Guab inhibitor compounds and uses thereof

Abstract

The present disclosure provides heterocyclic antibacterial compounds, e.g., 1,4-dihydro-2H-pyrano[3,4-c]quinolone compounds, that are inhibitors of GuaB in mycobacteria. The compounds advantageously inhibit mycobacterial growth and survival, and as such, the compounds are useful to treat infectious disease caused by mycobacteria (e.g., tuberculosis, leprosy, nontuberculous mycobacterial infections, or a combination thereof). Pharmaceutical compositions comprising said compounds are also provided.

Description

CLAIM OF PRIORITY This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 548,788, filed on Feb 1, 2024, the entire contents of which are hereby incorporated by reference. TECHNICAL FIELD This invention relates to heterocyclic antibacterial compounds, and in some embodiments to l,4-dihydro-2H-pyrano [3,4-c] quinolone compounds that are inhibitors of GuaB in mycobacteria, useful, e g , to inhibit mycobacterial growth and survival, and subsequently to treat infectious disease caused by mycobacteria. BACKGROUND Bacterial infections remain one of the leading causes of death worldwide. For example, tuberculosis (“TB”) is an infectious disease typically caused by Mycobacterium tuberculosis (“MTB”) bacteria; TB is the largest single infectious cause of death among young people and adults in the world, accounting for nearly two million deaths per year. SUMMARY The present disclosure is based, at least in part, on a realization that 1,4-dihydro-2H-pyrano[3,4-c]quinolone compounds potently inhibit the enzyme inosines’-monophosphate dehydrogenase (IMPDH, known in bacteria as GuaB). The enzyme catalyzes the rate-limiting step in de novo purine biosynthesis and is conserved from humans to bacteria. De novo synthesis of guanine nucleotides is required for the growth and viability of cells, due to the structural role of nucleotides in DNA and RNA. Advantageously, the compounds within the present claims selectively inhibit mycobacterial GuaB (as opposed to other bacteria and human IMPDH). Hence, the compounds are advantageously useful in treating mycobacterial infections such as TB as well as the nontuberculous mycobacteria (“NTM”) infections. In one general aspect, the present discloisure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: In another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In yet another general aspect, the present disclosure provides a method of treating a bacterial infection caused by a species of the genus mycobacterium, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound Formula (I), or a pharmaceutically acceptable salt thereof. On some embodiments, provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating a bacterial infection caused by a species of the genus mycobacterium. In some embodiments, provided is a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a method of treating a bacterial infection caused by a species of the genus mycobacterium. In some embodiments, provided is a use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a manufacture of a medicament for treating a bacterial infection caused by a species of the genus mycobacterium. In some embodiments, the bacterial infection is caused by Mycobacterium tuberculosis, Mycobacterium leprae, or one or more nontuberculous mycobacterium species, or a combination thereof, the bacterial infection is tuberculosis or leprosy. In some embodiments, the bacterial infection is caused by nontuberculous mycobacterium species selected from Mycobacterium fortuitum complex (MAC) (Mycobacterium fortuitum, Mycobacterium peregrinum, Mycobacterium porcinum), or Mycobacterium abscessus complex (Mycobacterium abscessus subspecies abscessus, Mycobacterium abscessus subspecies bolletii, Mycobacterium abscessus subspecies massiliense'), or a combination thereof. In some embodiments, the subject has a co-morbid condition selected from cystic fibrosis, chronic obstructive pulmonary disease, chronic pulmonary disorder, bronchiectasis, non-CF bronchiectasis, emphysema, and acquired immune deficiency syndrome. In some embodiments, the method comprises coadministering the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional antibacterial therapeutic agents (e.g., bedaquiline, pretomanid, sutezolid, moxifloxacin, and / or pyrazinamide, or a pharmaceutically acceptable salt thereof). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF DRAWINGS FIG. 1A contains a schematic representation of the de novo purine biosynthesis pathway in M.tb, and GuaBi impact on de novo guanine biosynthesis. FIG. IB contains chemical structure, whole cell activity, chemical, and pharmacokinetic properties of GuaB inhibitor (compound of Example 17). FIG. IC contains an image showing crystal structure of Ex. 17 bound toM tuberculosis GuaB2 protein (with IMP) bound, determined at 1.35 A resolution. FIG. 2A contains line plot showing viability ofMt / ?H37Rv treated with 0.6 pM (lOxMIC) Ex. 17 cmpd, and 1 pM (lOxMIC) isoniazid enumerated over time by plating for colony forming units (CFUs). Untreated was the DMSO vehicle control. FIG. 2B contains a line plot showing viability of M / / ?H37Ra treated with 0, 0.09, 0.19, and 0.39 pM Ex. 17 cmpd overtime by plating for CFUs. FIG. 2C contains a line plot showing viability of M / / >H37Ra treated with 0, 0.78, 1.56, and 3.12 pM isoniazid overtime by plating for CFUs. FIG. 2D contains a line plot showing viability of Mrf?H37Rv treated with DMSO vehicle control, 1 pM isoniazid, and 0, 0.006, 0.06, 0.6, and 6 pM Ex. 17 cmpd over time by plating for CFUs. FIG. 3 A contains a graph showing in vivo activity of Ex. 17 cmpd as a single agent against virulentM.tb H37Rv in acute mouse infection model. C57B1 / 6 mice were infected intratracheally with Mtb using a high dose (1E5 CFU / mouse), and treatment with escalating doses (0, 5, 10, 25, 50 and 100 mpk) of Ex. 17 cmpd was initiated 24 hours later by oral gavage twice per day (BID) for 8 consecutive days followed by enumeration of lung bacterial burden by plating for colony forming units (CFUs). Isoniazid was used as a positive control. FIG. 3B contains a graph showing in vivo activity of Ex. 17 cmpd as a single agent against virulentM.tb H37Rv in a chronic mouse infection model. C57B1 / 6 mice were infected intranasally with Mtb using a low dose (100 CFU / mouse) aerosol and allowed to establish a chronic infection for 21 days, after which Ex. 17 cmpd was delivered orally at 200 mg / kg once / day (QD) or 100 mg / kg twice / day (BID) for one month (day 49) or two months (day 77), followed by enumeration of lung bacterial burden by plating for colony forming units (CFUs). Isoniazid (10 mg / kg QD) was used as a positive control. FIG. 4A contains bar graph showing in vivo activity of GuaB inhibitor Ex. 17 cmpd against Mycobacterium tuberculosis Erdman as a single agent, and in combinations with other antibiotics in the progressive lethal Kramnik (C3Heb / FeJ) mouse model of infection after one and two months of treatment. Kramnik mice were infected with Mtb Erdman using a low dose aerosol infection and allowed to progress for 56 days, after which treatment was begun once / day oral treatment with Ex. 17 alone, or in various combinations of antibiotics for one or two months, followed by enumeration of the bacterial burden in mouse lung by plating for CFUs. Treatment combinations were: Bedaquiline (B) + pretomanid (P), B+P+moxifloxacin (M), and B+P+M+Ex. 17. Addition of GuaBi on top of B+P+M led to no detectable bacteria in the lungs of 1 / 2 of mice after 2 months dosing. Significant reduction in bacteria load using this combination indicated a more rapid time to cure in the combination that included GuaBi. FIG. 4B contains bar graph showing in vivo activity of GuaB inhibitor Ex. 17 cmpd against Mycobaterium tuberculosis Erdman as a single agent, and in combinations with other antibiotics in the progressive lethal Kramnik (C3Heb / FeJ) mouse model of infection after one and two months of treatment. Kramnik mice were infected with Mtb Erdman using a low dose aerosol infection and allowed to progress for 56 days, after which treatment was begun once / day oral treatment with Ex. 17 alone, or in various combinations of antibiotics for one or two months, followed by enumeration of the bacterial burden in mouse lung by plating for CFUs. Treatment combinations were: B+P, B+P + sutezolid (S), B+P+S+Ex.17. Addition of GuaBi on top of B+P+S led to no detectable bacteria in 2 / 5 mice after 2 months dosing. FIG. 4C contains bar graph showing in vivo activity of GuaB inhibitor Ex. 17 cmpd against Mycobaterium tuberculosis Erdman as a single agent, and in combinations with other