.80 (m, 2H). LC / MS (ESI) (m / z): 436.2 (M+H)+. Example 58 (2R,5R)-5-((6-(4-(difluoromethoxy)-2-hydroxyphenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxylic acid Step 1: 1-(Tert-butyl) 2-ethyl (2S,5R)-5-((6-(4-(difluoromethoxy)-2-(methoxymethoxy)- phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a mixture of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-chloro-5-methylpyridazin-3-yl)amino)- piperidine-1,2-dicarboxylate (1.5 g, 3.76 mmol) and 2-(4-(difluoromethoxy)-2- (methoxy- methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 11, 1.86 g, 5.64 mmol) in 1,4-dioxane (20 mL) and water (3 mL) was added K3PO4(2.39 g, 11.3 mmol) and SPhos Pd G2(0.54 g, 0.75 mmol) at RT under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 100 °C for 3 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~50% EtOAc in PE) to give the title compound (1.2 g) as an oil. LC / MS (ESI) (m / z): 566.9 (M+H)+. Step 2: (2R,5R)-1-(tert-butoxycarbonyl)-5-((6-(4-(difluoromethoxy)-2- (methoxymethoxy)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-(4-(difluoromethoxy)-2- (methoxymethoxy)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (1 g, 1.76 mmol) in EtOH (10 mL) was added EtONa / EtOH solution (10 mL, 20% wt.) and the mixture was stirred at RT overnight. The mixture was acidified with 1 N aq. HCl to pH=3 and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (Welch-Ultimate AQ-C18, 21.2*250 mm, 5~95% MeOH in H2O with 0.1% TFA) to afford the title compound (400 mg) as a solid, which was the later eluting isomer from HPLC column. LC / MS (ESI) m / z: 539.3 (M+H)+. Step 3: (2R,5R)-5-((6-(4-(difluoromethoxy)-2-hydroxyphenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxylic acid To a solution of (2R,5R)-1-(tert-butoxycarbonyl)-5-((6-(4-(difluoromethoxy)-2- (methoxymethoxy)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid (300 mg, 0.56 mmol) in DCM (2 mL) was added HCl in 1,4-dioxane (2 mL, 4 M) and the mixture was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure to dryness to afford the title compound (190 mg) as a solid. For final product, the title compound was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% NH4HCO3) and as intermediate, it was directly used in the next reaction without purification.1H NMR (400 MHz, CD3OD) δ 7.22 (d, J = 8.3 Hz, 1H), 6.93 (t, J = 74.1 Hz, 1H), 6.81 (s, 1H), 6.73 (dd, J = 8.4, 2.0 Hz, 1H), 6.69 (d, J = 2.1 Hz, 1H), 4.31 – 4.25 (m, 1H), 3.71 – 3.68 (m, 1H), 3.54 – 3.49 (m, 1H), 3.40 – 3.37 (m, 1H), 2.32 – 2.24 (m, 1H), 2.14 (s, 3H), 2.10 – 1.99 (m, 2H), 1.89 – 1.82 (m, 1H). LC / MS (ESI) m / z: 395.3 (M+H)+. Example 59 (2R,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxylic acid arbonyl)-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid and (2R,5R)-1-(tert-

[0019] butoxycarbonyl)-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxylic acid A solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)- 5- methylpyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (500 mg, 0.928 mmol) in EtONa / EtOH solution (10 mL, 20% wt.) was stirred at 30 ℃ for 16 hrs. The mixture was quenched with ice-water and washed with EtOAc twice. The aqueous layer was acidified with 3 N aq. HCl to pH ~ 5 and extracted with DCM three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (Welch-Ultimate AQ-C18250*21.2 mm, 18 ~ 95% MeCN in H2O with 0.1% TFA) to give Compound 2-1 (100 mg, eluted first) followed by Compound 2-2 (90 mg, eluted second) as solids. Hydrolyzing Compound 1 with LiOH in THF / water separately gave Compound 2-1 as product, which helped in assigning the structures of the isomers. Compound 2-1:1H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 7.39 - 7.32 (m, 2H), 7.19 - 7.16 (m, 2H), 4.94 - 4.85 (m, 1H), 4.15 - 4.07 (m, 1H), 3.96 - 3.91 (m, 1H), 3.85 (s, 3H), 3.40 - 3.33 (m, 1H), 2.48 - 2.32 (m, 1H), 2.23 (s, 3H), 2.18 - 2.14 (m, 1H), 2.01 - 1.82 (m, 2H), 1.48 - 1.35 (m, 9H). Compound 2-2:1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 7.40 - 7.34 (m, 3H), 7.20 - 7.14 (m, 2H), 4.93 - 4.78 (m, 1H), 4.31 - 4.21 (m, 1H), 3.86 (s, 3H), 3.53 - 3.43 (m, 1H), 3.03 - 2.95 (m, 1H), 2.48 - 2.45 (m, 1H), 2.26 (s, 3H), 2.13 - 2.09 (m, 1H), 1.88 - 1.70 (m, 2H), 1.48 (s, 9H). LC / MS (ESI) m / z: 511.2 (M+H)+. Step 2: (2R,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxylic acid To a solution of (2R,5R)-1-(tert-butoxycarbonyl)-5-((6-(2-methoxy-4- (trifluoromethyl)phenyl)- 5-methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid (20 mg, 0.039 mmol) in DCM (4 mL) was added BBr3(48.9 mg, 0.196 mmol) at -78oC and the mixture was stirred at -78oC to RT for 1 hr. The mixture was quenched with MeOH at - 60oC and concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 10 ~ 90% MeOH in H2O with 0.1% NH4HCO3) to give the title compound (4 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.17 (s, 1H), 6.83 (s, 1H), 4.32 - 4.27 (m, 1H), 3.74 - 3.71 (m, 1H), 3.55 - 3.51 (m, 1H), 3.40 - 3.36 (m, 1H), 2.33 - 2.24 (m, 1H), 2.21 - 2.15 (m, 1H), 2.14 (s, 3H), 2.08 - 2.00 (m, 1H), 1.90 - 1.81 (m, 1H). LC / MS (ESI) m / z: 397.1 (M+H)+. Example 60 (2R,5R)-5-((6-(4-(difluoromethoxy)-2-hydroxyphenyl)-5-methylpyridazin-3-yl)amino)-1- methylpiperidine-2-carboxylic acid 142 To a mixture of (2R,5R)-5-((6-(4-(difluoromethoxy)-2-hydroxyphenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxylic acid (40 mg, 0.1 mmol) and 37% aq. HCHO (0.2 mL) in MeOH (1 mL) were added NaBH3CN (18.9 mg, 0.3 mmol) followed by three drops of AcOH at 0 ℃ and the mixture was stirred at RT for 20 mins. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep- HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (15 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.25 – 7.21 (m, 1H), 6.89 (s, 1H), 6.85 (t, J = 74 Hz, 1H), 6.77 – 6.73 (m, 1H), 6.72 – 6.69 (m, 1H), 4.40 – 4.35 (m, 1H), 3.85 – 3.79 (m, 1H), 3.63 – 3.60 (m, 1H)6, 3.36 – 3.35 (m, 1H), 2.94 (s, 3H), 2.36 – 2.27 (m, 1H), 2.23 – 2.20 (m, 1H), 2.17 (s, 3H), 2.06 – 1.99 (m, 1H), 1.91 – 1.86 (m, 1H). LC / MS (ESI) (m / z): 409.3 (M+H)+. The examples listed in Error! Reference source not found.5 below were prepared following the methods and protocols described for the synthesis of Example 58 & Example 60 from appropriate starting materials. Table 5. Examples Prepared Using Procedure for Example 58 & Example 60

[0020] Example 65 Ethyl (2R,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxylate To a solution of (2R,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxylic acid (10 mg, 0.025 mmol) in MeOH (1.5 mL) was added SOCl2(8.9 mg, 0.075 mmol) at RT. The mixture was stirred at 70oC for 1 hr. The mixture was concentrated to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 5~90% MeOH in H2O with 0.1% NH4HCO3) to give the title compound (2.1 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.40 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.17 (s, 1H), 6.80 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.12 – 4.08 (m, 1H), 3.55 – 3.53 (m, 1H), 3.11 – 3.02 (m, 2H), 2.14 (s, 3H), 1.97 – 1.92 (m, 4H), 1.30 (t, J = 7.1 Hz, 3H). LC / MS (ESI) (m / z): 425.1 (M+H)+. The examples listed in Error! Reference source not found.6 below were prepared following the methods and protocols described for the synthesis of Example 65 from appropriate starting materials. Table 6. Examples Prepared Using Procedure for Example 65 Example 70 Ethyl (2R,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)- 1-methylpiperidine-2-carboxylate To a solution of ethyl (2R,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin- 3-yl)amino)piperidine-2-carboxylate (20 mg, 0.05 mmol) and 37% aq. HCHO solution (0.1 mL) in MeOH (1 mL) was added AcOH (5 mg) and NaBH3CN (9 mg, 0.15 mmol) and the mixture was stirred at RT for 30 mins. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (3 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.16 (s, 1H), 6.79 (s, 1H), 4.26 – 4.18 (m, 3H), 3.04 – 2.96 (m, 2H), 2.65 – 2.56 (m, 1H), 2.33 (s, 3H), 2.13 (s, 3H), 1.97 – 1.83 (m, 3H), 1.78 – 1.69 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H). LC / MS (ESI) m / z: 439.2 (M+H)+. Example 71 (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxamide Step 1: Tert-butyl (2S,5R)-2-carbamoyl-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of (2S,5R)-1-(tert-butoxycarbonyl)-5-((6-(2-methoxy-4- (trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid (60 mg, 0.118 mmol) in DMF (2 mL) was added NH4Cl (19 mg, 0.353 mmol), DIPEA (46 mg, 0.353 mmol) and HATU (89 mg, 0.235 mmol) at RT and the mixture was stirred at RT overnight. The mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~10% MeOH in DCM) to give the title compound (40 mg) as a solid. LC-MS (ESI) (m / z): 510.4 (M+H)+. Step 2: (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino) piperidine-2-carboxamide To a solution of tert-butyl (2S,5R)-2-carbamoyl-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)- 5- methylpyridazin-3-yl)amino)piperidine-1-carboxylate (40 mg, 0.079 mmol) in DCM (1 mL) was added BBr3(56 mg, 0.236 mmol) at -78oC. The mixture was stirred at -78oC to RT for 1 hour. The mixture was quenched with MeOH at -78oC and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (6 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 7.16 (s, 1H), 6.96 (s, 1H), 6.67 – 6.62 (m, 2H), 3.86 – 3.75 (m, 1H), 3.27 – 3.22 (m, 1H), 3.03 – 2.97 (m, 1H), 2.35 – 2.28 (m, 1H), 2.11 – 2.05 (m, 1H), 2.02 (s, 3H), 1.96 – 1.88 (m, 1H), 1.45 – 1.35 (m, 2H). LC-MS (ESI) (m / z): 396.1 (M+H)+. The examples listed in Error! Reference source not found.7 below were prepared following the methods and protocols described for the synthesis of Example 71 from appropriate starting materials. Table 7. Examples Prepared Using Procedure for Example 71 1 Example 75 (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)-1- methylpiperidine-2-carboxamide Step 1: (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxamide To a solution of tert-butyl (2S,5R)-2-carbamoyl-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)- 5- methylpyridazin-3-yl)amino)piperidine-1-carboxylate (35 mg, 0.069 mmol) in DCM (2 mL) was added BBr3(0.05 mL, 0.069 mmol ) at -78 ℃. The mixture was stirred at -78oC to RT for 3 hours. The mixture was quenched with MeOH at -78oC and concentrated under reduced pressure to dryness to give the title compound (20 mg) as a solid. LC-MS (ESI) (m / z): 396.1 (M+H)+. Step 2: (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)-1-methylpiperidine-2-carboxamide To a solution of (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxamide (20 mg, 0.051 mmol) in MeOH (2 mL) was added AcOH (0.010 mL, 0.025 mmol), 37% aq. HCHO (0.015 mL) and NaBH3CN (3.2 mg, 0.051 mmol) at 0 ℃. The mixture was stirred at 25 °C for 30 minutes. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (4 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.40 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 6.76 (s, 1H), 4.17 – 4.05 (m, 1H), 2.50 – 2.40 (m, 1H), 2.27 (s, 3H), 2.22 – 2.15 (m, 1H), 2.13 (s, 3H), 2.03 – 1.96 (m, 1H), 1.94 – 1.88 (m, 1H), 1.79 – 1.70 (m, 1H), 1.39 – 1.28 (m, 2H). LC-MS (ESI) (m / z): 410.1 (M+H)+. Example 76 (2R,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)-1- h l i i i 2 i The title compound was prepared following methods and protocols described in Example 75 as a solid.1H NMR (400 MHz, CD3OD) δ 7.40 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.17 (s, 1H), 6.85 (s, 1H), 4.35 – 4.28 (m, 1H), 3.04 – 2.95 (m, 1H), 2.66 – 2.57 (m, 1H), 2.48 – 2.40 (m, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 2.09 – 2.03 (m, 1H), 1.92 – 1.81 (m, 1H), 1.79 – 1.71 (m, 1H), 1.64 – 1.54 (m, 1H). LC-MS (ESI) (m / z): 410.2 (M+H)+. Example 77 2-Aminoethyl (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin- 3- yl)amino)piperidine-2-carboxylate Step 1: 2-(2-((Tert-butoxycarbonyl)amino)ethyl) 1-(tert-butyl) (2S,5R)-5-((6-(2-methoxy- 4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1,2-dicarboxylate To a solution of (2S,5R)-1-(tert-butoxycarbonyl)-5-((6-(2-methoxy-4-(trifluoromethyl)- phenyl)- 5-methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid (50 mg, 0.098 mmol) in DCM (2 mL) was added tert-butyl (2-hydroxyethyl)carbamate (24 mg, 0.147 mmol), DMAP (18 mg, 0.147 mmol) and EDCI (28 mg, 0.147 mmol) at RT and the mixture was stirred at RT for 1 hour. The mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~10% MeOH in DCM) to give the title compound (30 mg) as a solid. LC-MS (ESI) (m / z): 654.4 (M+H)+. Step 2: 2-Aminoethyl (2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-2-carboxylate To a solution of 2-(2-((tert-butoxycarbonyl)amino)ethyl) 1-(tert-butyl) (2S,5R)-5-((6-(2- methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1,2- dicarboxylate (30 mg, 0.046 mmol) in DCM (1 mL) was added BBr3(34 mg, 0.138 mmol) at -78oC. The mixture was stirred at -78oC to RT for 1 hr. The mixture was quenched with MeOH at -78oC and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (3 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 6.76 (s, 1H), 4.00 – 3.91 (m, 1H), 3.63 – 3.59 (m, 2H), 3.50 – 3.45 (m, 1H), 3.35 – 3.32 (m, 2H), 3.28 – 3.24 (m, 1H), 2.49 – 2.42 (m, 1H), 2.28 – 2.21 (m, 1H), 2.13 (s, 3H), 2.10 – 2.05 (m, 1H), 1.70 – 1.60 (m, 1H), 1.57 – 1.48 (m, 1H). LC-MS (ESI) (m / z): 440.4 (M+H)+. The examples listed in Error! Reference source not found.8 were prepared following the methods and protocols described for the synthesis of Example 77 from appropriate starting materials. Table 8. Examples Prepared Using Procedure for Example 77 Example 98 2-(6-(((3R,6S)-6-(hydroxymethyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol Step 1: Tert-butyl (2S,5R)-2-(hydroxymethyl)-5-((6-(2-methoxy-4- (trifluoromethyl)phenyl)- 5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of 1-(tert-butyl) 2-ethyl (2S,5R)-5-((6-(2-methoxy-4-(trifluoromethyl)- phenyl)- 5-methylpyridazin-3-yl)amino)piperidine-1,2-dicarboxylate (400 mg, 0.743 mmol) in THF (5 mL) was added LiAlH4(56.4 mg, 1.49 mmol) at 0oC and the mixture was stirred at RT overnight. The reaction mixture was quenched with Na2SO4.10H2O at 0oC and filtered. The filtrate was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in PE) to give the title compound (140 mg) as a solid. LC-MS (ESI) m / z: 497.2 (M+H)+. Step 2: 2-(6-(((3R,6S)-6-(hydroxymethyl)piperidin-3-yl)amino)-4-methylpyridazin-3-yl)- 5- (trifluoromethyl)phenol To a solution of tert-butyl (2S,5R)-2-(hydroxymethyl)-5-((6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (30 mg, 0.060 mmol) in DCM (2 mL) was added BBr3(0.12 mL, 0.12 mmol, 1M in DCM) at -78 ℃ and the mixture was stirred at -78 ℃ to RT for 3 hrs. The mixture was quenched with MeOH at -78 ℃ and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (15 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.15 (s, 1H), 6.75 (s, 1H), 4.05 – 3.87 (m, 1H), 3.58 – 3.54 (m, 1H), 3.49 – 3.44 (m, 2H), 2.70 – 2.63 (m, 1H), 2.47 – 2.42 (m, 1H), 2.24 – 2.21 (m, 1H), 2.14 (s, 3H), 1.83 – 1.80 (m, 1H), 1.51 – 1.36 (m, 2H). LC-MS (ESI) (m / z): 383.2 (M+H)+. Example 99 2-(6-(((3R,6S)-6-(hydroxymethyl)-1-methylpiperidin-3-yl)amino)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol To a solution of 2-(6-(((3R,6S)-6-(hydroxymethyl)piperidin-3-yl)amino)-4-methylpyridazin-3- yl)-5-(trifluoromethyl)phenol (30 mg, 0.078 mmol) in MeOH (2 mL) was added AcOH (0.010 mL) and 37% aq. HCHO (0.015 mL) followed by NaBH3CN (4.9 mg, 0.078 mmol) at 0 ℃ and the mixture was stirred at 25 °C for 30 mins. The mixture was quenched with ice-water and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (6 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.17 (s, 1H), 6.76 (s, 1H), 4.17 – 4.10 (m, 1H), 3.71 – 3.64 (m, 2H), 3.38 – 3.35 (m, 1H), 2.47 (s, 3H), 2.22 – 2.17 (m, 3H), 2.13 (s, 3H), 1.94 – 1.89 (m, 1H), 1.71 – 1.62 (m, 1H), 1.47 – 1.40 (m, 1H). LC-MS (ESI) (m / z): 397.1 (M+H)+. Example 100 ((2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidin-2-yl)methyl carbamate Step 1: Tert-butyl (2S,5R)-2-((carbamoyloxy)methyl)-5-((6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of tert-butyl (2S,5R)-2-(hydroxymethyl)-5-((6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (240 mg, 0.483 mmol) in DCM (4 mL) was added 2,2,2-trichloroacetyl isocyanate (137 mg, 0.726 mmol) 0 °C and the mixture was stirred at RT for 1 hr. The mixture was concentrated under reduced pressure to dryness and the residue was dissolved in MeOH (2 mL). The resulting mixture was stirred at RT for 30 mins. The mixture was concentrated under reduced pressure to dryness to give the title compound (200 mg) as a solid. LC / MS (ESI) m / z: 540.3 (M+H)+. Step 2: ((2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidin-2-yl)methyl carbamate The title compound was prepared following methods and protocols described in Example 66 step 2 as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 6.75 (s, 1H), 4.07 – 4.03 (m, 1H), 3.99 – 3.89 (m, 2H), 3.47 – 3.42 (m, 1H), 2.86 – 2.77 (m, 1H), 2.46 – 2.40 (m, 1H), 2.25 – 2.22 (m, 1H), 1.83 – 1.80 (m, 1H), 1.49 – 1.37 (m, 2H). LC-MS (ESI) (m / z): 426.2 (M+H)+. Example 101 ((2S,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)-1- methylpiperidin-2-yl)methyl carbamate The title compound was prepared following methods and protocols described in Example 67 as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.16 (s, 1H), 6.74 (s, 1H), 4.15 – 4.09 (m, 3H), 3.30 -3.27 (m, 1H), 2.38 (s, 3H), 2.21 – 2.17 (m, 2H), 2.13 (s, 3H), 2.05 – 2.00 (m, 1H), 1.88 – 1.83 (m, 1H), 1.65 – 1.57 (m, 1H), 1.39 – 1.33 (m, 1H). LC-MS (ESI) (m / z): 440.1 (M+H)+. Example 102 (7R,9aR)-7-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)hexahydro-2H-pyrido[1,2-a]pyrazin-1(6H)-one Step 1: (2R,5R)-1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-((6-(2-hydroxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid To the solution of (2R,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3- yl)amino)piperidine-2-carboxylic acid (30 mg, 0.076 mmol) in MeOH (1 mL) were added tert- butyl (2-oxoethyl)carbamate (12 mg, 0.076 mmol), AcOH (9 mg, 0.152 mmol) and NaBH3CN (14 mg, 0.227 mmol) and the mixture was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (25 mg) as a solid. LC / MS (ESI) m / z: 540.2 (M+H)+. Step 2: (2R,5R)-1-(2-aminoethyl)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid To a solution of (2R,5R)-1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-((6-(2-hydroxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid (30 mg, 0.054 mmol) in 1,4-dioxane (0.5 mL) was added HCl / 1,4-dioxane (0.5 mL, 4 M) and the mixture was stirred at RT for 20 minutes. The mixture was neutralized with sat. aq. NaHCO3solution and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (25 mg) as a solid. LC-MS (ESI) (m / z): 440.2 (M+H)+. Step 3: (7R,9aR)-7-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)hexahydro-2H-pyrido[1,2-a]pyrazin-1(6H)-one To a solution of (2R,5R)-1-(2-aminoethyl)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid (20 mg, 0.046 mmol) in DMF (1 mL) was added DIPEA (18 mg, 0.137 mmol) and HATU (26 mg, 0.068 mmol) at RT and the mixture was stirred at RT overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 5~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (3 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.16 (s, 1H), 6.90 (s, 1H), 4.28 – 4.24 (m, 1H), 3.57 – 3.50 (m, 1H), 3.23 – 3.17 (m, 1H), 3.14 – 3.09 (m, 1H), 2.88 – 2.83 (m, 1H), 2.70 – 2.65 (m, 1H), 2.61 – 2.51 (m, 2H), 2.14 (s, 3H), 2.12 – 2.07 (m, 2H), 1.75 – 1.66 (m, 2H). LC / MS (ESI) (m / z): 422 (M+H)+. Example 103 (7R,9aS)-7-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)hexahydro-2H-pyrido[1,2-a]pyrazin-1(6H)-one