antibiotics in the progressive lethal Kramnik (C3Heb / FeJ) mouse model of infection after one and two months of treatment. Kramnik mice were infected with Mtb Erdman using a low dose aerosol infection and allowed to progress for 56 days, after which treatment was begun once / day oral treatment with Ex. 17 alone, or in various combinations of antibiotics for one or two months, followed by enumeration of the bacterial burden in mouse lung by plating for CFUs. The effect of treatment combinations on bacterial burden measured in mouse lung after one month oral dosing: Ex. 17, B+P, B+P+Ex. 17, B+P+S, B+P+S+Ex. 17, B+P+M, B+P+M+Ex. 17, and B+P+M+pyrazinamide (Z). Significant reduction in bacteria load using Ex. 17 alone was observed after one month dosing. FIG. 4D contains bar graph showing in vivo activity of GuaB inhibitor Ex. 17 cmpd against Mycobaterium tuberculosis Erdman as a single agent, and in combinations with other antibiotics in the progressive lethal Kramnik (C3Heb / FeJ) mouse model of infection after one and two months of treatment. Kramnik mice were infected with Mtb Erdman using a low dose aerosol infection and allowed to progress for 56 days, after which treatment was begun once / day oral treatment with Ex. 17 cmpd alone, or in various combinations of antibiotics for one or two months, followed by enumeration of the bacterial burden in mouse lung by plating for CFUs. Treatments as described in FIG. 4C, but after a two month dosing regimen using the same combinations. BPMZ was used as the positive control in this model. FIG. 4E contains a graph showing the effect of guanine supplementation on combination treatment regiments including Ex. 17 cmpd. Lung homogenates from Kramnik mice infected with Mtb (Erdman strain) and treated 8 weeks with different antibiotic combinations were enumerated by CFU plating on 7H11 agar plates with activated charcoal, with or without 0. ImM guanine supplementation. FIG. 5 contains a table showing Mouse PK data summary for acute C57B1 / 6 M / / ?H37Rv lung infection model for Ex. 17 cmpd. Unbound values were calculated based on the experimentally determined plasma protein binding of Ex. 17 cmpd to predict coverage of the Ex. 17 cmpd MIC in vivo. FIG. 6 contains a line plot showing minimal bactericidal concentration (MBC) againstMtbH37Ra in vitro. FIG. 7 contains a graph showing in vivo activity of Ex. 74 cmpd as a single agent against virulentM.tb H37Rv in acute mouse infection model. DETAILED DESCRIPTION Mycobacterium tuberculosis is the causative agent of the disease tuberculosis, which is a highly challenging infection to treat in part because of its ability to enter a “dormant” or metabolically quiescent stage in which the bacteria are less susceptible to antibacterial drugs, but can re-activate in the host and cause further damage and spread to others. This ability to evade treatment through dormancy is one factor leading to the standard treatment of drug-susceptible tuberculosis involving a four-drug cocktail administered from 4 to 6 months, with drug-resistant tuberculosis requiring 9 or even 20 months of treatment (Tuberculosis, World Health Organization, °Ctober). Non-tuberculous mycobacterial infection is a pulmonary infection whose rates are increasing globally. This broad category of infectious diseases includes over a hundred bacterial species identified to date, belonging to the genus Mycobacterium but which are not the more commonly known infectious species Mycobacterium tuberculosis or Mycobacterium leprae, which cause tuberculosis and leprosy respectively. NTM species naturally exist in a diversity of natural and man-made environments that overlap with human activity, and are considered an opportunistic pathogen that °Ccurs in certain groups of individuals. These may include those with genetic or acquired lung diseases (e.g., cystic fibrosis, chronic obstructive pulmonary disease) and those with genetic or acquired immune system suppression (e.g., Mendelian susceptibility to mycobacterial disease, AIDS, hematological cancers, or organ donation recipients). NTM infections can be categorized as the pulmonary system infections (“PNTM”) and disseminated infections (“DNTM”). Currently, treatment of PNTM requires administration of multiple drugs over an extended, months-long period, with varying levels of success and frequent re-infection. The variation of mycobacterial species within the NTM group further complicates treatment and outcomes (See Ratnatunga et al, 2020, The Rise of Non-Tuberculosis Mycobacterial Lung Disease, Front. Immunology., 11, 303). Accordingly, in some embodiments, the present disclosure provides a method of treating a bacterial (e.g., mycobacterial) infection in a subject (e.g., in need thereof), the method comprising administering to the subject a therapeutically effective amount of a compound within the present claims (e.g., a compound of Formula I as described herein), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is in need of treatment. For example, the subject may be diagnosed with the bacterial infection, prior to administering the compound of this disclosure, by a treating physician or a diagnostician. The diagnosis can be made on the basis of a clinical observation and / or any suitable diagnostic test or procedure (e.g., skin test, blood test, chest X-ray, sputum microscopy, or culture in liquid or solid media). In some embodiments, the bacterial infection is an infection caused by one or more species of the genus mycobacterium (e.g., the infection is mycobacterial infection). In some embodiments, the infection is caused by Mycobacterium tuberculosis. In some embodiments, the infection is tuberculosis (e.g., active, latent, and / or contagious TB). In some embodiments, tuberculosis is pulmonary. In some embodiments, the method of this disclosure include inhibiting, reducing, halting, and / or reversing one or more symptoms of pulmonary tuberculosis. Suitable examples of symptoms typically associated with tuberculosis may include fever, chills, fatigue, persistent cough, coughing up blood or phlegm, shortness of breath, and / or chest pain. In some embodiments, tuberculosis is extrapulmonary (e.g., involving infected organs and tissues outside of the lungs). Suitable examples of extrapulmonary TB include TB lymphadenitis, skeletal TB, miliary TB, genitourinary TB, liver TB, gastrointestinal TB, TB meningitis, TB peritonitis, TB pericarditis, and cutaneous TB. In some embodiments, the tuberculosis infection (pulmonary or extrapulmonary) is drug resistant (e.g., bacterial strain causing infection does not respond sufficiently, or respond at all, to first-line antibiotic treatments). For example, the infection may be multi-drug-resistant tuberculosis, pre-extensively drug resistant tuberculosis, or extensively drug-resistant tuberculosis. In some embodiments, the subject has pulmonary tuberculosis, or extra-pulmonary tuberculosis, or both. In some embodiments, the infection is caused by a non-tuberculous mycobacteria. Accordingly, in some embodiments, the present disclosure provides a method of treating an infection caused by a nontuberculous mycobacteria (NTM infection) in a subject (e.g., in need thereof), as described herein. In some embodiments, the NTM infection is caused by Mycobacterium bovis, Mycobacterium africanum, Mycoacterium microti, Mycobacterium canetti, Mycobacterium leprae, or a combination thereof. In some embodiments, the NTM infection is caused by Mycobacterium fortuitum complex (Mycobacterium fortuitum, Mycobacterium peregrinum, Mycobacterium porcinum), Mycobacterium chelonae, Mycobacterium abscessus complex (Mycobacterium abscessus subspecies abscessus, Mycobacterium abscessus subspecies bolletii, Mycobacterium abscessus subspecies massiliense), Mycobacterium smegmatis, Mycobacterium mycogenicum, Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium gordonae, Mycobacterium scrofulaceum, Mycobacterium avium complex (Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium chimaera), Mycobacterium terrae complex, Mycobacterium ulcerans, Mycobacterium xenopi, Mycobacterium ximiae, Mycobacterium malmoense, Mycobacterium szulgai, Mycobacterium asiaticum, or Mycobacterium haemophilum, or a combination thereof. In some embodiments, the infection is caused by Mycobacterium avium complex. In some embodiments, the infection is caused by Mycobacterium abscessus complex. In some embodiments, the infection is caused by Mycobacterium avium complex or Mycobacterium abscessus complex, or a combination thereof. In some embodiments, the subject has tuberculosis, or NTM infection, or both. In some embodiments, the NTM infection is pulmonary. In some embodiments, the NTM