[0021] The title compound was prepared following methods and protocols described in Example 102 as a solid.1NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.16 (s, 1H), 6.75 (s, 1H), 4.20 – 4.09 (m, 1H), 3.51 – 3.46 (m, 1H), 3.43 – 3.37 (m, 1H), 3.22 – 3.16 (m, 1H), 2.95 – 2.88 (m, 1H), 2.65 – 2.60 (m, 1H), 2.59 – 2.51 (m, 1H), 2.39 – 2.31 (m, 1H), 2.27 – 2.21 (m, 1H), 2.13 (s, 3H), 2.07 – 2.00 (m, 1H), 1.61 – 1.51 (m, 1H), 1.46 – 1.38 (m, 1H). LC-MS (ESI) (m / z): 422.2 (M+H)+. Example 104 (7R,9aR)-7-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)hexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one Step 1: (2R,5R)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-((6-(2-hydroxy-4- (trifluoromethyl) phenyl)-5-methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid To the solution of (2R,5R)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidine-2-carboxylic acid (40 mg, 0.101 mmol) in MeOH (1 mL) were added 2- ((tert-butyldimethylsilyl)oxy)acetaldehyde (18 mg, 0.101 mmol), AcOH (12 mg, 0.202 mmol) and NaBH3CN (19 mg, 0.303 mmol) and the mixture was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure to dryness to give the title compound (40 mg) as a solid. LC-MS (ESI) m / z: 555.3 (M+H)+. Step 2: (7R,9aR)-7-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)hexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one To a solution of (2R,5R)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-((6-(2-hydroxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino)piperidine-2-carboxylic acid (30 mg, 0.054 mmol) in DCM (1 mL) was added TFA (0.5 mL) and the mixture was stirred at RT for 1 hour. The mixture was concentrated under reduced pressure to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (6 mg,) as a solid.1H NMR (400 MHz, CD3OD) δ 7.40 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.17 (s, 1H), 6.92 (s, 1H), 4.59 – 4.50 (m, 1H), 4.41 – 4.33 (m, 1H), 4.31 – 4.25 (m, 1H), 3.71 – 3.65 (m, 1H), 3.14 – 3.08 (m, 1H), 2.93 – 2.84 (m, 2H), 2.75 – 2.68 (m, 1H), 2.57 – 2.49 (m, 1H), 2.20 – 2.15 (m, 1H), 2.14 (s, 3H), 1.92 – 1.83 (m, 1H), 1.77 – 1.66 (m, 1H). LC-MS (ESI) m / z: 423.1 (M+H)+. Example 105 (7R,9aS)-7-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)amino) hexahydropyrido[2,1-c][1,4]oxazin-1(6H)-one The title compound was prepared following methods and protocols described in Example 104 as a solid.1H NMR (400 MHz, CD3OD) δ 7.40 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.17 (s, 1H), 6.92 (s, 1H), 4.59 – 4.50 (m, 1H), 4.41 – 4.33 (m, 1H), 4.31 – 4.25 (m, 1H), 3.71 – 3.65 (m, 1H), 3.14 – 3.08 (m, 1H), 2.93 – 2.84 (m, 2H), 2.75 – 2.68 (m, 1H), 2.57 – 2.49 (m, 1H), 2.20 – 2.15 (m, 1H), 2.14 (s, 3H), 1.92 – 1.83 (m, 1H), 1.77 – 1.66 (m, 1H). LC-MS (ESI) m / z: 423.1 (M+H)+. Example 106 2-(6-(Amino(1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol, bis FA salt Step 1: Tert-butyl 3-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)piperidine-1-carboxylate To a solution of tert-butyl 3-acetylpiperidine-1-carboxylate (0.95 mL, 4.40 mmol) in THF (15 mL) was added LiHMDS (5.50 mL, 5.50 mmol, 1M in THF) at -78 ℃ under N2atmosphere and the mixture was stirred at this temperature for 30 mins. To the reaction mixture was added 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)-sulfonyl)methanesulfonamide (1.70 g, 4.84 mmol) and the resulting mixture was stirred at -78 ℃ and allowed to warm up to RT overnight. The mixture was quenched with water at 0 ℃ and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~10% EtOAc in PE) to give the title compound (980 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 5.19 (d, J = 3.6 Hz, 1H), 5.00 (d, J = 4.0 Hz, 1H), 4.14 – 4.11 (m, 1H), 3.93 – 3.83 (m, 1H), 2.92 – 2.74 (m, 2H), 2.47 – 2.33 (m, 1H), 2.05 – 1.95 (m, 1H), 1.77 – 1.67 (m, 1H), 1.53 – 1.39 (m, 2H), 1.45 (s, 9H). Step 2: Tert-butyl 3-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1- carboxylate To a mixture of tert-butyl 3-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)piperidine-1-carboxylate (1.00 g, 2.78 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (710 mg, 2.78 mmol) in 1,4-dioxane (15 mL) was added potassium phenoxide (550 mg, 4.17 mmol), PPh3(40 mg, 0.14 mmol) and Pd(PPh3)2Cl2(200 mg, 0.28 mmol) under N2atmosphere. The mixture was degassed with N2three times and stirred under N2at 55 ℃ for 3 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~10% EtOAc in PE) to afford the title compound (700 mg) as an oil.1H NMR (400 MHz, CDCl3) δ 5.83 (s, 1H), 5.65 (s, 1H), 4.09 – 4.05 (m, 2H), 2.70 – 2.51 (m, 2H), 2.32 – 2.19 (m, 1H), 1.84 – 1.76 (m, 1H), 1.69 – 1.59 (m, 1H), 1.51 – 1.37 (m, 2H), 1.45 (s, 9H), 1.28 (s, 12H). Step 3: Tert-butyl 3-(1-(6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)vinyl)piperidine-1-carboxylate To a mixture of 6-chloro-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4- methylpyridazine (Intermediate 5, 500 mg, 1.50 mmol) and tert-butyl 3-(1-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate (507 mg, 1.50 mmol) in DME (5 mL) and water (1 mL) was added Na2CO3(319 mg, 3.01 mmol) and Pd(PPh3)2Cl2(106 mg, 0.15 mmol) at RT under N2atmosphere, the mixture was degassed with N2three times and stirred under N2atmosphere at 80 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~20% EtOAc in PE) to afford the title compound (150 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 7.54 – 7.46 (m, 3H), 7.42 (d, J = 7.9 Hz, 1H), 5.81 (s, 1H), 5.44 (s, 1H), 5.14 (s, 2H), 4.29 – 4.13 (m, 1H), 4.09 – 3.97 (m, 1H), 3.39 (s, 3H), 3.31 – 3.21 (m, 1H), 2.87 – 2.73 (m, 2H), 2.23 (s, 3H), 2.13 – 2.05 (m, 1H), 1.76 – 1.70 (m, 1H), 1.61 – 1.48 (m, 2H), 1.48 – 1.38 (m, 10H). LC / MS (ESI) m / z: 508 (M+H)+. Step 4: Tert-butyl 3-(6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5- methylpyridazine-3-carbonyl)piperidine-1-carboxylate To a solution of tert-butyl 3-(1-(6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)vinyl)piperidine-1-carboxylate (200 mg, 0.394 mmol) in THF (2 mL), t- BuOH (2 mL) and water (1 mL) was added OsO4(10.0 mg, 0.039 mmol) and NMO (115 mg, 0.985 mmol) at RT and the mixture was stirred at 30oC for 1 hr. NaIO4(340 mg, 1.57 mmol) was added and the resulting mixture was stirred at 30oC for another 1 hr. The mixture was quenched with sat. aq. Na2S2O3solution and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~16% EtOAc in PE) to give the title compound (145 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.59 – 7.39 (m, 3H), 5.15 (s, 2H), 4.34 – 4.12 (m, 2H), 4.03 – 3.85 (m, 1H), 3.39 – 3.25 (m, 4H), 3.02 – 2.84 (m, 1H), 2.36 – 2.18 (m, 4H), 1.85 – 1.76 (m, 1H), 1.69 – 1.63 (m, 2H), 1.43 (s, 9H). LC / MS (ESI) m / z: 510.1 (M+H)+. Step 5: (6-(2-(Methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)(piperidin-3-yl)methanone A mixture of tert-butyl 3-(6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5- methylpyridazine-3-carbonyl)piperidine-1-carboxylate (140 mg, 0.275 mmol) in DCM (2 mL) and TFA (0.7 mL) was stirred at RT for 0.5 hr. The mixture was concentrated under reduced pressure to dryness to give the title compound (110 mg) as an oil, which was directly used in the next reaction without purification. LC / MS (ESI) m / z: 410 (M+H)+. Step 6: (6-(2-(Methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1- methylpiperidin-3-yl)methanol To a mixture of (6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin- 3- yl)(piperidin-3-yl)methanone (60 mg, 0.147 mmol), 37% aq. HCHO solution (0.3 mL) and AcOH (0.01 mL, 0.175 mmol) in DCE (2 mL) was added NaBH3CN (18.4 mg, 0.293 mmol) at 0oC and the mixture was stirred at 30oC for 20 mins. The mixture was quenched with sat. aq. NaHCO3solution and extracted with CHCl3 / i-PrOH (v / v, 3 / 1) three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to dryness to give the title compound (60 mg, 96.6% yield) as an oil. LC / MS (ESI) m / z: 426 (M+H)+. Step 7: (6-(2-(Methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1- methylpiperidin-3-yl)methyl methanesulfonate To a solution of (6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)(1- methylpiperidin-3-yl)methanol (100 mg, 0.235 mmol) in DCM (5 mL) was added TEA (0.131 mL, 0.940 mmol) and MsCl (0.036 mL, 0.470 mmol) at 0oC under N2atmosphere and the mixture was stirred at RT for 1 hr. The mixture was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to dryness to give the title compound (110 mg) as an oil. LCMS (ESI) m / z: 504 (M+H)+. Step 8: 6-(Azido(1-methylpiperidin-3-yl)methyl)-3-(2-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-4-methylpyridazine To a solution of (6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)(1-methylpiperidin-3-yl)methyl methanesulfonate (60 mg, 0.119 mmol) in DMF (2 mL) was added NaN3(38.7 mg, 0.596 mmol) at RT and the mixture was stirred at 60oC for 3.5 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (35 mg) as a solid. LCMS (ESI) m / z: 451 (M+H)+. Step 9: (6-(2-(Methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1- methylpiperidin-3-yl)methanamine To a solution of 6-(azido(1-methylpiperidin-3-yl)methyl)-3-(2-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-4-methylpyridazine (35 mg, 0.078 mmol) in MeOH (2 mL) was added Pd / C (5 mg, 10% wt.) at RT under N2atmosphere and the mixture was stirred under a H2balloon at 30oC for 1 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (30 mg) as a solid. LCMS (ESI) m / z: 425 (M+H)+. Step 10: 2-(6-(Amino(1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol, bis FA salt To a solution of (6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)(1-methylpiperidin-3-yl)methanamine (20 mg, 0.047 mmol) in MeOH (1 mL) was added HCl / 1,4-dioxane (0.5 mL, 4M) at 0oC and the mixture was stirred at 30oC for 1 hr. The mixture was concentrated to dryness and the residue was purified by prep-HPLC (Welch ultimate XB- C1821.2*250 mm, 20~95% MeCN in H2O with 0.1% FA) to give the title compound (6 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.65 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.28 – 7.26 (m, 2H), 4.08 – 3.95 (m, 1H), 3.13 – 3.00 (m, 1H), 2.78 – 2.70 (m, 1H), 2.26 (s, 3H), 2.19 – 2.13 (m, 4H), 2.05 – 1.94 (m, 3H), 1.88 – 1.77 and 1.74 – 1.66 (m x 2, 1H), 1.65 – 1.55 (m, 1H), 1.46 – 1.34 (m, 1H), 1.31 – 1.19 (m, 1H), 1.00 – 0.85 (m, 1H). LC / MS (ESI) m / z: 381.3 (M+H)+. Example 107 N-((6-(2-Hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1- methylpiperidin-3-yl)methyl)acetamide Step 1: N-((6-(2-(Methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)(1-methylpiperidin-3-yl)methyl)acetamide To a solution of (6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)(1-methylpiperidin-3-yl)methanamine (8 mg, 0.019 mmol) in DCM (1 mL) was added TEA (0.026 mL, 0.188 mmol) and AcCl (10 mg, 0.127 mmol) at 0oC under N2atmosphere and the mixture was stirred at 30oC for 0.5 hr. The mixture was concentrated under reduced pressure to dryness to give the title compound (8 mg) as an oil. LCMS (ESI) m / z: 467 (M+H)+. Step 2: N-((6-(2-Hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1- methylpiperidin-3-yl)methyl)acetamide To a solution of N-((6-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin- 3- yl)(1-methylpiperidin-3-yl)methyl)acetamide (8 mg, 0.017 mmol) in MeOH (1 mL) was added HCl / 1,4-dioxane (1 mL) at 0oC and the mixture was stirred at 30oC for 1 hr. The mixture was concentrated to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm*5 um, 3~95% MeOH in H2O with 0.1%FA) to give the title compound (1.5 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.54 – 8.48 (m, 1H), 7.52 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.29 – 7.27 (m, 2H), 5.01 – 4.89 (m, 1H), 2.88 – 2.84 (m, 1H), 2.17 (s, 6H), 2.12 – 2.08 (m, 1H), 2.03 – 1.95 (m, 2H), 1.92 (s, 3H), 1.91 – 1.83 (m, 1H), 1.82 – 1.70 (m, 2H), 1.60 – 1.52 (m, 1H), 1.50 – 1.41 (m, 1H). LCMS (ESI) m / z: 423 (M+H)+. Examples 108 3-((6-(2-Hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)-1- methylpiperidin-4-one, FA salt (partial) and Examples 109 3-((6-(2-Hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)-1- methylpiperidin-4-ol, FA salt Step 1: Methyl 6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3- carboxylate To a solution of 6-chloro-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylpyridazine (1 g, 2.24 mmol) in MeOH (10 mL) and DMF (2 mL) were added Pd(dppf)Cl2(240 mg, 0.330 mmol) and TEA (2.3 mL, 16.6 mmol) under N2atmosphere. The reaction mixture was degassed with N2three times and stirred under 15 psi of CO atmosphere at 70oC for 15 hrs. After cooling to RT, the reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue is purified by flash chromatography (silica gel, 0~5 % MeOH in DCM) to give the title compound (800 mg) as a solid. LC / MS (ESI) (m / z): 327 (M+H)+. Step 2: (6-(2-Methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methanol To a solution of NaBH4(406 mg, 10.7 mmol) in THF (8 mL) and EtOH (2 mL) was added CaCl2(476 mg, 4.29 mmol) at 0oC and the mixture was stirred at 0oC for 0.5 hr. Then methyl 6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-carboxylate (700 mg, 2.15 mmol) was added to the mixture at 0oC and the resulting mixture was stirred at 0oC for 0.5 hr. The mixture was poured into sat. aq. NH4Cl solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue is purified by flash chromatography (silica gel, 0~10 % MeOH in DCM) to give the title compound (400 mg) as a solid. LC / MS (ESI) (m / z): 299 (M+H)+. Step 3: 6-(2-Methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-carbaldehyde To a solution of (6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methanol (400 mg, 1.34 mmol) in DCM (20 mL) was added Dess-Martin periodinane (1.14 g, 2.69 mmol) at 0oC and the mixture was stirred at 20oC for 1.5 hrs. The mixture was washed with sat. aq. NaHCO3solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~5 % MeOH in DCM) to give the title compound (350 mg) as a solid. LC / MS (ESI) (m / z): 297 (M+H)+. Step 4: 3-((6-(2-Methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methylene)-1- methylpiperidin-4-one To a solution of 6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-carbaldehyde (1.20 g, 4.05 mmol) in EtOH (15 mL) were added 1-methylpiperidin-4-one (688 mg, 6.08 mmol), AcOH (0.070 mL, 1.22 mmol) and pyrrolidine (0.102 mL, 1.22 mmol) at RT, and the mixture was stirred at 40oC for 7 hrs. After cooling to RT, the mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~10 % MeOH in DCM) to give the title compound (350 mg) as a solid. LC / MS (ESI) (m / z): 392 (M+H)+. Step 5: 3-((6-(2-Methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)-1- methylpiperidin-4-one To a solution of 3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methylene)-1-methylpiperidin-4-one (350 mg, 0.894 mmol) in MeCN (10 mL) was added Pd / C (95 mg, 10% wt.), the mixture was degassed with N2three times and stirred under a H2balloon at RT for 16 hrs. The mixture was filtered through a pad of Celite, and the filter cake was washed with MeCN. The filtrate was concentrated under reduced pressure to give the title compound (300 mg) as a solid. LC / MS (ESI) (m / z): 394 (M+H)+. Step 6: 3-((6-(2-Hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)-1- methylpiperidin-4-one, FA salt (partial) (Example 108) To a solution of 3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)-1- methylpiperidin-4-one (300 mg, 0.763 mmol) in DCM (5 mL) was added BBr3(3.8 mL, 3.8 mmol, 1 M in DCM) drop-wisely at -20oC and the mixture was stirred at -20oC for 5 hrs. The reaction mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% FA) to give the title compound (250 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.28 – 7.26 (m, 2H), 3.34 (d, J = 5.9 Hz, 1H), 3.32 – 3.24 (m, 2H), 3.04 – 2.98 (m, 2H), 2.75 – 2.64 (m, 2H), 2.37 (td, J = 11.6, 3.2 Hz, 1H), 2.29 (s, 3H), 2.25 – 2.21 (m, 1H), 2.15 (s, 3H). LC / MS (ESI) (m / z): 380 (M+H)+. Step 7: 3-((6-(2-Hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)-1- methylpiperidin-4-ol, FA salt (Example 109) To a solution of 3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)-1-methylpiperidin-4-one (30 mg, 0.079 mmol) in MeOH (3 mL) was added NaBH4(6 mg, 0.158 mmol) at 0oC and the mixture was stirred at RT for 1 hr. The reaction mixture was quenched with sat. aq. NH4Cl solution and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% FA) to give the title compound (1 mg) as a solid.1 NMR (400 MHz, DMSO-d6) δ 7.50 – 7.44 (m, 2H), 7.27 – 7.26 (m, 2H), 3.40 – 3.46 (m, 1H), 3.23 – 3.18 (m, 1H), 2.81 (d, J = 11.6 Hz, 1H), 2.69 – 2.56 (m, 2H), 2.19 (s, 3H), 2.15 (s, 3H), 2.13 – 2.06 (m, 1H), 2.03 – 1.80 (m, 3H), 1.59 – 1.45 (m, 1H). LC / MS (ESI) (m / z): 382 (M+H)+. Example 110 & 111 Diastereomers of 3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)-1-methylpiperidin-4-ol To a solution of 3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)- 1- methylpiperidin-4-one (150 mg, 0.395 mmol) in MeOH (5 mL) was added NaBH4(15 mg, 0.395 mmol) at 0oC and the mixture was stirred at 25oC for 1 hour. The reaction mixture was quenched with ice-water and extracted with DCM twice. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H 2O with 0.1% FA) and further purified by chiral SFC to give Example 110 (peak 1, Rt= 2.420 min) and Example 111 (peak 2, Rt= 3.483 min) as solids. Chiral SFC condition: Column: ChiralPak C-IG, 250×20 mm I.D., 5µm; Mobile phase: A= CO2and B= EtOH (0.1% 2M NH3in MeOH); Gradient: B 25%; Flow rate: 60 mL / min. Example 110:1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 7.52 – 7.39 (m, 2H), 7.34 – 7.22 (m, 2H), 4.95 – 4.75 (m, 1H), 3.40 – 3.38 (m, 1H), 3.20 – 3.12 (m, 1H), 2.72 – 2.65 (m, 1H), 2.59 – 2.52 (m, 2H), 2.15 (s, 3H), 2.08 (s, 3H), 1.96 – 1.88 (m, 2H), 1.85 – 1.78 (m, 1H), 1.74 – 1.65 (m, 1H), 1.54 – 1.43 (m, 1H). LC-MS (ESI) m / z: 382.1 (M+H)+. Example 111:1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.49 – 7.43 (m, 2H), 7.29 – 7.25 (m, 2H), 3.74 – 3.65 (m, 1H), 3.40 – 3.34 (m, 1H), 3.21 – 3.13 (m, 1H), 2.77 – 2.69 (m, 1H), 2.62 – 2.53 (m, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 2.04 – 1.91 (m, 2H), 1.87 – 1.72 (m, 2H), 1.55 – 1.45 (m, 1H). LC-MS (ESI) m / z: 382.1 (M+H)+. Example 112 2-(6-((4-Amino-1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5- (trifluoromethyl)phenol, bis FA salt To a solution of 3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)- 1- methylpiperidin-4-one (30 mg, 0.079 mmol) in EtOH (5 mL) were added hydroxylamine hydrochloride (17 mg, 0.240 mmol) and Py (19 mg, 0.240 mmol) at RT and the mixture was stirred at 60oC for 0.5 hr. The mixture was concentrated under reduced pressure to dryness and the residue was dissolved in MeOH (1 mL). Raney Nickel (23 mg) was added to the above mixture under N2atmosphere. The resulting mixture was degassed with N2three times and stirred under a H2 balloon at RT overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% FA) to give the title compound (5 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.45 – 7.43 (m, 1H), 7.30 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 3.25 – 3.18 (m, 1H), 3.04 – 2.96 (m, 1H) 2.92 – 2.57 (m, 4H), 2.47 – 2.32 (m, 2H), 2.18 (s, 3H), 2.16 (s, 3H), 1.99 – 1.92 (m, 1H), 1.77 – 1.75 (m, 1H). LC / MS (ESI) (m / z): 381 (M+H+). Example 113 (S)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidin-1-yl)propanoic acid, FA salt (partial) Step 1: (S)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-(piperidin-3- ylmethyl)pyridazine hydrochloride To a solution of tert-butyl (S)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin- 3-yl)methyl)piperidine-1-carboxylate (2.0 g, 4.30 mmol) in DCM (20 mL) was added HCl / 1,4-dioxane (20 mL, 4 M) at 0oC and the mixture was stirred at RT for 2 hrs. The mixture was concentrated under reduced pressure to dryness to give the title compound (1.6 g) as a solid, which was directly used in the next reaction without purification. LC-MS (ESI) m / z: 366.2 (M+H)+. Step 2: Methyl (S)-3-(3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidin-1-yl)propanoate To a solution of (S)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-(piperidin-3- ylmethyl)pyridazine hydrochloride (221 mg, 0.55 mmol) in MeOH (5 mL) was added Cs2CO3(358.6 mg, 1.10 mmol) and methyl acrylate (57 mg, 0.66 mmol) at 0 °C and the mixture was stirred at RT for 1 hour. The resulting mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~75% EtOAc in PE) to give the title compound (230 mg) as a solid. LC-MS (ESI) m / z: 452.2 (M+H)+. Step 3: (S)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidin-1-yl)propanoic acid, FA salt (partial) To a solution of methyl (S)-3-(3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin- 3-yl)methyl)piperidin-1-yl)propanoate (200 mg, 0.44 mmol) in DMF (3 mL) was added NaSEt (76 mg, 0.88 mmol) and the mixture was stirred under N2atmosphere at 150oC for 20 mins. The mixture was cooled to RT, quenched with 1.0 M aq. HCl and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by pre-HPLC (YMC-Actus Triart C18250*20 mm, 20~95% MeCN in H2O with 0.1% FA) to give the title compound (35 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.59 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 3.60 – 3.45 (m, 2H), 3.29 – 3.24 (m, 2H), 3.07 – 2.81 (m, 4H), 2.58 (t, J = 6.6 Hz, 2H), 2.48 – 2.37 (m, 1H), 2.28 (s, 3H), 2.05 – 1.96 (m, 1H), 1.93 – 1.71 (m, 2H), 1.46 – 1.33 (m, 1H). LC-MS (ESI) m / z: 424.2 (M+H)+. Example 114 Methyl (S)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidin-1-yl)propanoate, FA salt (partial) To a solution of (S)-3-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidin-1-yl)propanoic acid (90 mg, 0.21 mmol) in MeOH (2 mL) was added conc. H2SO4(0.2 mL) and the mixture was stirred under N2atmosphere at 80oC for 2 hrs. The mixture was neutralized with sat. aq. NaHCO3solution at 0oC and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by pre-HPLC (YMC-Actus Triart C18250*20 mm, 20~95% MeCN in H2O with 0.1% FA) to give the title compound (23 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.56 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.22 (s, 1H), 3.67 (s, 3H), 3.07 – 3.00 (m, 2H), 2.96 – 2.84 (m, 4H), 2.67 – 2.54 (m, 2H), 2.28 (s, 3H), 2.25 – 2.09 (m, 3H), 1.86 – 1.73 (m, 2H), 1.71 – 1.57 (m, 1H), 1.28 – 1.08 (m, 1H). LC-MS (ESI) m / z: 438.2 (M+H)+. The examples listed in Error! Reference source not found.9 were prepared following the methods and protocols described for the synthesis of Example 113. Table 9. Examples Prepared Using Procedure for Example 113

[0022] Example 117 Methyl (S)-4-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidin-1-yl)butanoate, FA salt (partial) Example 118 (S)-4-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidin-1-yl)butanoic acid Step 1: Methyl (S)-4-(3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidin-1-yl)butanoate To a solution of (S)-3-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl-6-(piperidin-3- ylmethyl)pyridazine hydrochloride (165 mg, 0.41 mmol) in DMF (5 mL) was added K2CO3 (170 mg, 1.23 mmol) and methyl 4-bromobutanoate (111 mg, 0.62 mmol) at 0 °C and the mixture was stirred at 60oC for 16 hrs. The resulting mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~56% EtOAc in PE) to give the title compound (170 mg) as a solid. LC-MS (ESI) m / z: 466.2 (M+H)+. Step 2: Methyl (S)-4-(3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidin-1-yl)butanoate FA salt & (S)-4-(3-((6-(2-hydroxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)piperidin-1-yl)butanoic acid To a solution of methyl (S)-4-(3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)methyl)piperidin-1-yl)butanoate (150 mg, 0.32 mmol) in DMF (3 mL) was added NaSEt (83 mg, 0.96 mmol) and the mixture was stirred under N2atmosphere at 150oC for 30 mins. The mixture was cooled to RT, quenched with 1 M aq. HCl and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by pre-HPLC (YMC- Actus Triart C18250*20 mm, 20~95% MeCN in H2O with 0.1% FA) to give Example 118 (3.6 mg) followed by Example 117 (8 mg) as solids. Example 117:1H NMR (400 MHz, CD3OD) δ 7.61 (s, 1H), 7.51 – 7.49 (m, 1H), 7.45 – 7.42 (m, 2H), 3.87 (s, 3H), 3.58 – 3.51 (m, 2H), 3.14 – 3.11 (m, 2H), 3.06 – 2.94 (m, 2H), 2.89 – 2.76 (m, 2H), 2.49 – 2.39 (m, 3H), 2.20 (s, 3H), 2.02 – 1.76 (m, 5H), 1.42 – 1.33 (m, 1H). LC- MS (ESI) m / z: 452.5 (M+H)+. Example 118:1H NMR (400 MHz, CD3OD) δ 7.62 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 3.55 – 3.49 (m, 2H), 3.14 – 3.09 (m, 2H), 3.06 – 2.96 (m, 2H), 2.86 – 2.73 (m, 2H), 2.49 – 2.36 (m, 3H), 2.28 (s, 3H), 2.00 – 1.79 (m, 5H), 1.42 – 1.29 (m, 1H). LC-MS (ESI) m / z: 438.5 (M+H)+. The examples listed in Error! Reference source not found.10 were prepared following the methods and protocols described for the synthesis of Example 117 and Example 118. Table 10. Examples Prepared Using Procedure for Example 117 and Example 118