infection is extrapulmonary. In some embodiments, the subject has pulmonary NTM infection, or extra-pulmonary NTM infection, or both. In some embodiments, the methods of this disclosure include treating Johne’s disease, Buruli or Bamsdale ulcer, Crohn’s disease, pulmonary disease or pulmonary infection, a respiratory tract infection (RTI), an upper respiratory tract infection, a lower respiratory tract infection, a nasopharyngeal infection, pneumonia, nosocomial pneumonia, community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator associated pneumonia (VAP), Mycobacterium avium complex (MAC) lung disease, disseminated Mycobacterium avium complex (DMAC), disseminated Mycobacterium avium intracellulare complex (DMAIC), MAC mastitis, MAC pyomyositis, granuloma disease, genitourinary infection, bacteremia, a bloodstream infection (BSI), central line associated bloodstream infection, intraabdominal infection (IAI), complicated intra-abdominal infection (cIAI), skin and soft tissue infection (SSTI), complicated skin and soft tissue infection (cSSTI), surgical site infection (SSI), complicated surgical site infection (cSSI), skin and skin structure infection (SSSI), complicated skin and skin structure infection (cSSSI), osteomyelitis, prosthetic joint infection, or a post-operative infection, by administering to a subject (e.g., in need thereof) a therapeutically effective amount of the compound as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is diagnosed with a comorbid condition. Suitable examples of comorbid conditions include cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic pulmonary disorder (CPD), bronchiectasis, non-CF bronchiectasis (NCFB), emphysema, acquired immune deficiency syndrome, or any combination of the foregoing. In some embodiments, the subject has tuberculosis or an NTM infection, and one or more of the comorbid conditions. In some embodiments, the method of this disclosure includes administering to the subject a compound as described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents. For example, the compound of this disclosure may be co-administered to the subject with one or more tuberculosis or nontuberculous mycobacterium therapeutic agents. The compound may be administered to the subject simultaneously with the additional therapeutic agent (in the same pharmaceutical composition or dosage form or in different compositions or dosage forms) or consecutively (the additional therapeutic agent may be administered in a separate pharmaceutical composition or dosage form before or after administration of the compound). In some embodiments, the one or more additional therapeutic agents is an antibiotic. In some embodiments, the one or more therapeutic agents is selected from rifampicin, rifapentine, ethambutol, pyrazinamide, isoniazid, levofloxacin, moxifloxacin, gatifloxacin, ofloxacin, kanamycin, amikacin, aztreonam, azithromycin, capreomycin, streptomycin, ethionamide, prothionamide, cycloserine, terididone, para-aminosalicylic acid, clofazimine, clarithromycin, amoxicillin-clavulanate, pretomanid, prothionamide, isoxyl, thiacetazone, a diarylquinoline such as bedaquiline or TBAJ-587, nitroimidazo-oxazine PA-824 (pretomanid), delaminid (OPC-67683), an oxazolidinone such as linezolid, tedizolid, radezolid, sutezolid, posizolid, or TBI-223, EMB analog SQ109, OPC-16732, GSK 3036656, GSK3036656A (also known as GSK070), GSK2556286, GSK3211830, a benzothiazinone such as BTZ043 or PBTZ169, an azaindole such as TBA-7371, a dinitrobenzamide, and a beta-lactam such as sanfetrinem, meropenem, faropenem, ertapenem, tebipenem, gepotidacin, thiacetazone, or meropenem-clavulanate. In some embodiments, the compound of this disclosure is administered to the subject in combination with bedaquiline, pretomanid, sutezolid, moxifloxacin, and / or pyrazinamide, or a pharmaceutically acceptable salt thereof. Compounds In some embodiments, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 3; q is 0 or 1; r is an integer from 0 to 3; XisOorNRN; RN is selected from H, C1-3 alkyl, and C1-3 haloalkyl; ring A is selected from C3-10 cycloalkyl and 3-10 membered heterocycloalkyl; m is an integer from 0 to 8; each R2, R3, and R4 is independently selected from-CN, -OH, D, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; each R1 is independently selected from C1-6 alkyl, Cm haloalkyl, Cy1, C(=O)Cy1, oxo, halo, -CN, -ORla, -NRlaR2a, -C(O)NRlaR2a, -C(O)ORla, -C(O)Rla, -NRlaC(O)R2a, -S(O)2Rla, and -NH-S(O)2Rla, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, -ORlb, -NRlbR2b, -C(O)NRlbR2b, and -NRlbC(O)R2b; each Cy1 is independently selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCyl; each RCyl is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, -CN, -ORlb, -NRlbR2b, -C(O)NRlbR2b, and -NRlbC(O)R2b, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, -ORlb, -NRlbR2b, -C(O)NRlbR2b, -NRlbC(O)R2b, each Rla, R2a, Rlb, and R2b is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and Cy2, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, -CN, halo, -ORlc, and -NRlcR2c; each Cy2 is independently selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, -CN, -ORld, and -NRldR2d; and each Rlc, R2c, Rld and R2d is independently selected from H, C1-6 alkyl, and Ci-6 haloalkyl. In some embodiments, X is O. In some embodiments, X is NRN. In some embodiments, RN is H. In some embodiments, RN is C1-3 alkyl. In some embodiments, X is NH. In some embodiments, p is 1. In some embodiments, p is 0. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, the sum of n, p, and q is 0, 1, or 2. In some embodiments, R2 is CN. In some embodiments, R2 is OH. In some embodiments, R2 is D. In some embodiments, R2 is halo. In some embodiments, R2 is C1-6alkyl. In some embodiments, R2 is C1-6haloalkyl. In some embodiments, R2 is Ci-6 alkoxy. In some embodiments, R2 is C1-6 haloalkoxy. In some embodiments, each of R2, R3, and R4 is independently selected from D, C1-6 alkyl, and halo. In some embodiments, the compound has formula: or a pharmaceutically acceptable salt thereof. In some embodiments, ring A is a monocyclic C3-10 cycloalkyl or 3-10 membered heterocycloalkyl. In some embodiments, ring A is a monocyclic C3-10 cycloalkyl. In some embodiments, ring A is a monocyclic 3-10 membered heterocycloalkyl. In some embodiments, ring A is selected from: In some embodiments, ring A is a polycyclic C3-10 cycloalkyl. In some embodiments, ring A is a bridged C3-10 cycloalkyl or a spirocyclic C3-10 cycloalkyl. In some embodiments, ring A is a bridged C3-10 cycloalkyl. . In some embodiments, ring A is a spirocyclic C3-10 cycloalkyl. In some embodiments, ring A is a polycyclic 3-10 membered heterocycloalkyl. In some embodiments, ring A is abridged 3-10 membered heterocycloalkyl or a spirocyclic 3-10 membered heterocycloalkyl. In some embodiments, ring A is a bridged 3-10 membered heterocycloalkyl. In some embodiments, ring A is a spirocyclic 3-10 membered heterocycloalkyl. In some embodiments, ring A is selected from: In some embodiments: n=:N is n=N In some embodiments, m is an integer from 0 to 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, each R1 is independently selected from Ci-6 alkyl, Cw haloalkyl, Cy1, C(=O)Cy1, oxo, halo, -CN, -ORla, -C(O)NRlaR2a, -C(O)ORla, -C(O)Rla, -S(O)2Rla, and -NH-S(O)2Rla, wherein said Ci-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, -ORlb, -NRlbR2b, and -NRlbC(O)R2b. In some embodiments, R1 is Cy1. In some embodiments, R1 is C(=O)Cy1. In some embodiments, Cy1 is C3-10 cycloalkyl. In some embodiments, Cy1 is 3-10 membered heterocycloalkyl. In some embodiments, each RCyl is independently selected from C1-6 alkyl, Ci-6 haloalkyl, halo, -CN, -ORlb, and -NRlbR2b, wherein said C1-6 alkyl is optionally substituted with -ORlb. In some embodiments, each Rla, R2a, Rlb, and R2b is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and Cy2, wherein said C1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy2, -ORlc, and -NRlcR2c. In some embodiments, each Cy2 is independently selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with a substituent selected from C1-6alkyl and C1-6 haloalkyl. In some embodiments: X is selected from O and NH; the sum of n, p, and q is 0, 1, or 2; each R2, R3, and R4 is independently selected from D, Ci-6 alkyl, and halo; ring A is selected from a monocyclic C3-10 cycloalkyl, a monocyclic 3-10 membered heterocycloalkyl, a bridged C3-10 cycloalkyl, a spirocyclic C3-10 cycloalkyl, a bridged 3-10 membered heterocycloalkyl, and a spirocyclic 3-10 membered heterocycloalkyl. m is an integer from 0 to 3; each R1 is independently selected from C1-6 alkyl, Cm