[0023] Example 127 Ethyl 3-((3S,4S)-4-hydroxy-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate Step 1: Tert-butyl (3S,4S)-4-hydroxy-3-((6-(2-(methoxymethoxy)-4-(trifluoromethyl) phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate To a solution of 6-chloro-3-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4- methylpyridazine (150 mg, 0.45 mmol) in 1,4-dioxane (4 mL) were added tert-butyl (3S,4S)- 3-amino-4-hydroxypiperidine-1-carboxylate (195 mg, 0.90 mmol), Cs2CO3(441 mg, 1.35 mmol), BerttPhos (48 mg, 0.09 mmol) and Pd2(dba)3(41 mg, 0.05 mmol) under N2atmosphere at RT and the mixture was stirred under N2atmosphere at 100 ℃ overnight. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0 - 70% EtOAc in PE) to give the title compound (66 mg) as a solid. LC / MS (ESI) (m / z): 513.3 (M+H)+. Step 2: (3S,4S)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidin-4-ol hydrochloride To a solution of tert-butyl (3S,4S)-4-hydroxy-3-((6-(2-(methoxymethoxy)-4-(trifluoromethyl) phenyl)-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (66 mg, 0.13 mmol) in 1,4- dioxane (2 mL) was added HCl / 1,4-dioxane (2 mL, 4 M) and the mixture was stirred at RT for 2 hrs. The mixture was concentrated under reduced pressure to dryness to give the title compound (62 mg) as a solid, which was used directly without further purification. LC / MS (ESI) (m / z): 369.3 (M+H)+. Step 3: Ethyl 3-((3S,4S)-4-hydroxy-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)amino)piperidin-1-yl)propanoate To a mixture of (3S,4S)-3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)amino)piperidin-4-ol hydrochloride (41 mg, 0.10 mmol) and ethyl acrylate (0.02 mL, 0.16 mmol) in EtOH (2 mL) was added TEA (0.06 mL, 0.66 mmol) at RT and the mixture was stirred at RT for 3 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18250*20 mm, 20 - 95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (13 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.04 - 3.96 (m, 1H), 3.64 - 3.52 (m, 1H), 3.23 - 3.16 (m, 1H), 2.91 - 2.82 (m, 1H), 2.76 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 7.2 Hz, 2H), 2.33 - 2.24 (m, 1H), 2.20 - 2.14 (m, 1H), 2.13 (s, 3H), 2.06 - 1.99 (m, 1H), 1.75 - 1.64 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H). LC / MS (ESI) (m / z): 469.2 (M+H)+. Example 128 (S)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3- yl)methyl)pyridazine-4-carboxylic acid Step 1: Methyl (S)-3-((1-(tert-butoxycarbonyl)piperidin-3-yl)methyl)-6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazine-4-carboxylate To a solution of 4-(6-chloro-4-methylpyridazin-3-yl)-3-methoxybenzonitrile (500 mg, 1.386 mmol) in DMA (5 mL) was added CuI (52.8 mg, 0.277 mmol) and Pd(dppf)Cl2dichloromethane complex (113.1 mg, 0.139 mmol) under N2atmosphere, the mixture was degassed with N2three times and (R)-((1-(tert-butoxycarbonyl)piperidin-3-yl)methyl)zinc(II) iodide solution (3 mL, 4.6 mmol, 1.54 M in DMF) was added. The mixture was degassed with N2three times and stirred under N2atmosphere at 80oC for 2 hrs. The mixture was cooled to RT, quenched with ice-water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~35% EtOAc in PE) to give the title compound (150 mg) as an oil. LC-MS (ESI) m / z: 524.4 (M+H)+. Step 2: Methyl (S)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3- ylmethyl)pyridazine-4-carboxylate To a solution of methyl (S)-3-((1-(tert-butoxycarbonyl)piperidin-3-yl)methyl)-6-(2-methoxy- 4- (trifluoromethyl)phenyl)-5-methylpyridazine-4-carboxylate (140 mg, 0.27 mmol) in 1,4- dioxane (1 mL) was added HCl / 1,4-dioxane (1 mL, 4 M) and the mixture was stirred at RT for 1 hour. The mixture was basified with sat. aq. NaHCO3 solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (110 mg) as a brown solid. LC / MS (ESI) m / z: 424.1 (M+H)+. Step 3: Methyl (S)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin-3-yl)methyl)pyridazine-4-carboxylate To a mixture of methyl (S)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3- ylmethyl)pyridazine-4-carboxylate (110 mg, 0.26 mmol), 37% aq. HCHO (0.1 mL) and AcOH (31.2 mg, 0.52 mmol) in MeOH (1 mL) was added NaBH3CN (49.0 mg, 0.78 mmol) at 0oC and the mixture was stirred at RT for 30 mins. The mixture was quenched with sat. aq. NaHCO3solution and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to dryness to give the title compound (90 mg) as a solid. LC / MS (ESI) m / z: 438.2 (M+H)+. Step 4: (S)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3- yl)methyl)pyridazine-4-carboxylic acid，Formic acid salt To a solution of methyl (S)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin-3-yl)methyl)pyridazine-4-carboxylate (90 mg, 0.21 mmol) in DCM (1 mL) was added BBr3(0.63 mL, 0.63 mmol, 1M in DCM) drop-wisely at -78oC and the mixture was stirred at RT for 1 hour. The reaction mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by pre-HPLC (YMC-Actus Triart C18250*20 mm, 10~95% MeCN in H2O with 0.1% FA) to give the title compound (5 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.09 (d, J = 7.7 Hz, 1H), 6.89 (s, 1H), 6.67 (d, J = 7.8 Hz, 1H), 2.96 – 2.85 (m, 3H), 2.83 – 2.75 (m, 1H), 2.38 – 2.30 (m, 1H), 2.30 (s, 3H), 2.22 (s, 3H), 1.97 – 1.88 (m, 1H), 1.86 – 1.75 (m, 2H), 1.73 – 1.54 (m, 2H), 1.13 – 0.99 (m, 1H). LC-MS (ESI) m / z: 410.1 (M+H)+. Example 129 (S)-6-(2-Hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin-3- yl)methyl)pyridazine-4-carboxamide To a solution of (S)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1-methylpiperidin- 3- yl)methyl)pyridazine-4-carboxylic acid (10 mg, 0.024 mmol) in DMF (1 mL) were added NH4Cl (1.96 mg, 0.037 mmol), DIEA (9.47 mg, 0.073 mmol) and HBTU (13.9 mg, 0.037 mmol) and the mixture was stirred under N2atmosphere at RT for 2 hrs. The mixture was concentrated to dryness and the residue was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 5~95% MeCN in H2O with 0.1% NH4HCO3) to give the title compound (2 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 7.20 (s, 1H), 3.01 – 2.89 (m, 4H), 2.33 (s, 3H), 2.26 (s, 3H), 2.14 – 2.08 (m, 1H), 2.03 – 1.95 (m, 1H), 1.83 – 1.74 (m, 2H), 1.65 – 1.57 (m, 1H), 1.35 – 1.33 (m, 1H), 1.18 – 1.08 (m, 1H). LC-MS (ESI) (m / z): 409.4 (M+H)+. Example 130 (S)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-3-((1-methylpiperidin-3-yl)methyl) pyridazine-4-carbonitrile

[0024] Step 1: 3-Chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile To a mixture of 3,6-dichloropyridazine-4-carbonitrile (200 mg, 1.15 mmol) and (2-methoxy- 4-(trifluoromethyl)phenyl)boronic acid (253 mg, 1.15 mmol) in 1,4-dioxane (5 mL) and water (2 mL) were added K2CO3(400 mg, 2.88 mmol) and Pd(dtbpf)Cl2(74 mg, 0.115 mmol) under N2atmosphere. The mixture was degassed with N2atmosphere three times and stirred under N2 atmosphere at 90 °C for 3 hrs. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to dryness. The residue was purified by flash chromatography (silica gel, 0~10% of EtOAc in PE) to give the title compound (230 mg) as a solid.1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.73 (s, 1H), 3.45 (s, 3H). LC-MS (ESI) (m / z): 314.0 (M+H)+. Step 2: Tert-butyl (S)-3-((4-cyano-6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3- yl)methyl)piperidine-1-carboxylate To a solution of 3-chloro-6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazine-4-carbonitrile (430 mg, 1.37 mmol) in DMA (2 mL) was added CuI (52 mg, 0.27 mmol) and Pd(dppf)Cl2(112 mg, 0.14 mmol) under N2atmosphere, the mixture was degassed with N2three times and (R)-((1-(tert-butoxycarbonyl)piperidin-3-yl)methyl)zinc(II) iodide solution (3.5 mL, 5.4 mmol, 1.54 M in DMF) was added. The resulting mixture was degassed with N2three times and stirred under N2atmosphere at 80 °C for 2 hrs. The mixture was cooled to RT, diluted with ice-water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~20% EtOAc in PE) to give the title compound (140 mg) as a solid. LC-MS (ESI) m / z: 477.2 (M+H)+. Step 3: (S)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-3-(piperidin-3-ylmethyl)pyridazine- 4- carbonitrile To a solution of tert-butyl (S)-3-((4-cyano-6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin- 3- yl)methyl)piperidine-1-carboxylate (130 mg, 0.27 mmol) in 1,4-dioxane (1 mL) was added HCl / 1,4-dioxane (1.0 mL, 4 M) at 0 ℃ and the mixture was stirred at RT for 1 hr. The mixture was concentrated under reduced pressure to dryness to give the title compound (90 mg) as a solid. LC-MS (ESI) m / z: 377.1 (M+H)+. Step 4: (S)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-3-((1-methylpiperidin-3-yl)methyl) pyridazine-4-carbonitrile To a mixture of (S)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-3-(piperidin-3-ylmethyl) pyridazine-4-carbonitrile (90 mg, 0.24 mmol) and 37% aq. HCHO solution (0.04 mL, 1.2 mmol) in MeOH (1 mL) was added NaBH3CN (45 mg, 0.72 mmol) at 0 ℃ and the mixture was stirred at RT for 30 mins. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to dryness to give the title compound (80 mg) as a solid. LCMS (ESI) (m / z): 391.1 (M+H)+. Step 5: (S)-6-(2-hydroxy-4-(trifluoromethyl)phenyl)-3-((1-methylpiperidin-3-yl)methyl) pyridazine-4-carbonitrile To a solution of (S)-6-(2-methoxy-4-(trifluoromethyl)phenyl)-3-((1-methylpiperidin-3- yl)methyl) pyridazine-4-carbonitrile (80 mg, 0.21 mmol) in DCM (1 mL) was added boron tribromide (0.63 mL, 0.63 mmol, 1 M in DCM) drop-wisely at -78 ℃ and the mixture was stirred at RT for 30 mins. The reaction mixture was quenched with sat. aq. NaHCO3solution at 0 ℃ and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by pre-HPLC (YMC-Actus Triart C18250*20 mm, 20~95% MeCN in H2O with 0.1% FA) to give the title compound (5 mg) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.38 – 7.29 (m, 2H), 3.10 – 3.06 (m, 2H), 2.83 – 2.74 (m, 2H), 2.24 (s, 3H), 2.23 – 2.18 (m, 1H), 2.09 – 1.95 (m, 2H), 1.70 – 1.64 (m, 2H), 1.54 – 1.45 (m, 1H), 1.15 – 1.05 (m, 1H). LC / MS (ESI) m / z: 377.2 (M+H)+. Example 131 (S)-2-(5-(aminomethyl)-4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)- 5- (trifluoromethyl)phenol, FA salt