haloalkyl, Cy1, C(=O)Cy1, oxo, halo, -CN, -ORla, -C(O)NRlaR2a, -C(O)ORla, -C(O)Rla, -S(O)2Rla, and -NH-S(O)2Rla, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, -ORlb, -NRlbR2b, and -NRlbC(O)R2b; each RCyl is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, -CN, -ORlb, and -NRlbR2b, wherein said C1-6 alkyl is optionally substituted with -ORlb; each Rla, R2a, Rlb, and R2b is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and Cy2, wherein said C1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy2, -ORlc, and -NRlcR2c; each Cy2 is independently selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with a substituent selected from C1-6 alkyl and C1-6 haloalkyl; and or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) is selected from any one of the following compounds: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from any one of the following compounds: or a pharmaceutically acceptable salt thereof. It should be understood that alternative systems of naming the same chemical structure exist. In any disagreement between the provided name and chemical structure, the structure controls. Compositions, formulations, and routes of administration Provided herein are pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described in, for example, “Pharmaceuticals - The Science of Dosage Form Designs,” M. E. Aulton, Churchill Livingstone, 1988, which is hereby incorporated by reference in its entirety. In some embodiments, the pharmaceutical composition is for oral administration. Further provided is a process for the preparation of a pharmaceutical composition, comprising combining one or more disclosed compounds, or pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable excipients. Pharmaceutical compositions may be prepared, for example, according to conventional dissolution, mixing, granulating, or coating methods, or combinations thereof. Such pharmaceutically acceptable excipients may include, for example, sugars; starches; cellulose and its derivatives; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils; glycols; polyethylene glycols (PEG); esters; agar; buffering agents; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; non-toxic compatible lubricants; coloring agents; releasing agents; coating agents; sweetening; and flavoring and perfuming agents. Preservatives and antioxidants can also be present in the pharmaceutical composition, according to the judgment of the formulator. Depending on the intended mode of administration, the disclosed pharmaceutical compositions can be in solid, semi-solid, or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. These modes may include systemic or local administration such as oral or parenteral administration modes. In some embodiments, the pharmaceutical composition provided herein comprises one or more disclosed compounds, and / or pharmaceutically acceptable salts thereof, and is for oral administration. In other embodiments, the pharmaceutical composition is for intravenous administration. Solid dosage forms for oral administration may include capsules (e.g., soft and hard-filled gelatin capsules), tablets, pills, powders, and granules. Solid dosage forms may be prepared, in some embodiments, with one or more coatings and / or shells such as release controlling coatings, for example enteric coatings. Liquid dosage forms for oral administration may include, for example, a pharmaceutically acceptable excipient such as water or other solvents, solubilizing agents, emulsifiers, oils, polyethylene glycols and fatty acid esters, adjuvants, sweetening agents, flavoring agents, or perfuming agents, or any combinations thereof. Injectible pharmaceutical compositions include, for example, sterile injectable aqueous compositions (e.g., solutions, suspensions, or emulsions), or oleaginous suspensions. The subject matter further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary excipient or carrier therefore. Veterinary excipients or carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or by any other desired route. In the pharmaceutical compositions of the present application, a compound of the present disclosure is present in an effective amount (e.g., a therapeutically effective amount). Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. Definitions As used herein, the term "about" means "approximately" (e.g., plus or minus approximately 10% of the indicated value). At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Cg alkyl. At various places in the present specification various cycloalkyl and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group. As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency. Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6, and the like. As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, w-propyl, isopropyl, w-butyl, tert butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1 -butyl, w-pentyl, 3-pentyl, w-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. As used herein, the term “Cn-m haloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, the term “Cn-m alkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., w-propoxy and isopropoxy), butoxy (e.g., w-butoxy and tertbutoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “Cn-m haloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include mono-or polycyclic groups (e.g., having 2, 3 or 4 fused or bridged rings or groups and / or spirocycles). Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10). In some embodiments, the cycloalkyl is a C3-10monocyclic or polyicyclic (e.g., bycyclic) cyclocalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cyclocalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic or polycyclic (e.g., bicyclic) 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groups. The polycyclic heterocycloalkyl groups include fursed and bridged rings or groups and / or spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached to the rest of the molecule through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. In some embodiments, the heterocycloalkyl ring is saturated. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i. e., having a bond in common with) to the heterocycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Also included in the definition of heterocycloalkyl are moieties that have one or more cycloalkyl rings fused, briged, or that form a spirocyclic group (e.g., having an atom in common with) with the heterocycloalkyl ring. In some embodiments, the heterocycloalkyl is a monocyclic 46 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. As used herein, the term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=O), or attached to a heteroatom forming a sulfoxide or sulfone group. The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, and tautomers of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. If a stereoisomeric form is not specified, the depicted structure and / or associated chemical name are intended to include (in the alternative) all possible stereoisomers of the compound. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. In some embodiments, any asymmetrically substituted carbon atom has the (^ / -configuration. In some embodiments, any asymmetrically substituted carbon atom has the (SZ-configuration. Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide -imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. As used herein, the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology). As used herein the term “pharmaceutically acceptable salt” refers to a salt formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds of Formula (I) include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, as well as organic acids such as tartaric acid, succinic acid, citric acid, as well as related inorganic and organic acids. In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds of Formula (I) include hydroxides of alkali metals, including sodium and potassium, as well as ammonia and mono-, di-, or tri-alkylamines, and similar bases. In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as “D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium). EXAMPLES Abbreviations used throughout the examples: DAST: diethylaminosulfur trifluoride; DCE: dichloroethane; DCM: dichloromethane; DEA: diethylamine; DIPEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: 5 dimethylformamide; DMSO: dimethylsulfoxide; EtOAc: ethyl acetate; EtOH: ethanol; HOAc: acetic acid; HPLC: high performance liquid chromatography; IPA: isopropanol; KOAc: Potassium acetate; LCMS: liquid chromatography-mass spectrometry; MeOH: methanol; MsCl: methanesulfonyl chloride; MTBE: methyl tert-butyl ether; NBS: N-bromosuccinimide; NMR: nuclear magnetic resonance; 10 PTSA: p-toluenesulfonic acid; TBAF: tetra-n-butylammonium fluoride; TBSC1: tertbutyldimethylsilyl chloride; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin layer chromatography; prep-TLC: preparative thin layer chromatography; SFC: supercritical fluid chromatography. Chiral SFC analytical separation methods referenced in the following synthetic examples are summarized in 15 the table below: Method Column Mobile Phase Flow Rate Col. Temp A Chiralpak IG-3 100x4.6 mm I.D., 3 pm A: CO2 B: 40% isopropanol (0.05% DEA) in CO2 2.8 mL / min 35 °C B Chiralpak IC-3 100x4.6 mml.D. 3 pm A: CO2 B: 50% ethanol (0.05% DEA) in CO2 2.8 mL / min 35 °C C Chiralpak AD-3, 150x4.6 mm I.D., 3 pm A: CO2 B: 40% MeOH (0.05% DEA) 2.5 mL / min 35 °C D Chiralpak AD, 150x21.2 mm I.D., 3 pm A: CO2 B: 30% MeOH (0.05% DEA) 2.5 mL / min 40 °C E Cellulose 2 100*4.6 mm I.D., 3 pm A: CO2 B: 50% ethanol (0.05% DEA) 2.8 mL / min 35 °C F Chiralpak ID, 150x21.2 mm, 5 pm A: CO2 B: 35 % MeOH (0.1% NH4OH) 60 mL / min 40 °C G Chiralpak IH, 250x30 mm, 5 pm A: CO2 B: 20-30 % MeOH (0.1%NH4OH) 70 mL / min 40 °C H Chiralpak IC, 150x21.1mm, 5 pm A: CO2 B: 35 % MeOH (0.1% NH4OH) 70 mL / min 40 °C I Chiralpak OX, 150x21.1mm, 5 pm A: CO2 B: 30% MeOH (0.1% NH4OH) 70 mL / min 40 °C J Chiralcel IC 250x30 mm, 10 pm 60 ml / min 40 °C K Chiralpak IG 250x30 mm, 10 pm A: CO2 B: 35 % EtOH (0.1% NH4OH) 60 ml / min 40 °C Method Column Mobile Phase Flow Rate Col. Temp L Chiralpak IG 250x30 mm, 10 pm A: CO2 B: 35 %EtOH(0.1% NH4OH) 60 ml / min 40 °C M Chiralpak AD-3, 50x4.6 mm I.D., 3 pm A: CO2 B: 40% EtOH (0.05% DEA) 2.5 mL / min 40 °C N Chiralpak OJ, 150x4.6 mm, 3 pm A: CO2 B: 5-40% MeOH (0.1% NH4OH) 2.5 mL / min 40 °C O Phenomenex-Cellulose-2, 250 mmx50 mm,10 pm A: CO2 B: 25% EtOH (0.1% NH4OH) 200 mL / min 40 °C P Chiralpak IG-3 100x4.6 mm I.D., 3 pm A: CO2 B: 5-40% EtOH (0.05% DEA) in CO2 2.5 mL / min 40 °C Q Chiralpak AD-3, 50x4.6 mm I.D., 3 pm A: CO2 B: 5-40% iso-propanol (0.05% DEA) 4 mL / min 35 °C R Chiralpak AD-3, 150x4.6 mm I.D., 3 pm A: CO2 B: 40% ETOH (0.05% DEA) 2.5 mL / min 35 °C S Chiralpak IC-3 150x4.6 mml.D. 3 pm A: CO2 B: 50% iso-propanol (0.05% DEA) 2.5 mL / min 35 °C T Chiralpak AD-3, 150x4.6 mm I.D., 3 pm A: CO2 B: 40% IPA (0.05% DEA) 2.5 mL / min 40 °C U Chiralpak AD-3, 50x4.6 mm I.D., 3 pm A: CO2 B: 40% EtOH (0.05% DEA) 4 mL / min 35 °C V Chiralpak IG-3, 50x4.6 mm I.D., 3 pm A: CO2 B: 40% IPA (0.05% DEA) 4 mL / min 35 °C W Chiralpak OD-3, 150x4.6 mm I.D., 3 pm A: CO2 B: 5-40% MeOH (0.05% DEA) 2.5 mL / min 35 °C X Chiralpak AS-3 100x4.6 mml.D., 3 pm A: CO2 B: 5-40% EtOH (0.05% DEA) 2.8mL / min 35 °C Y DAICEL CHIRALPAK AD(250mmx30mm,10um); A: CO2 B: 45% MeOH (0.1%NH3H2O) 200 mL / min 40 °C Z Chiralpak OD-3, 100x4.6 mm I.D., 3 pm A: CO2 B: 5-40% EtOH (0.05% DEA) 2.8mL / min 35 °C AA Chiralpak AD-3, 150x4.6 mm I.D., 3 pm A: CO2 B: 50% MeOH (0.1% isopropylamine) 2.5 mL / min 35 °C AB Chiralpak IA, 250x30 mm, 5 pm A: CO2 B: 35 % MeOH (0.1% NH4OH) 60 mL / min 40 °C AC Chiralpak IB-N, 250x21.3 mm, 5 pm A: CO2 B: 35 % EtOH (0.1% NH4OH) 70 mL / min 40 °C Headgroup compounds H-4           H-5          H-6 Synthesis of Headgroup H-l Step 1: 4-(benzyloxy)-2-bromo-l-nitrobenzene (compound 2 in above)'. To 5 DMF (2.59 L) in a chemical reactor was added 3-bromo-4-nitrophenol (518 g, 2.38 mol) and K2CO3 (492 g, 3.56 mol). The mixture was stirred at 25 °C for 0.5 h, then benzyl bromide (609 g, 3.56 mol) was added. The mixture was stirred at 25 °C for 12 h, then water (7.70 L) was added. The mixture was stirred for five mins, then filtered. The filter cake was then dissolved in EtOAc, and washed with brine. The organic 10 phase was then dried over Na2SO4, filtered and concentrated under reduced pressure, to afford the title compound (580 g, 79.2% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) d 8.09-8.07 (d, J= 4.00 Hz, 1H), 7.56-7.55 (d, J= 2.00 Hz, 1H) 7.44-7.35 (m, J= 18.0 Hz, 5H), 7.24-7.21 (m, J= 6.00 Hz, 1H) 5.27 (s, 2H). Step 2: 2-(5-(benzyloxy)-2-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 3 in above scheme): To a chemical reactor was added 1,4-dioxane (2.43 L) 4-(benzyloxy)-2-bromo-1 -nitrobenzene (348 g, 1.13 mol), Bis(pinacolato)diborane (430 g, 1.69 mol), and KO Ac (332 g, 3.39 mol). The mixture was degassed and purged with N2 gas, then Pd(dppf)C12 (24.7 g, 33.8 mmol) was added. The mixture was stirred at 25 °C for 16 h, then cooled to r.t. MTBE (900 mL) was added, and the mixture was stirred for 5 mins, then fdtered. The mother liquor was concentrated under reduced pressure, then triturated with petroleum ether, to afford title compound (295.6 g, 90% purity, 66.2% yield) as a gray solid. 'H NMR (400 MHz, CDCh) d 8.17-8.15 (d, J = 4.0 Hz 1H), 7.42-7.41 (m, J = 8.0 Hz, 5H) 7.05-7.02 (m, J = 6.00 Hz, 2H), 5.16 (s, 2H) 1.44 (s, 12H). Step 3: 4-bromo-5,6-dihydro-2H-pyran-3-carbaldehyde (compound 7 in above scheme): To a chemical reactor was added DCM (1.25 L), followed by DMF (365 g, 4.99 mol). The mixture was cooled to 0 °C, then PBn was added. The mixture was stirred at 0 °C for Ih, then tctrahydro-4 / / -pyran-4-onc (250 g, 2.50 mol) was added. The mixture was allowed to warm to r.t. then stir for 12 h. The mixture was neutralized with sat. aq. NaHCOs, then extracted with MTBE to afford the title compound (189 g, 39.8% yield) as a black oil, which was carried on directly without further purification. Tf NMR (400 MHz, CDCh) 3 9.93 (s, 1 H), 4.33 (t, J = 2.4 Hz, 2 H), 3.78-3.89 (m, 2 H), 2.73-2.86 (m, 2 H). Step 4: 5-(5-(benzyloxy)-2-nitrophenyl)-3,6-dihydro-2H-pyran-4-carbaldehyde, (compound 4 in above scheme): To a chemical reactor was added 1,4-dioxane (2.00 L) and water (0.80 L), followed by 2-(5-(benzyloxy)-2-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (400 g, 1.13 mol), 4-bromo-5.6-dihydro-2 / / -pyran-3-carbaldehyde (215 g, 1.13 mol), and K2CO3 (466 g, 3.38 mol). The mixture was degassed, then Pd(dppf)Ch (24.7 g, 33.4 mmol) was added. The mixture was stirred at 80 °C for 2h. The mixture was cooled to r.t., diluted with 800 mL of water, and extracted with MTBE. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product as a black oil, carried directly on to the next step without further purification (340 g, 89% purity, 79.1% yield). 'HNMR (400 MHz, CDCh) d = 9.30 (s, IH), 8.178.15 (d, J= 4.00 Hz, IH) 7.42-7.38 (m, J= 8.0 Hz, 5H), 7.05-7.00 (m, J= 10.0 Hz, 2H)5.16(s, 2H), 1.44 (s, 12H). Step 5: 9-(benzyloxy)-l ,4-dihydro-2H-pyrano[3,4-c] quinoline (compound 5 in above scheme): Two reactions run in parallel: To each chemical reactor was added 2-MeTHF (1.40 L) and water (0.56 L), followed by 5-(5-(benzyloxy)-2-nitrophenyl)-3,6-dihydro-2H-pyran-4-carbaldehyde (280 g, 0.825 mol) and ammonium chloride (132 g, 2.48 mol). The mixture was heated to 80 °C, then iron powder was added (230 g, 4.13 mol). The mixture was stirred at 80 °C for 3h, then the two batches were combined and filtered. The filtrate was concentrated under reduced pressure, then triturated with MeOH to afford the title compound (288 g, 59.9% yield) as an orange solid. 'HNMR (400 MHz, CDC13) d 8.46 (d, 1H), 8.03-8.01 (d, J= 4.0 Hz, 1H) 7.527.37 (m, J= 30.0 Hz, 6H), 7.19-7.18 (d, J= 2.0 Hz, 1H) 5.21 (s, 2H), 4.93 (s, 2H), 4.16-4.13 (m, 7= 6.0 Hz, 2H) 3.09-3.07 (m, J= 4.0 Hz, 2H). Step 6: Crude l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-ol (H-l in scheme above). Three reactions were run in parallel. To each chemical reactor was added methanol (1.00 L) followed by 9-(benzyloxy)-l,4-dihydro-2H-pyrano[3,4-c]quinoline (143 g, 0.49 mmol), then Pd / C (14.3 g, 10% purity). The mixture was degassed with H2, then the mixture was stirred at 60 °C for 12h under H2 atmosphere (30 psi). The three batches were combined, and filtered. The filter cake was washed with THF, then the filter cake mixture of Pd / C and H-l were carried on directly to the next step. Step 7: l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl acetate (Compound 8 in above scheme). To a chemical reactor was added THF (1.00 L), crude 1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-ol (219 g, 1.09 mol) and triethylamine (368 g, 3.65 mol). The mixture was cooled to 10 °C, then acetyl chloride was added (192 g, 2.45 mol). The mixture was stirred at 25 °C for 3h, then filtered. The filtrate was concentrated, affording crude title compound (260 g, 1.07 mol) as a black solid. The crude was then carried to the next step directly, without further purification. Step 8: l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-ol (H-l in scheme above). To a chemical reactor was added THF (1.00 L) followed by l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl acetate (260 g, 1.07 mol), and sodium hydroxide (6 M in water, 534 mL). The mixture was stirred at 40 °C for 2h, then cooled to 25 °C. The solution was acidified to pH=6 with citric acid, then the solid was filtered, affording the title compound as a yellow solid (210 g, 66.4% yield). Tf NMR (400 MHz, DMSO-d6) 6 10.0 (s, 1H), 8.37 (s, 1H) 7.84-7.82 (d, J= 4.0 Hz, 1H), 7.27-7.24 (m, J= 6.0 Hz, 1H) 7.12-7.11 (d, J= 2.0 Hz, 1H), 4.81 (s, 2H), 4.03-4.00 (m, J= 6.0 Hz, 2H) 2.98-2.95 (m, J= 6.0 Hz, 2H). LCMS M / Z (M+) 202.1. Synthesis of Headgroup H-2 Step 1: (S)-but-3-yn-2-yl methanesulfonate'. To a solution of (5)-(-)-3-butyn-2-ol (3.4 mL, 42.8 mmol) and EtsN (11.9 mL, 85.6 mmol) in DCM (60 mL) at 0 °C was added MsCl (5.0 mL, 64.5 mmol) dropwise. Then the reaction was stirred at r.t. for 1 hour. TLC (33% ethyl acetate in petroleum ether, Rf = 0.5) indicated the reaction was completed. Sat. NaHCOs aqueous solution (30 mL) and water (80 mL) were added. After phase separation, the aqueous layer was further extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (20-40% ethyl acetate in petroleum ether) to afford (5)-but-3-yn-2-yl methane sulfonate (5.2 g, 82% yield) as a pale yellow oil. r.t. 