[0025] Step 1: Tert-butyl (S)-3-((4-((((benzyloxy)carbonyl)amino)methyl)-6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)piperidine-1-carboxylate To a mixture of tert-butyl (S)-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3- yl)methyl)piperidine-1-carboxylate (Intermediate 8, 200 mg, 0.43 mmol) and ((benzyloxy)carbonyl)glycine (180 mg, 0.86 mmol) in MeCN (2 mL) and water (2 mL) was added K2S2O8(174.7 mg, 0.65 mmol) and AgNO3(14.6 mg, 0.086 mmol) under N2atmosphere at RT, the mixture was degassed with N2three times and stirred at 60 °C overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~30% EtOAc in PE) to give the title compound (80 mg) as a solid. LC-MS (ESI) m / z: 629.6 (M+H)+. Step 2: Benzyl (S)-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin-3- ylmethyl)pyridazin-4-yl)methyl)carbamate To a solution of tert-butyl (S)-3-((4-((((benzyloxy)carbonyl)amino)methyl)-6-(2-methoxy-4- (trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)piperidine-1-carboxylate (80 mg, 0.127 mmol) in 1,4-dioxane (1 mL) was added HCl / 1,4-dioxane (1 mL, 4 M) and the mixture was stirred at RT for 1 hour. The mixture was basified with sat. aq. NaHCO3solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (65 mg) as a solid. LC / MS (ESI) m / z: 529.3 (M+H)+. Step 3: Benzyl (S)-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin-3-yl)methyl)pyridazin-4-yl)methyl)carbamate To a mixture of benzyl (S)-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-(piperidin- 3-ylmethyl)pyridazin-4-yl)methyl)carbamate (65 mg, 0.123 mmol), 37% aq. HCHO (0.1 mL) and AcOH (14.8 mg, 0.246 mmol) in MeOH (2 mL) was added NaBH3CN (23.2 mg, 0.369 mmol) at 0oC and the mixture was stirred at RT for 30 mins. The mixture was quenched with sat. aq. NaHCO3solution and extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (55 mg) as a solid. LC-MS (ESI) m / z: 543.5 (M+H)+. Step 4: (S)-2-(5-(aminomethyl)-4-methyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3- yl)- 5-(trifluoromethyl)phenol, FA salt To a solution of benzyl (S)-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl-3-((1- methylpiperidin-3-yl)methyl)pyridazin-4-yl)methyl)carbamate (55 mg, 0.101 mmol) in DCM (1 mL) was added BBr3(0.5 mL, 0.50 mmol, 1M in DCM) drop-wisely at -78oC and the mixture was stirred at RT for 50 mins. The reaction mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by pre-HPLC (YMC-Actus Triart C18 250*20 mm, 10~95% MeCN in H2O with 0.1% FA) to give the title compound (5 mg) as a solid.1H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 4.21 (s, 2H), 3.59 – 3.50 (m, 1H), 3.48 – 3.38 (m, 1H), 3.21 – 3.09 (m, 2H), 3.01 – 2.90 (m, 1H), 2.88 – 2.84 (m, 1H), 2.83 (s, 3H), 2.69 – 2.56 (m, 1H), 2.33 (s, 3H), 2.06 – 1.94 (m, 2H), 1.90 – 1.78 (m, 1H), 1.53 – 1.38 (m, 1H). LC-MS (ESI) m / z: 395.4 (M+H)+. Example 132 & Example 133 Diastereomers of methyl 5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3- yl)methyl)-1-methylpiperidine-2-carboxylate Step 1: 1-(Tert-butyl) 2-methyl (Z)-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methylene)piperidine-1,2-dicarboxylate To a solution of 2,2,6,6-tetramethylpiperidine (708 mg, 5.01 mmol) in anhydrous THF (10 mL) was added n-butyllithium (2.0 mL, 5.0 mmol, 2.5 M in hexane) at 0 ℃ under N2atmosphere and the mixture was stirred at 0 ℃ for 10 mins. A solution of bis(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)methane (1.3 g, 5.01 mmol) in THF (5 mL) was added to the mixture and the mixture was stirred at 0 ℃ for 15 mins. The mixture was cooled to -78 ℃ and a solution of 1-(tert-butyl) 2-methyl 5-oxopiperidine-1,2-dicarboxylate (860 mg, 3.34 mmol) in THF (5 mL) was added drop-wisely. The resulting mixture was stirred at -78 ℃ for 1 hr and at 0 ℃ for 16 hrs. The mixture was quenched with ice-water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to dryness. The residue was purified by flash chromatography (silica gel, 0~10% of EtOAc in PE) to give the title compound (550 mg) as an oil. LC-MS (ESI) (m / z): 382.2 (M+H)+. Step 2: 1-(Tert-butyl) 2-methyl (E)-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)methylene)piperidine-1,2-dicarboxylate To a mixture of 1-(tert-butyl) 2-methyl (Z)-5-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methylene)piperidine-1,2-dicarboxylate (250 mg, 0.66 mmol) and 6-chloro-3-(2-methoxy- 4- (trifluoromethyl)phenyl)-4-methylpyridazine (198 mg, 0.66 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added Cs2CO3 (641 mg, 1.97 mmol) and Pd(dppf)Cl2 (48 mg, 0.07 mmol) under N2atmosphere. The mixture was degassed with N2three times and stirred under N2atmosphere at 90 ℃ for 2 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by flash chromatography (silica gel, 0~10% EtOAc in PE) to give the title compound (230 mg) as a solid. LC-MS (ESI) (m / z): 522.3 (M+H)+. Step 3: 1-(Tert-butyl) 2-methyl 5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)methyl)piperidine-1,2-dicarboxylate To a solution of 1-(tert-butyl) 2-methyl (E)-5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)- 5- methylpyridazin-3-yl)methylene)piperidine-1,2-dicarboxylate (230 mg, 0.44 mmol) in MeOH (5 mL) was added PtO2(20 mg, 0.04 mmol) under N2temperature and the mixture was stirred under a H2balloon at RT overnight. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (220 mg) as a solid. LC-MS (ESI) m / z: 524.2 (M+H)+. Step 4: Methyl 5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidine-2-carboxylate To a solution of 1-(tert-butyl) 2-methyl 5-((6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin-3-yl)methyl)piperidine-1,2-dicarboxylate (50 mg, 0.09 mmol) in DCM (1 mL) was added BBr3(0.29 mL, 0.29 mmol, 1 M in DCM) drop-wisely at -78oC and the mixture was stirred at RT for 50 mins. The mixture was quenched with sat. aq. NaHCO3solution at 0oC and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the title compound (30 mg) as an oil, which was directly used in the next reaction without purification. LC-MS (ESI) m / z: 410.1 (M+H)+. Step 5: Rel-methyl (2R,5S)-5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- methylpyridazin- 3-yl)methyl)-1-methylpiperidine-2-carboxylate To a mixture of methyl 5-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3- yl)methyl)piperidine-2-carboxylate (30 mg, 0.07 mmol) and 37% aq. HCHO (0.02 mL) in MeOH (1 mL) was added NaBH3CN (17.8 mg, 0.22 mmol) at 0 ℃ and the mixture was stirred at RT for 30 mins. The mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*20 mm, 5~95% MeCN in H2O with 0.1% NH4HCO3) to give Example 132 (firstly eluted, 1.4 mg) and Example 133 (secondly eluted, 1.3 mg) as solids. Example 132:1H NMR (400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.26 – 7.20 (m, 2H), 3.60 (s, 3H), 2.80 – 2.73 (m, 3H), 2.59 – 2.55 (m, 1H), 2.13 (s, 3H), 2.05 (s, 3H), 2.00 – 1.93 (m,...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I): ,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, phenyl, or C3-6cycloalkyl; X is NR5, S, O, or CR6R7; Y is a bond or CHR7; W is H or C1-6alkyl; R1at each occurrence is independently selected from H, oxo (=O), halogen, NO2, C1-8alkyl, CN, C1-8alkyl-CN, OR9, C1-8alkyl-OR10, NRaRb, C1-8alkyl-NRaRb, C(O)OR11, C1-8alkyl- C(O)OR12, C1-8alkyl-O-C1-6alkylene-C(O)OR12, NHC(O)R13, C(O)NH-C1-8alkylene-OR9, C(O)NRcRd, C(O)NHR11, -C(O)-C1-8alkylene-NRaRb, -C(O)O-C1-8alkylene-NRcRd, -C(O)-C1-8alkylene-C(O)NRcRd, -C(O)-C1-8alkylene-OR11, C1-8alkyl-C(O)NRcRd, C1-8alkyl- OC(O)NRcRd, and C1-8alkyl-S(O)2R14, provided that R1is not oxo (=O) when A is phenyl or 5- to 6-membered heteroaryl; wherein two adjacent R1together with the atoms in Ring A to which they are attached form a 5- or 6-membered carbocyclyl or heterocyclyl group optionally substituted by one, two, or three substituents independently selected from halogen, CN, OH, C1-6alkyl, C1-6haloalkyl, O-C1-6alkyl, O-C1-6haloalkyl, and oxo (=O); R2is H, OH, -C1-4alkyl, or -C1-4alkyl-O-C1-4alkyl; R3at each occurrence is independently selected from H, halogen, OH, CN, C1-6alkyl, C1-6haloalkyl, O-C1-6alkyl, C1-6alkyl-OR9, O-C1-6haloalkyl, S(O)2NRcRd, S(O)2R15, C3-6cycloalkyl, 5- or 6-membered heteroaryl, or 5- or 6-membered heterocyclyl; or alternatively two adjacent R3together with the carbon atoms in the phenyl ring to which they are attached form a 5-membered heteroaryl or 5-membered heterocyclyl fused to the phenyl ring, whereinthe fused 5-membered heteroaryl or 5-membered heterocyclyl is optionally substituted by one, two, or three substituents independently selected from R23; R4is H, -C1-6alkyl, or -C1-4alkyl-O-C1-4alkyl, provided that when W is H, then R4is not H; R5at each occurrence is independently H, C1-8alkyl, -C(O)-C1-6alkyl, or -C(O)-OC1-6alkyl; R6at each occurrence is independently H, OR16, or NHR17; R7at each occurrence is independently H, C1-6alkyl, or OR16; or alternatively when X is CR6R7, R6and R7together may form oxo (=O); R8is independently selected from H, C1-6alkyl, CN, C1-6alkyl-CN, C1-6alkyl-OR10, -6- -or alternatively, R5and R8together with the carbon and nitrogen atoms between them form a 5- or 6-membered heterocyclyl ring optionally comprising one additional heteroatom selected from N, O, and S; or alternatively, R6and R8together with the carbon atoms between them form a 5- or 6-membered carbocylyl or heterocyclyl ring comprising one or two heteroatoms independently selected from N, O, and S; wherein the heterocyclyl formed between R5and R8and carbocyclyl or heterocyclyl formed between R6and R8are each optionally substituted by one, two, or three substituents independently selected from halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O-C1-4haloalkyl, and oxo (=O); R9at each occurrence is independently hydrogen or C1-6alkyl; R10at each occurrence is independently hydrogen, C1-6alkyl, benzyl, or C(O)N(RcRd); R11at each occurrence is independently hydrogen, C1-8alkyl or C3-8cycloalkyl each optionally substituted by one, two, or three substituents independently selected from OR9and N(RcRd); R12at each occurrence is independently hydrogen, C1-8alkyl, 4- to 6-membered heterocyclyl, or C3-8cycloalkyl; R13at each occurrence is independently hydrogen or C1-6alkyl;R14at each occurrence is independently C1-6alkyl; R15at each occurrence is independently C1-6alkyl or C1-6haloalkyl; R16at each occurrence is independently hydrogen or C1-6alkyl; R17at each occurrence is independently hydrogen or C(O)-C1-6alkyl; R18at each occurrence is independently hydrogen or C1-6alkyl; R19at each occurrence is independently hydrogen or C1-6alkyl; R20at each occurrence is independently hydrogen or C1-6alkyl; R21at each occurrence is independently C1-6alkyl or benzyl; R22at each occurrence is independently hydrogen or C1-6 alkyl; R23at each occurrence is independently halogen, OH, CN, C1-6alkyl, C1-6alkyl-OR9, C3-6cycloalkyl, C1-6haloalkyl, O-C1-6alkyl, or O-C1-6haloalkyl; Raat each occurrence is independently hydrogen or C1-8alkyl, or C(O)OR21; Rbat each occurrence is independently hydrogen or C1-6alkyl; Rcat each occurrence is independently hydrogen or C1-6alkyl; Rdat each occurrence is independently hydrogen or C1-6alkyl; m is 0, 1, 2, 3, or 4; and n is 0, 1, or 2; provided that the compounds of Formulas (A), (A-1), (B), (B-1), and (C) as defined or individually listed below are excluded:, wherein: m is 1 or 2; R1ais H, CH3, isopropyl, or cyclopropyl;R1is H, OH, =O, or CH3; R2is OH; R3ais H, F, CN, CH3, or CF3; R3is H or F; R4is H or CH3; R6is H, OH, or OCH3; R7is H, CH3, OH, or OCH3; R8is H or CH3; and W is H or CH3;wherein: m is 1, 2, or 3; n is 1 or 2; R1ais H, CH3, CH2CH3, CH(CH3)2, CH2CH2F, CH2CF3, CH2CH2OH, or CH2C(CH3)2OH; R1is H, CO2H, OH, =O, CH3, CF3, or F; R2is OH; R3ais H, F, Cl, CN, CH3, CF3, CH2CH3, CO2H, OCF3, or cyclopropyl; R3is H or CH3; R4is H or CH3; R5is H or CH3; R8is H, CH3, CN, CH2OH, or CF3; and W is H, F, CF3, or CH3;wherein: W is CH3; R8is H or CH3; and R1ais CH2CH2NH2, CH2CH2NHBoc, C(O)CH2NH2, C(O)CH2NHBoc, CO2But, CH2CO2H, CH2CO2But, CH2CH2CO2H, CH2CH2CO2Et, CH2C(CH3)2CO2H, or CH2C(CH3)2CO2CH3;wherein: R1ais CH3; R2is OH; R3ais H, F, CN, or CF3; R4is H or CH3; R8is H or CH3; and W is H or CH3; and ,,or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a ring structure selected from phenyl, pyridinyl, pyrazolyl, imidazolyl, piperidinyl, piperazinyl, cyclobutyl, cyclopentyl, and cyclohexyl; and W, m, n, and R1through R8are each as defined in claim 1.