'H NMR (400 MHz, CDC13) d = 5.32 - 5.27 (m, 1H), 3.13 (s, 3H), 2.72 (d, J= 2.4 Hz, 1H), 1.68 (d, J= 7.2 Hz, 3H). Step 2: (R)-9-(but-3-yn-2-yloxy)-2,4-dihydro-lH-pyrano[3,4-c] quinoline (Headgroup H-2): To a solution of 2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-ol (2.6 g, 12.92 mmol) and K2CO3 (3.6 g, 25.8 mmol) in DMF (40 mL) was added (5)-but-3-yn-2-yl methane sulfonate (2.9 g, 19.4 mmol). The mixture was heated at 80 °C for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography column on silica gel (50% ethyl acetate in petroleum ether) to give (J?)-9-(but-3-yn-2-yloxy)-2,4-dihydro-lH-pyrano[3,4-c]quinoline (2.4 g, 73.3% yield) as a pale yellow solid. 'H NMR (400MHz, CDCh) d = 8.47 (s, 1H), 8.06 - 8.00 (m, 1H), 7.41 (dd, J= 2.8, 9.2 Hz, 1H), 7.34 (d, J= 2.8 Hz, 1H), 5.04 (dq, J= 1.6, 6.8 Hz, 1H), 4.93 (s, 2H), 4.16 (qd, J= 5.6, 12.0 Hz, 2H), 3.12 (t, J= 5.6 Hz, 2H), 2.53 (d, J= 2.0 Hz, 1H), 1.76 (d, J = 6.8 Hz, 3H). LCMS M / Z (M+H) = 254.1. Synthesis of Headgroup H-3 H-3 Step 1: 9-bromo-2,4-dihydro-lH-pyrano[3,4-c]quinoline: To a solution of 9-bromo-2,4-dihydro-lH-pyrano[3,4-c]quinoline (300 mg, 1.1 mmol) in CD3OD (3 mL) was added NaOMe (184 mg, 3.4 mmol). The mixture was stirred at 65 °C for 12 hours. The mixture was diluted with water, then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give crude product 9-bromo-2,4-dihydro-lH-pyrano[3,4-c]quinoline (270 mg, 1.0 mmol, 90 % yield) as a light yellow solid, which is pure enough for next step without further purification. 'H NMR (400 MHz, CDCh) 5 8.60 (s, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.97 (d, J= 8.8 Hz, 1H), 7.77 (dd, J= 8.8, 2.0 Hz, 1H), 4.94 (s, 2H), 4.14 (s, 2H). LCMS M / Z (M+H)+ = 266.1. Step 2: l,l-dideuterio-2,4-dihydropyrano[3,4-c]quinolin-9-ol (Headgroup H-3): Under N2, a mixture of 9-bromo-l,l-dideuterio-2,4-dihydropyrano[3,4-c]quinoline (270 mg, 1.1 mmol), KOH (227 mg, 4.1 mmol), t-BuXphos (86.2 mg, 0.2 mmol), Pd2(dba)3 (92.9 mg, 0.1 mmol) in 1,4-dioxane (3 mL) and water (3 mL) was heated at 80 °C for 16 h. The reaction mixture was cooled to 25 °C, then adjusted the pH = 4 by 2 M aq. HC1 solution. The mixture was extracted with ethyl acetate, then combined organic layer was washed with sat. NaHCOs solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica (solvent gradient: 2.5 % ethanol, 22.5% ethyl acetate 75% petroleum ether) to afford the title compound l,l-dideuterio-2,4-dihydropyrano[3,4-c]quinolin-9-ol (140 mg, 0.68 mmol, 67.9 % yield) as a grey solid. TfNMR (400MHz, DMSO-Je) 5 = 10.03 (s, 1H), 8.37 (s, 1H), 7.83 (d, 7= 8.8 Hz, 1H), 7.25 (dd, J= 2.8, 9.2 Hz, 1H), 7.11 (d, J= 2.4 Hz, 1H),4.81 (s, 2H),4.01 (s, 2H). LCMS M / Z (M+H)+ = 204 Step 1: 9-((triisopropylsilyl)oxy)-l,4-dihydro-2H-pyrano[3,4-c] quinoline 6-oxide: To a solution of 2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy(triisopropyl)silane (500 mg, 1.40 mmol) in DCM (5 mL) was added 3-chloroperoxybenzoic acid (626.7 mg, 2.80 mmol, 77 mass%), portion wise at 0 °C. The resulting mixture was stirred at 20 °C for 3 hour. Upon completion, the reaction mixture was diluted with DCM and washed with 5% NaHSOs aqueous solution, saturated NaHCOs solution and brine. The organic layer was dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with (0-10% MeOH in DCM) to afford the title compound (397.9 mg, 76% yield) as a white solid. 'H NMR (400 MHz, CDCh) 5 8.65 (d, J= 9.4 Hz, 1H), 8.12 (s, 1H), 7.32 (dd, J= 9.4, 2.5 Hz, 1H), 7.22 (d, J= 2.5 Hz, 1H), 4.77 (t, J= 1.5 Hz, 2H), 4.13 (t, J= 5.7 Hz, 2H), 3.04 - 2.90 (m, 2H), 1.39 - 1.27 (m, 3H), 1.14 (d, J= 7.3 Hz, 18H). LCMS M / Z (M+H)+=374.3. Step 2: 2,2,2-trifluoroacetate;trimethyl-(9-triisopropylsilyloxy-2,4-dihydro-lH-pyrano[3,4-c]quinolin-5-yl)ammonium: To a stirred solution of triisopropyl-[(6-oxido-2,4-dihydro-lH-pyrano[3,4-c]quinolin-6-ium-9-yl)oxy]silane (50 mg, 0.13 mmol) and trimethylamine (0.67 mmol, 1.0 mol / L in THF) in dichloromethane (2.0 mL) was added trifluoroacetic anhydride (84 mg, 0.40 mmol,) at 0 °C. The mixture was stirred at r.t. for 2 hour. Then the mixture was concentrated under reduced pressure to afford 2,2,2-trifluoroacetate;trimethyl-(9-triisopropylsilyloxy-2,4-dihydro-lH-pyrano[3,4-c]quinolin-5-yl)ammonium as a crude mixture. LCMS M / Z (M+) 415.2. Step 3: 5-fluoro-2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-ol (Headgroup H-4): The crude mixture of 2,2,2-trifluoroacetate;trimethyl-(9-triisopropylsilyloxy-2,4-dihydro-lH-pyrano[3,4-c]quinolin-5-yl)ammonium was dissolved in N,N-dimethylformamide (1.0 mL). The tetrabutylammonium fluoride (0.40 mmol, 1.0 mol / L in THF) was added at 25 °C. The reaction mixture was heated to 90 °C and allowed to stir for 16 hour. After that, the mixture was cooled to 25 °C, isopropyl acetate and water were added. The layers was separated and the organic layer was washed with brine and dried over sodium sulfate. The mixture was fdtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with (MeOH 0-10% in DCM) to afford the title compound (12.0 mg, 0.055 mmol, 41% yield) as a brown solid. 'H NMR (400 MHz, CDCh) 5 7.83 (d, J= 9.0 Hz, 1H), 7.29 - 7.27 (m, 1H), 7.19 - 7.14 (m, 1H), 5.13 (s, 1H), 4.85 (d, J= 1.8 Hz, 2H), 4.12 (t, J= 5.7 Hz, 2H), 3.07 (ddt, J= 5.7, 4.0, 1.8 Hz, 2H). LCMS M / Z (M+H) 220.0. Synthesis of Headgroup H-5 H-5 Step 1: 9-bromo-5-methyl-2,4-dihydro-lH-pyrano[3,4-c]quinoline: To a stirred solution of 9-bromo-2,4-dihydro-lH-pyrano[3,4-c]quinoline (1.0 g, 3.8 mmol) in THF (30 mL) was added the methyllithium (5.9 mL, 9.5 mmol, 1.6 mol / L in diethyl ether) dropwise at -78 °C. The reaction mixture was allowed to stir at this temperature for 2.5 hour, and then raise to 25 °C for 16 hour. After that, the reaction mixture was quenched with saturated NaHCOs aqueous solution and extracted with isopropyl acetate and dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was flush through column chromatography on silica gel eluting with (0-100% isopropyl acetate in heptane) to afford 9-bromo-5-methyl-2,4,5,6-tetrahydro-lH-pyrano[3,4-c]quinoline as a crude mixture. To this crude mixture was added acetone (8.0 mL), ceric ammonium nitrate (1.02 g, 1.86 mmol) and water (4.0 mL) at 25 °C. The resulting mixture was allowed to stir at 25 °C for 16 hour. After that, the reaction mixture was quenched with saturated NaHCOs aqueous solution and extracted with isopropyl acetate and dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was flush through column chromatography on silica gel eluting with (0-100% isopropyl acetate in heptane) to afford 9-bromo-5-methyl-2,4-dihydro-lH-pyrano[3,4-c]quinoline (392.9 mg, 37% Yield) as yellow solid. 1H NMR (400 MHz, CDCh) 5 8.01 (d, 7=2.1 Hz, 1H), 7.88 (d, 7= 8.9 Hz, 1H), 7.73 (dd,7=8.9, 2.2 Hz, 1H), 4.84 (t, 7= 1.7 Hz, 2H), 4.10 (t, 7= 5.7 Hz, 2H), 3.12 (tt, 7= 5.7, 1.6 Hz, 2H), 2.54 (s, 3H). LCMS M / Z (M+H) 277.9. Step 2: 5-methyl-2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-ol (Headgroup H-5): To a mixture of Pd(dppf)C12xDCM (56.6 mg, 0.069 mmol), potassium acetate (149.8 mg, 1.5 mmol), bis(pinacolato)diboron (211.4 mg, 0.83 mmol) in 1,4-dioxane (4.0 mL) was added 9-bromo-5-methyl-2,4-dihydro-lH-pyrano[3,4-c]quinoline (192.9 mg, 0.69 mmol) at 25 °C. The mixture was stirred at 90 °C for 18 hours. Then the mixture was filtered, washed with isopropyl acetate and MeOH and concentrated under reduced pressure to give the crude mixture of 5-methyl-9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,4-dihydro-lH-pyrano[3,4-c]quinoline. LCMS M / Z (M+H) 326.0. To the residue was added hydrogen peroxide (0.33 mL, 30 mass% in water) and dichloromethane (5.0 mL) at 0 °C. The mixture was allowed to warm to 22 °C and stir for 30 min. Then dichloromethane and water were added and the layers were separated. The aqueous layer was extracted with dichloromethane and dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with (0-10% MeOH in DCM) to afford the 5-methyl-l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-ol (110.0 mg, 74% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-7?) 