3. The compound of claim 1 or 2, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: X is NR5, S, or CHR6; Y is a bond or CHR7; W is H or C1-4 alkyl; m is 0, 1, 2, or 3; andn is 0, 1, or 2. R1at each occurrence is independently selected from H, oxo (=O), halogen, NO2, C1-6alkyl, CN, C1-6alkyl-CN, OR9, C1-6alkyl-OR10, NRaRb, C1-6alkyl-NRaRb, C(O)OR11, C1-8alkyl-C(O)OR12, C1-6alkyl-O-C1-4alkylene-C(O)OR12, NHC(O)R13, C(O)NH-C1-6alkylene- OR9, C(O)NRcRd, C(O)NHR11, -C(O)-C1-6alkylene-NRaRb, -C(O)O-C1-8alkylene-NRcRd, - C(O)-C1-6alkylene-C(O)NRcRd, -C(O)-C1-6alkylene-OR11, C1-8alkyl-C(O)NRcRd, C1-6alkyl- OC(O)NRcRd, and C1-6alkyl-S(O)2R14, provided that R1is not oxo (=O) when A is phenyl or 5- to 6-membered heteroaryl; wherein two adjacent R1together with the atoms in Ring A to which they are attached form a 5- or 6-membered carbocyclyl or heterocyclyl group optionally substituted by one, two, or three substituents independently selected from halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O-C1-4haloalkyl, and oxo (=O); R2is H, OH, CH3, or CH2OCH3; R3at each occurrence is independently selected from H, halogen, OH, CN, C1-4alkyl, C3-6cycloalkyl, C1-4haloalkyl, C1-4alkyl-OR9, O-C1-4alkyl, O-C1-4haloalkyl, S(O)2NRcRd, S(O)2R15, 5-membered heteroaryl, and 5-membered heterocyclyl; or alternatively two adjacent R3together with the carbon atoms in the phenyl ring to which they are attached form a 5- membered heteroaryl fused to the phenyl ring, wherein the fused 5-membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from R23; R4is H, CH3, or -C1-4alkyl-O-C1-4alkyl, provided that when W is H, then R4is not H; R5at each occurrence is independently H or C1-6alkyl; R6is H, OR16, or NHR17; R7is H, C1-4alkyl, or OR16; R8is independently selected from H, C1-4alkyl, CN, C1-4alkyl-CN, C1-4alkyl-OR10, C(O)OR18, C1-4alkyl-C(O)OR19, CON(RcRd), C1-4alkyl-NRcRd, C1-4alkyl-OC(O)N(RcRd), C1-4alkyl-C(O)N(RcRd), C1-4alkyl-NHC(O)R20, C1-4alkyl-NHC(O)OR21, C1-4alkyl- NHC(O)N(RcRd), C1-4alkyl-NHC(=N-R22)N(RcRd), C(O)-NHC(O)N(RcRd), C(O)-NHC(=N- R22)N(RcRd), and C1-4alkyl-S(O)2NRcRd; or alternatively, R5and R8together with the carbon and nitrogen atoms between them form a 6-membered heterocyclyl ring optionally comprising one additional heteroatom selected from N, O, and S; or alternatively, R6and R8together with the carbon atoms between them form a 6-membered carbocylyl or heterocyclyl ring comprising a heteroatom selected from N,O, and S; wherein the heterocyclyl formed between R5and R8and carbocyclyl or heterocyclyl formed between R6and R8are each optionally substituted by one, two or three substituents independently selected from halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O-C1-4haloalkyl, and oxo (=O). R9at each occurrence is independently hydrogen or C1-4alkyl; R10at each occurrence is independently hydrogen, C1-4alkyl, benzyl, or C(O)N(RcRd); R11at each occurrence is independently hydrogen, C1-6alkyl or C3-6cycloalkyl each optionally substituted by one, two, or three substituents independently selected from OR9and N(RcRd); R12at each occurrence is independently hydrogen, C1-6alkyl, or C3-6cycloalkyl; R13at each occurrence is independently hydrogen or C1-4 alkyl; R14at each occurrence is independently C1-4alkyl; R15at each occurrence is independently C1-4alkyl or C1-4haloalkyl; R16at each occurrence is independently hydrogen or C1-4alkyl; R17at each occurrence is independently hydrogen or C(O)-C1-4alkyl; R18at each occurrence is independently hydrogen or C1-4alkyl; R19at each occurrence is independently hydrogen or C1-4alkyl; R20at each occurrence is independently hydrogen or C1-4alkyl; R21at each occurrence is independently C1-4alkyl or benzyl; R22at each occurrence is independently hydrogen or C1-4alkyl; R23at each occurrence is independently halogen, OH, CN, C1-4alkyl, C1-4alkyl-OR9, C3-6cycloalkyl, C1-4haloalkyl, O-C1-4alkyl, or O-C1-4haloalkyl; Raat each occurrence is independently hydrogen or C1-6alkyl, or C(O)OR21; Rbat each occurrence is independently hydrogen or C1-4alkyl; Rcat each occurrence is independently hydrogen or C1-4alkyl; and Rdat each occurrence is independently hydrogen or C1-4alkyl.

4. The compound of any one of claims 1 to 3, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein:X-Y is selected from, and ; W is H or CH3; n is 1 or 2; m is 1, 2, or 3; R1at each occurrence is independently selected from H, CH3, OH, =O, NH2, NHCOCH3, CH2OH, CH2OCONH2, CH2CH2CH2OH, CH2CO2H, CH2CH2CO2H, CO2H, CO2CH3, CO2Et, CO2iPr, CH2CN, CH2CH2CN, CH2CH2CH2CN, CH2CONH2, CH2CH2CONH2, CH2CH2CH2CONH2, CH2CO2CH3, CH2CO2Et, CH2CH2CO2CH3, CH2CH2CO2Et, CH2CH2CO2CH2CH2CH3, CH2CH2CO2CH2(CH2)2CH3, CH2CH2CO2iPr, CH2CH2CO2But, CH2CH2CO2-cyclobutyl, CH2(CH2)2CO2H, CH2(CH2)2CO2CH3, CH2(CH2)2CO2Et, CH2(CH2)3CO2H, CH2(CH2)3CO2CH3, CH2(CH2)3CO2Et, CH2(CH2)4CO2H, CH2(CH2)4CO2CH3, CH2(CH2)4CO2Et, CH2(CH2)5CO2H, CH2(CH2)5CO2CH3, CH2(CH2)5CO2Et, CH(CH3)CH2CO2H, CH(CH3)CH2CO2CH3, CH(CH3)CH2CO2Et, CH2CH(CH3)CO2H, CH2CH(CH3)CO2CH3, CH2CH(CH3)CO2Et, CH2CH(CH3)CH2CH2CO2H, CH2CH(CH3)CH2CH2CO2CH3, CH2CH(CH3)CH2CH2CO2Et, CH2C(CH3)2CO2H, CH2C(CH3)2CO2CH3, CH2C(CH3)2CO2Et, CH2CH2OCH2CO2H, CH2CH2CONHEt, CH2CH2CONHBut, CH(CH3)CO2H, CH(CH3)CO2Et, CON(CH3)2, CONHCH3, CONHCH2CH2OH, CO2CH2CH2OH, CO2CH2CH2CH2OH, CO2CH2(CH2)3OH, CO2CH2(CH2)4OH, CO2CH2CH(OH)CH2OH, CO2CH(CH2OH)2, CO2CH2CH2NH2, CO2CH(CH2NH2)2, CH2CH2SO2CH3, CO2But, CO2CH2CH2CH2C(O)NH2, CO2CH2C(O)NH2, CO2CH2C(O)NHCH3, CO2-cyclopentyl-NH2, CH2CH2NH2, and CH2CH2OH, and - C(CH3)2OH; R2is H or OH; R3is selected from halogen, OH, -CF3, -CH3, -CH2CH3, isopropyl, cyclopropyl, -CN, - OCF3, -OCHF2, -OCH3, -CH2OH,or alternatively two adjacent R3together with the carbon atoms in the phenyl ring to which they are attached form a pyrrole ring fused to the phenyl ring, wherein the fused pyrrole ring is optionally substituted by one or two substituents independently selected from R23;R4is H, CH3, or CH2OCH3, provided that when W is H, then R4is not H; R5at H or C(O)CH3; R6is H, OH, NH2, or NHC(O)CH3; R7is H, CH3, or OH; and R8is selected from H, -CN, -CO2H, -CONH2, -CH2NH2, -CH2OH, -CH2CH2CO2CH3, -CH2NHCOCH3, -CH2NHCOOCH3, -CH2OCONH2, -CH2CH2CO2H, -CH2CH2CONH2, -R23at each occurrence is independently halogen, OH, CN, -CF3, -CH3, -CH2CH3, isopropyl, cyclopropyl, -OCF3, -OCHF2, -OCH3, or -CH2OH.

5. The compound of any one of claims 1 to 4, having the structure of Formula (II):or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or piperidinyl; and R5is H, C1-6alkyl, or C(O)-C1-4alkyl.

6. The compound of claim 5, having the structure of Formula (II-1):, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: W is H or C1-4alkyl; n is 1 or 2; m is 1, 2, or 3;R1ais selected from H, C1-4alkyl, C1-6alkyl-OR10, C1-6alkyl-NRaRb, C(O)OR11, C1-8alkyl-C(O)OR12, C1-6alkyl-O-C1-4alkylene-C(O)OR12, C1-8alkyl-C(O)NRcRd, C1-6alkyl-CN, C(O)NRcRd, and C(O)NHR11; R1at each occurrence is independently selected from H, C1-4alkyl, OH, =O, CN, NRaRb, NHC(O)R13, C1-4alkyl-OR10, C1-4alkyl-OC(O)NRcRd, C1-8alkyl-C(O)OR12, C(O)OR11, C1-6alkyl-CN, C1-4alkyl-C(O)NRcRd, C(O)NRcRd, C(O)NHR11, C(O)NH-C1-4alkylene-OR9, -C(O)-C1-4alkylene-OR11, -C(O)-C1-4alkylene-NRaRb, CO2CH(CH2NH2)2, - C(O)-C1-4alkylene-C(O)NRcRd,, CO2-cyclopentyl-NH2, and C1-4alkyl-S(O)2R14; or alternatively, R1aand an adjacent R1together with the nitrogen and carbon atoms to which they are attached form a 6-membered heterocyclyl optionally substituted by one, two or three substituents independently selected from halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O-C1-4haloalkyl, and oxo (=O); R2is H or OH; R3at each occurrence is independently selected from H, halogen, OH, CN, C1-4alkyl, C1-4haloalkyl, C3-6cyclopropyl, O-C1-4alkyl, O-C1-4haloalkyl, C1-4alkyl-OR9, S(O)2NRcRd, S(O)2R15, and 5-membered heteroaryl; or alternatively two adjacent R3together with the carbon atoms in the phenyl ring to which they are attached form a pyrrole ring fused to the phenyl ring, wherein the fused pyrrole ring is optionally substituted by one or two substituents independently selected from R23; R4is H, C1-4alkyl, or CH2OCH3, provided that when W is H, then R4is not H; R5is H or C1-4alkyl, or -C(O)-C1-4alkyl; R8is selected from H, C1-4alkyl, CN, C1-4alkyl-CN, C1-4alkyl-OR10, C(O)OR18, C1-4alkyl-C(O)OR19, CON(RcRd), C1-4alkyl-NRcRd, C1-4alkyl-OC(O)N(RcRd), C1-4alkyl- C(O)N(RcRd), C1-4alkyl-NHC(O)R20, C1-4alkyl-NHC(O)OR21, C1-4alkyl-NHC(O)N(RcRd), C1-4alkyl-NHC(=N-R22)N(RcRd), C(O)-NHC(O)N(RcRd), C(O)-NHC(=N-R22)N(RcRd), and - CH2S(O)2NRcRd; or alternatively, R5and R8together with the nitrogen and carbon atoms between them form a 6-membered heterocyclyl optionally substituted by one, two or three substituents independently selected from halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, O-C1-4haloalkyl, and oxo (=O); R9at each occurrence is independently hydrogen or C1-4alkyl;R10at each occurrence is independently hydrogen, C1-4alkyl, benzyl, or C(O)N(RcRd); R11at each occurrence is independently hydrogen, C1-6alkyl or C3-6cycloalkyl each optionally substituted by one, two, or three substituents independently selected from OR9and N(RcRd); and R12at each occurrence is independently hydrogen, C1-6alkyl, or C3-6cycloalkyl; R13at each occurrence is independently hydrogen or C1-4alkyl; R14at each occurrence is independently C1-4 alkyl; R15at each occurrence is independently C1-4alkyl or C1-4haloalkyl; R18at each occurrence is independently hydrogen or C1-4alkyl; R19at each occurrence is independently hydrogen or C1-4alkyl; R20at each occurrence is independently hydrogen or C1-4alkyl; R21at each occurrence is independently C1-4alkyl or benzyl; R22at each occurrence is independently hydrogen or C1-4alkyl; R23at each occurrence is independently halogen, OH, CN, C1-4alkyl, C1-4alkyl-OR9, C3-5cycloalkyl, C1-4haloalkyl, O-C1-4alkyl, and O-C1-4haloalkyl; Raat each occurrence is independently hydrogen or C1-6alkyl, or C(O)OR21; Rbat each occurrence is independently hydrogen or C1-4alkyl; Rcat each occurrence is independently hydrogen or C1-4alkyl; and Rdat each occurrence is independently hydrogen or C1-4alkyl.