5 10.80 (s, 1H), 8.11 (d, 7= 9.1 Hz, 1H), 7.58 (d, 7= 9.1 Hz, 1H), 7.37 (d, 7= 2.5 Hz, 1H), 4.86 (s, 2H), 4.04 (t, 7= 5.6 Hz, 2H), 3.23 (d, 7= 5.9 Hz, 2H), 2.70 (s, 3H). LCMS M / Z (M+H) 215.9. Synthesis of Headgroup H-6 Step 1: l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl trifluoromethane sulfonate: To a solution of pyridine (0.72 mL, 9.0 mmol) and 2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-ol (600 mg, 3 mmol) in DCM was added Tf2O (0.76 mL, 4.5 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 hs under nitrogen atmosphere. The reaction was then diluted with water and extracted with dichloromethane. The organics were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography (40% ethyl acetate in petroleum ether) to afford the title compound (850 mg, 85.5% yield) as a 5 yellow oil. LCMS M / Z (M+H) 334.1. Step 2: tert-butyl (l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)carbamate: A solution of tert-butyl carbamate (263.6 mg, 2.3 mmol), Xantphos (104.2 mg, 0.2 mmol), 2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yl trifluoromethanesulfonate (500 mg, 1.5 mmol), Pd2(dba)s (54.9 mg 0.06 mol), CS2CO3 (1466.4 mg, 4.5 mmol) in 1,410 dioxane (10 mL) was stirred at 80 °C for 16 hs under nitrogen atmosphere. The reaction was then concentrated, and the residue was purified by flash chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (400 mg, 88.8% yield) as a yellow solid. LCMS M / Z (M+H) 301.2. Step 3: 1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-amine: A solution of tert-15 butyl X-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yl)carbamate (400 mg, 1.3 mmol) in HCl / dioxane (10 mL, 4M) was stirred at 25 °C for 1 h. The reaction mixture was concentrated to afford the crude title compound (H-6, 1.6 g, 97.4% yield) as a yellow solid, which was used directly without further purification. LCMS M / Z (M+H) 201.1. T-9 T-8 T-25 T-26 T-27 T-28                    T-29 T-30 Synthesis of (1S, 3r)-3-(4-((S)-l-hydroxyethyl)-lH-l, 2,3-triazol-l-yl)-l-methylcyclobutane-l-carbonitrile (Tail group T-l) and (lR,3s)-3-(4-((S)-l-hydroxyethyl)-lH-l, 2,3-triazol-l-yl)-l-methylcyclobutane-l-carbonitrile (Tail group T-2) NH4CI, HATU, DIPEA DMF, rt, 2 h HCI MeOH, rt, 1 h pyridine, TFAA 0 °C, 3 h N3S(O)2F KHCO3 dmf / mtbe / h2o 0 °C, 1 h OTBS sodium ascorbate, CuSO4 t-BuOH / H2O, rt, 12 h OTBS TBAF THF, rt, 1 h confirmed by 2D NMR OH confirmed by 2D NMR TBAF THF, rt, 1 h OH Step 1: tert-butyl (3-carbamoyl-3-methylcyclobutyl)carbamate: To a solution of 3-(tert-butoxycarbonylamino)-l-methyl-cyclobutanecarboxylic acid (300.0 mg, 1.31 mmol), NH4CI (139.98 mg, 2.62 mmol) and HATU (547.28 mg, 1.44 mmol) in DMF (4 mL) was added DIPEA (0.65 mL, 3.93 mmol). The solution was stirred for 2 10 h at r.t., then diluted with water (10 mL) and ethyl acetate (10 mL). After phase separation, the water phase was further extracted with ethyl acetate (10 mL><3). The combined organic layers were washed with NaHCOs (1 x5 mL) and brine (10 mLx2). Then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica (solvent gradient: 40% 15 ethyl acetate in petroleum ether) to afford a mixture of cis and trans amides of tertbutyl N-(3-carbamoyl-3-methyl-cyclobutyl) carbamate (270 mg, 1.18 mmol, 90.4% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 7.13 (s, 1H, minor), 6.99 ((s, 1H, major), 6.81 (s, 1H, minor), 6.72 (s, 1H, major), 3.97 - 3.85 (m, 1H, major), 3.83 - 3.69 (m, 1H, minor), 2.61 - 2.52 (m, 2H, minor), 2.19 - 2.06 (m, 2H, major), 2.03 - 1.92 (m, 2H, major), 1.79 - 1.66 (m, 2H, minor), 1.35 (s, 9H, minor), 1.35 (s, 9H, major), 1.25 (s, 3H, major), 1.24 (s, 3H, minor). Step 2: 3-amino-l-methylcyclobutane-l-carboxamide hydrochloride'. A solution of tert-butyl N-(3 -carbamoyl-3 -methyl -cyclobutyl)carbamate (270.0 mg, 1.18 mmol) in HC1 (8 mL, 4 M in 1,4-dioxane) was stirred at r.t. for 1 h. The reaction mixture was concentrated under reduced pressure directly. The resulting residue was used for next step directly. Step 3: 3-azido-l-methylcyclobutane-l-carboxamide: To a stirred solution of 3-amino-l-methyl-cyclobutanecarboxamide hydrochloride (190.0 mg, 1.15 mmol) in DMF (1 mL) was added N-diazosulfamoyl fluoride (206.4 mg, 1.65 mmol) in MTBE (3 mL) and KHCO3 (577.7 mg, 5.77 mmol) in water (1 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, and then was used directly to next step without any workup. Step 4: (S)-3-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-1-methylcyclobutane-1-carboxamide: To the mixture of step 3 was added tert-butyl-dimethyl-[(lS)-l-methylprop-2-ynoxy]silane (627.7 mg, 3.41 mmol), CuSO4 (36.2 mg, 0.230 mmol) and sodium ascorbate (44.98 mg, 0.230 mmol). The mixture was stirred at r.t. for 12 h. The reaction was diluted with water (10 mL) and ethyl acetate (10 mL). After phase separation, the aqueous layer was extracted with ethyl acetate (10 mLx3). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica [solvent gradient: 30% EE(25% ethanol in ethyl acetate) in petroleum ether] to afford l-methyl-3-[4-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]cyclobutanecarboxamide (150 mg, 0.443 mmol, 39% yield) as a yellow oil. LCMS M / Z (M+H)+ = 339.1. Step 5: (IS, 3r)-3-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-methylcyclobutane-l-carbonitrile and (1R, 3s)-3-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -methylcyclobutane-1 -carbonitrile OTBS                    OTBS N=n'                         N=n' To a solution of l-methyl-3-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]cyclobutanecarboxamide (130.0 mg, 0.380 mmol) and pyridine (0.16 mL, 1.92 mmol) in DCM (4 mL) was added TFAA (0.16 mb, 1.15 mmol) dropwise at 0 °C. The mixture was stirred at r.t. for 3 h. The TLC (50% ethyl acetate in petroleum ether, Rf= 0.4 and 0.6) showed two new spots formed. The mixture was concentrated under reduced pressure directly and purified by flash chromatography (solvent gradient: 10% to 50% ethyl acetate in petroleum ether) to afford (lS,3r)-3-(4-((5)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-methylcyclobutane-l-carbonitrile (35 mg, 0.109 mmol, 28.4% yield) as a yellow oil (peak 1) and (U?,35')-3-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-methylcyclobutane-l-carbonitrile (55 mg, 0.171 mmol, 44.7% yield) as a yellow oil (peak 2). Relative configuration of the cyclobutane was confirmed by 2D NMR. Peak 1: 'HNMR (400 MHz, CDCh-d) 5 7.40 (s, 1H), 5.20 -5.12 (m, 1H), 5.12 - 5.06 (m, 1H), 3.23 - 3.10 (m, 2H), 2.96 - 2.79 (m, 2H), 1.68 (s, 3H), 1.52 (d, J= 6.4 Hz, 3H), 0.93 - 0.89 (m, 9H), 0.12 (s, 3H), 0.05 (s, 3H). LCMS M / Z (M+H)+ = 320.8. Peak 2: Tf NMR (400 MHz, CDCh-d) 5 7.49 (s, 1H), 5.21 -5.13 (m, 1H), 5.13 -5.07 (m, 1H), 3.28 - 3.12 (m, 2H), 2.81 -2.69(m, 2H), 1.70 (s, 3H), 1.53 (d, J= 6.4 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). LCMS M / Z (M+H)+ = 320.8. Step 6: (IS, 3r)-3-(4-((S)-l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)-l-methylcyclobutane-1-carbonitrile (Tail group Tl): To a stirred solution of (lS,3r)-3-(4-((5)-1 -((tert-butyldimethylsilyl )oxy )ethyl)-I / / -1,2.3-triazol-1 -yl)-1 -methylcyclobutane-1-carbonitrile (35.0 mg, 0.110 mmol) in THF (2 mL) was added TBAF (0.22 mL, 0.220 mmol, 1 M in THF). The mixture was stirred at r.t. for 1 h. The reaction was quenched with NH4CI (1 mL), then diluted with water (5 mL). The resulting solution was extracted with ethyl acetate (3x10 mL), and the organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude (lS,3r)-3-(4-((5)-l-hydroxyethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -methylcyclobutane-1 -carbonitrile (22 mg, 0.106 mmol, 97.7% yield) as a yellow oil. LCMS M / Z (M+H)+ = 207.2. The crude product was pure enough and used to next step directly. T-2 was prepared in a similar fashion to T-l, using (17?,3s)-3-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-127-l,2,3-triazol-l-yl)-l-methylcyclobutane-l-carbonitrile in Step 6. Synthesis of methyl (S)-3-(4-(l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)-l-methylcyclobutane-l-carboxylate (Tail group T-3) OH Step 1: methyl l-methyl-3-((methylsulfonyl)oxy)cyclobutanecarboxylate: To a mixture of methyl 3-hydroxy-1-methyl-cyclobutanecarboxylate 1 (4.3 g, 29.8 mmol) and EtsN (12.5 