7. The compound of claim 6, having the structure of Formula (II-2):, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: R1ais selected from H, CH3, CH2CH3, -CH2-cyclopropyl, CH2CO2H, CH2CO2CH3,CH2CO2Et, CH2CH2CO2H, CH2CH2CO2CH3, CH2CH2CO2Et, CH2CH2CO2CH2CH2CH3, CH2CH2CO2CH2(CH2)2CH3, CH2CH2CO2iPr, CH2CH2CO2But, CH2CH2CO2-cyclobutyl, CH2(CH2)2CO2H, CH2(CH2)2CO2CH3, CH2(CH2)2CO2Et, CH2(CH2)3CO2H, CH2(CH2)3CO2CH3, CH2(CH2)3CO2Et, CH2(CH2)4CO2H, CH2(CH2)4CO2CH3, CH2(CH2)4CO2Et, CH2(CH2)5CO2H, CH2(CH2)5CO2CH3, CH2(CH2)5CO2Et, CH(CH3)CH2CO2H, CH(CH3)CH2CO2CH3, CH(CH3)CH2CO2Et, CH2CH(CH3)CO2H, CH2CH(CH3)CO2CH3, CH2CH(CH3)CO2Et, CH2CH(CH3)CH2CH2CO2H, CH2CH(CH3)CH2CH2CO2CH3, CH2CH(CH3)CH2CH2CO2Et, CH2C(CH3)2CO2H, C ,R1at each occurrence is independently selected from H, CO2H, CO2CH3, CO2Et, CO2iPr, CO2But, CH2CONH2, CONHCH3, CON(CH3)2, CONHCH2CH2OH, CO2CH2CH2NH2, CO2CH2CH2OH, CO2CH(CH2OH)2, CO2CH2CH2CH2OH, CO2CH2CH2CH2CH2OH, CO2CH2CH2CH2CH2CH2OH, CO2CH2CH(OH)CH2OH, CO2CH(CH2NH2)2, CO2CH2CH2CH2C(O)NH2, CO2CH2C(O)NH2, CO2CH2C(O)NHCH3, CO2-cyclopentyl-NH2, CH2OH, C(CH3)2OH, CH(CH3)CO2H, CH(CH3)CO2CH3, CH(CH3)CO2Et, CH2CO2H, CH2CO2CH3, CH2CO2Et, and CH2OCONH2; R3is CF3, CH3, CH2CH3, isopropyl, cyclopropyl, CN, OCF3, OCHF2, CH2OH, OCH3, , - -8. The compound of claim 6, having the structure of Formula (II-3):1or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Q is O, S, NR5a, or CHR8b, wherein: R5ais hydrogen or C1-4alkyl; and R8aand R8bare independently hydrogen, halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, or O-C1-4haloalkyl.

9. The compound of claim 6, having the structure of Formula (II-4):, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein T is O, S, NR1c, or CHR1b, wherein: i is 0, 1, or 2; R1cis hydrogen or C1-4alkyl; and R1bat each occurrence is independently hydrogen, halogen, CN, OH, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, or O-C1-4haloalkyl.

10. The compound of claim 6, having the structure of Formula (II-5):or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: j is 0, 1, or 2; R23ais H or C1-4alkyl; R23at each occurrence is independently halogen, OH, CN, -CF3, -CH3, -CH2CH3, isopropyl, cyclopropyl, -OCF3, -OCHF2, -OCH3, or -CH2OH.

11. The compound of any one of claims 1 to 4, having the structure of Formula (III):or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or piperidinyl; and R6is H, OH, C1-4 alkyl, O-C1-4alkyl, or NHR17.

12. The compound of claim 11, having the structure of Formula (III-1):or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, or 3; W is H or CH3; R1ais selected from H, C1-4alkyl, C1-4alkyl-CN, C1-4alkyl-OR10, C1-4alkyl-NRaRb, C(O)OR11, -CO2H, -C(O)OR12, C(O)NH-C1-4alkylene-OR9, C1-4alkyl-C(O)NRcRd, C1-4alkyl- OC(O)NRcRd, and C1-4alkyl-S(O)2R14; R1at each occurrence is independently selected from H, oxo (=O), C1-4alkyl, OR9, C1-4alkyl-OR10, NRaRb, C1-4alkyl-NRaRb, and C(O)OR11;R2is OH; R3and R3aare independently selected from C1-4alkyl, C1-4haloalkyl, cyclopropyl, O-C1-4alkyl, O-C1-4haloalkyl, S(O)2NRcRd, S(O)2R15, and 5-membered heteroaryl; R4is H or CH2OCH3; R6is H, OH, C1-4alkyl, O-C1-4alkyl, or NHR17; and R8is selected from H, -CN, -CO2H, -C(O)OC1-4alkyl, -CONH2, -CH2NH2, and - CH2OH.

13. The compound of claim 12, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: m is 1 or 2; R1ais selected from CH3, CH2OH, CH2CH2CH2OH, CH2CO2H, CH2CH2CO2H, CH2CN, CH2CH2CN, CH2CH2CH2CN, CH2CONH2, CH2CH2CONH2, CH2CH2CH2CONH2, CH2CO2CH3, CH2CH2CO2CH3, CH2CH2CO2Et, CH2CH2CO2iPr, CH2CH2CO2But, CH2CH2CH2CO2CH3, and CH2CH2S(O)2CH3; R1at each occurrence is independently selected from H, OH, =O, NH2, NHCOCH3, CO2H, CO2CH3, and CO2Et; :or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein:Ring A is phenyl, piperidinyl, or C3-6cycloalkyl; R6at each occurrence is independently H, OR16, or NHR17; and R7at each occurrence is independently H, C1-6alkyl, or OR16.

15. The compound of claim 14, having the structure of Formula (IV-1):or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: W is H or CH3; R1at each occurrence is independently selected from H, halogen, OH, NH2, CN, NO2, NHCOCH3, CO2H, CO2CH3, and CO2Et, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, and O-C1-4haloalkyl; R2is OH; R3is CF3, OCF3, OCHF2, or OCH3; R4is H or CH2OCH3; R6is H, OH, NH2, NHC(O)CH3; R7is H, OH, or C1-4alkyl; and R8is H, -CN, -CO2H, -CONH2, or -CH2NH2.

16. The compound of claim 14, having the structure of Formula (IV-2):or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, or 3;R1ais selected from H, C1-4alkyl, C1-4alkyl-CN, C1-4alkyl-OR10, C1-4alkyl-NRaRb, C(O)OR11, -CO2H, -C(O)OR12, C(O)NH-C1-4alkylene-OR9, C1-4alkyl-C(O)NRcRd, C1-4alkyl- OC(O)NRcRd, and C1-4alkyl-SO2R14; R1at each occurrence is independently selected from H, oxo (=O), C1-4alkyl, OR9, C1-4alkyl-OR10, NRaRb, C1-4alkyl-NRaRb, and C(O)OR11; R7is H or C1-4alkyl; and R8is selected from H, -CN, -CO2H, -C(O)OC1-4alkyl, -CONH2, -CH2NH2, and - CH2OH.

17. The compound of claim 14, having the structure of Formula (IV-3):or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: j is 1, 2, or 3; m is 0, 1, 2, or 3; R1at each occurrence is independently selected from H, halogen, OH, NH2, CN, NO2, NHCOCH3, CO2H, CO2CH3, and CO2Et, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, and O-C1-4haloalkyl; R2is OH; R3is CF3, OCF3, OCHF2, or OCH3; R4is H or CH2OCH3; R6is H, OH, NH2, NHC(O)CH3; R7is H, OH, or C1-4alkyl; and R8is H, -CN, -CO2H, -CONH2, or -CH2NH2.

18. The compound of any one of claims 1 to 4, having the structure of Formula (V):or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or piperidinyl.

19. The compound of claim 18, having the structure of Formula (V-1):or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, or 3; R1ais selected from H, C1-4alkyl, C1-4alkyl-CN, C1-4alkyl-OR10, C1-4alkyl-NRaRb, C(O)OR11, -CO2H, -C(O)OR12, C1-6alkyl-C(O)OR12, C(O)NH-C1-4alkylene-OR9, C1-4alkyl- C(O)NRcRd, C1-6alkyl-OC(O)NRcRd, and C1-4alkyl-SO2R14; R1at each occurrence is independently selected from H, oxo (=O), C1-4alkyl, OR9, C1-4alkyl-OR10, NRaRb, C1-4alkyl-NRaRb, and C(O)OR11; and R8is selected from H, -CN, -CO2H, -C(O)OC1-4alkyl, -CONH2, -CH2NH2, and - CH2OH.

20. The compound of any one of claims 1 to 4, having the structure of Formula (VI):, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or piperidinyl; andR7is H or C1-4alkyl.

21. The compound of claim 20, having the structure of Formula (VI-1):or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, or 3; R1at each occurrence is independently selected from H, halogen, OH, NH2, CN, NO2, NHCOCH3, CO2H, CO2CH3, and CO2Et, C1-4alkyl, C1-4haloalkyl, O-C1-4alkyl, and O-C1-4haloalkyl; R2is OH; R3is CF3, OCF3, OCHF2, or OCH3; and R8is H, -CN, -CO2H, -CONH2, or -CH2NH2.

22. The compound of any one of claims 1 to 4, having the structure of Formula (VII):, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl or piperidinyl.

23. The compound of claim 22, having the structure of Formula (VII-1):or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, wherein: m is 1, 2, or 3; R1ais selected from H, C1-4alkyl, C1-4alkyl-CN, C1-4alkyl-OR10, C1-4alkyl-NRaRb, C(O)OR11, -CO2H, C1-6alkyl-C(O)OR12, C(O)NH-C1-4alkylene-OR9, C1-6alkyl-C(O)NRcRd, C1-4alkyl-OC(O)NRcRd, and C1-4alkyl-SO2R14; R1at each occurrence is independently selected from H, oxo (=O), C1-4alkyl, OR9, C1-4alkyl-OR10, NRaRb, C1-4alkyl-NRaRb, and C(O)OR11; and R8is selected from H, -CN, -CO2H, -C(O)OC1-4alkyl, -CONH2, -CH2NH2, and - CH2OH.

24. A compound of claim 1, selected from List 1 (Examples 1 to 382), excluding compounds provided in the provisos, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof.

25. A compound of claim 1, selected from List 2, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof.

26. A compound of claim 1, selected from List 3, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof.

27. A compound of claim 1, selected from List 4, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. A method for treating or preventing a disease or condition which is responsive to inhibition of NLRP3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 27, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 0.

30. A method for treating or preventing a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 27, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition of claim 0, wherein the disease or condition is a neurodegenerative disorder, a metabolic ailment, a cardiovascular ailment, an inflammatory syndrome, an autoinflammatory disease, a cancer, or a hereditary disease.

31. The method of claim 30, wherein the neurodegenerative disorder is Parkinson’s disease or Alzheimer’s disease; the metabolic ailment is type 2 diabetes, the cardiovascular ailment is atherosclerosis; the inflammatory disease is gout flares, osteoarthritis, ulcerative colitis, or Crohn’s disease; the autoinflammatory disease is multiple sclerosis or rheumatoid arthritis; the cancer is lung cancer; and the hereditary disease is Cryopyrin-associated periodic syndrome.

32. Use of a compound according to any one of claims 1 to 27, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a disease or condition selected from neurodegenerative disorders, metabolic ailments, cardiovascular disease, inflammatory syndromes, autoinflammatory diseases, cancers, and hereditary diseases.

33. A method or process for preparation of a compound according to any one of claims 1 to 27, or a stereoisomer, a tautomer, an isotopic derivative, or a pharmaceutically acceptable salt thereof, substantially as described and shown.

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