mL, 89.5 mmol) in DCM (60 mL) was added MsCl (4.95 mL, 64.0 mmol) slowly at 0 °C, the mixture was stirred at r.t. for 2 h. The mixture was quenched by sat. NaHCOs solution, then the resulting solution was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure to afford methyl 1-methyl-3-methylsulfonyloxy-cyclobutanecarboxylate (6.6 g, 29.7 mmol, 99.6% yield) as yellow oil. The crude product was pure enough for next step without further purification. Step 2: methyl 3-azido-l-methylcyclobutanecarboxylate: To a solution of methyl l-methyl-3-methylsulfonyloxy-cyclobutanecarboxylate (6.6 g, 29.6 mmol) in DMF (70 mL) was added NaNs (3.05 g, 46.8 mmol), and the mixture was stirred at 80 °C for 16 h. The mixture was diluted with water (100 mL), and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude methyl 3-azido-l-methyl-cyclobutanecarboxylate (4.7 g, 27.8 mmol, 93.8% yield) as a yellow solid, which was carried on to the next step without further purification. Step 3: (S)-methyl 3-(4-(l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)-l-methylcyclobutanecarboxylate (T-3): Tail group T-3 was prepared in a similar click reaction condition as the T-l intermediate. Synthesis of cis-l-(difluoromethyl)-3-(4-((S)-l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)cyclobutanol (Tail group T-4) OTBS OTBS NaN3 DMF, rt, 2 h C11SO4 sodium ascorbate f-BuOH / H2O, rt, 12 h pXf KHMDS THF, -78 °C, 3 h Step 1: 3-azidocyclobutanone: To a solution of 3-bromocyclobutanone (3.40 g, 22.8 mmol) in DMF (30 mL) was added NaNs (1.9 g, 28.5 mmol) at 0 °C. The mixture was stirred at r.t. for 2 hours. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure to afford crude 3-azidocyclobutanone (2.4 g, 21.6 mmol, 94.7% yield) as a yellow oil. 'HNMR (400 MHz, CDCh) 5 4.37 (tt, J= 5.2, 7.6 Hz, 1H), 3.49 - 3.35 (m, 2H), 3.28 - 3.12 (m, 2H). Step 2: (S)-3-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)cyclobutanone: To a solution of 3-azidocyclobutanone (2.40 g, 21.6 mmol) and tert-butyl-dimethyl-[(lS)-l-methylprop-2-ynoxy]silane (4.0 g, 21.6 mmol) in tBuOH (10 mL) and water (10 mL) was added CuSO4 (689.6 mg, 4.3 mmol) and sodium ascorbate (855.9 mg, 4.3 mmol). The mixture was stirred at r.t. for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford to give 3-[4-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]cyclobutanone (4.6 g, 15.6 mmol, 72.1% yield) as a light yellow solid. Tf NMR (400 MHz, DMSO-Je) 5 8.23 (s, 1H), 5.55 - 5.33 (m, 1H), 5.03 (q, J= 6.4 Hz, 1H), 3.73 - 3.60 (m, 4H), 1.45 (d, J= 6.4 Hz, 3H), 0.86 (s, 9H), 0.08 (s, 3H), 0.01 (s, 3H). LCMS M / Z (M+H)+= 296.3. Step 3: cis-3-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-(difluoro(phenylsulfonyl)methyl)cyclobutanol: Under N2 atmosphere, to a solution of 3-[4-[( IS)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl]cyclobutanone (1.0 g, 3.4 mmol) in THF (15 mL) was added difluoromethyl phenyl sulfone (1.3 g, 6.8 mmol) followed by LiHMDS (5.1 mL, 5.1 mmol, 1 M in THF) at -78 °C. The mixture was stirred at -78 °C for 2 hours. The reaction was quenched with sat. NH4CI solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica (0-30% ethyl acetate in petroleum ether) to afford l-[benzenesulfonyl(difluoro)methyl]-3-[4-[(lS)-l-[tert-butyl(dimethyl)silyl] oxyethyl]triazol-l-yl]cyclobutanol (620 mg, 1.3 mmol, 37.6% yield) as a white solid. 'H NMR (400 MHz, DMSO-Je) 5 8.03 - 7.97 (m, 3H), 7.93 -7.86 (m, 1H), 7.78 - 7.71 (m, 2H), 7.04 (s, 1H), 5.02 (q, J= 6.4 Hz, 1H), 4.90 (quin, J = 8.4 Hz, 1H), 3.30 - 3.20 (m, 2H), 2.80 (s, 2H), 1.43 (d, J= 6.4 Hz, 3H), 0.86 (s, 9H), 0.10 - 0.06 (m, 3H), 0.04 - -0.01 (m, 3H). LCMS M / Z (M+H)+ = 488.2. Step 4: cis-l-(difluoro(phenylsulfonyl)methyl)-3-(4-((S)-l-hydroxyethyl)-lH-1,2,3-triazol-l -yl)cyclobutanol: TBAF (5.1 mL, 5.1 mmol, 1 M in THF) was added to a solution of cA-3-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-(difluoro(phenylsulfonyl)methyl)cyclobutanol (500 mg, 1.0 mmol) in THF (10 mL), and the mixture was stirred at r.t. for 1 h. The mixture was diluted with water and extracted with ethyl acetate, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1 -[benzenesulfonyl(difluoro)methyl]-3-[4-[( IS)-1 -hydroxyethyl]triazol-1 -yl]cyclobutanol (380 mg, 1.0 mmol, 99.3% yield) as a yellow solid, which was carried on to the next step directly without further purification. 1H NMR (400 MHz, DMSO-dd) 8 8.03 (s, 1H), 7.99 (d, J= 7.6 Hz, 2H), 7.92 - 7.86 (m, 1H), 7.78 - 7.70 (m, 2H), 7.04 (s, 1H), 5.26 (d, J= 3.2 Hz, 1H), 4.90 - 4.74 (m, 2H), 3.28-3.21 (m, 2H), 2.87 -2.71 (m, 2H), 1.39 (d, J= 6.8 Hz, 3H). LCMS M / Z (M+H)+ = 374.1. Step 5: cis-l-(difluoromethyl)-3-(4-((S)-l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)cyclobutanol (T-4): To a solution of czs-l-(difluoro(phenylsulfonyl)methyl)-3-(4-((S)-l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)cyclobutanol (370 mg, 1.0 mmol) and anhydrous Na2HPO4 in anhydrous MeOH (10 mL) was added Na / Hg amalgam (2.4 g, 9.9 mmol) under N2 atmosphere at -20 °C. The mixture was stirred at 0 °C for 1 hour. The MeOH solution was decanted, and the residue solids were washed with ethyl acetate. The combined organics were concentrated under reduced pressure. The residue was purified by chromatography on silica (6% MeOH in DCM) to afford cis-1 -(difluoromethyl)-3-(4-((S)-1 -hydroxyethyl)- 1H-1,2,3-triazol-1 -yl)cyclobutanol (200 mg, 0.86 mmol, 86.5% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-r / e) 5 8.07 (s, 1H), 6.32 (s, 1H), 6.22 - 5.81 (m, 1H), 5.26 (d, J= 4.8 Hz, 1H), 4.90 - 4.71 (m, 2H), 3.01 - 2.87 (m, 2H), 2.71 - 2.57 (m, 2H), 1.40 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H)+=234. Synthesis of tail group T-5 DMF / MTBE / H2O, 0 °C, 1 h ii n3-s-f “ II o 4 KHCO3 (mixture) Step 1: rac-tert-butyl((lR, 3S, 4R)-3-cyano-4-hydroxycyclopentyl)carbamate and (lS,3R4S)-3-cyano-4-hydroxycyclopentyl)carbamate: To a solution of TMSCN (0.05 mL, 0.38 mmol) and cA-tert-butyl A-(6-oxabicyclo[3.1.0]hexan-3-yl)carbamate (50.0 mg, 0.25 mmol) in THF (2 mL) was added TBAF (0.38 mL, 0.38 mmol, IM in THF). The mixture was stirred at 60 °C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (25% ethyl acetate in petroleum ether) to afford rac-tert-butyl((lR,3S,4R & 7S,3R4S)-3-cyano-4-hydroxycyclopentyl)carbamate (50.0 mg, 0.22 mmol, 88.1% yield) as a white solid. 'H NMR (400MHz, CDC13) 5 5.06 (br s, 1H), 4.56 - 4.45 (m, 1H), 4.13- 4.04 (m, 1H), 3.04 - 2.92 (m, 1H), 2.54 - 2.31 (m, 2H), 2.30 - 2.22 (m, 1H), 1.90 - 1.78 (m, 1H), 1.44 (s, 9H) Step 2: rac-(lS,2R,4R & lR,2S,4S)-4-amino-2-hydroxycyclopentanecarbonitrile^TFA: To a solution of rac-tert-butyl ((1R,3S,4R &  / .S'. j / ?.7.S')-3-cyano-4-hydroxycyclopcntyl (carbamate (50.0 mg, 0.22 mmol) in DCM (2 mL) was added TFA (0.16 mL, 2.2 mmol). The reaction mixture was stirred at r.t. for 2 hours. The reaction was concentrated under reduced pressure, and the residue was carried on to the next step without purification. Step 3: rac-(lS,2R,4R & lR,2S,4S)-4-azido-2-hydroxycyclopentanecarbonitrile (T-5): rac-(\S.2RAR & lR,2S,4S)-4-azido-2-hydroxy-cyclopentanecarbonitrile T-5 was prepared in a similar diazo transfer reaction condition as T-l in a solution in DMF and MTBE. Synthesis of tail group T-6 Step 1: 3-hydroxypropyl benzoate: To a solution of 1-3-propanediol (0.77 mL, 10.67 mmol) and triethylamine (1.98 mL, 14.23 mmol) in dichloromethane (40 mL) was added benzoyl chloride (0.83 mL, 7.11 mmol) slowly at 0 °C. The mixture was allowed to stir at r.t. for 1 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (10 mLx3). The combined organic layers were washed with water (10 mLx2) and brine (10 mLx2), dried over Na2SO4, concentrated under reduced pressure and purified by flash chromatography (10% ethyl acetate in petroleum ether) to give 3-hydroxypropyl benzoate (780 mg, 60.8% yield) as a colorless oil. 'H NMR (400MHz, CDCh) 5 8.16 - 7.92 (m, 2H), 7.65 - 7.53 (m, 1H), 7.50 -7.39 (m, 2H),4.51 (t,7=6.4 Hz, 2H), 3.79 (t, J= 6.0 Hz, 2H), 2.11 - 1.96 (m, 2H). Step 2: 3-oxopropyl benzoate: To a solution of 3-hydroxypropyl benzoate (780.0 mg, 4.33 mmol) in CH2CI2 (10 mL) was added DMP (2753.8 mg, 6.49 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. A solution of sodium thiosulfate (10 mL) was added to the mixture, and the mixture was vigorously stirred for 30 min at 0 °C. Then acetic acid was neutralized with saturated NaHCOs (10 mL). The resulting precipitate was filtered and layers were partitioned. The aqueous layer was additionally extracted with dichloromethane (10 mLx2). The combined layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (40% ethyl acetate in petroleum ether) to give the tittle compound (600 mg, 78% yield) as a colorless oil. 'H NMR (400 MHz, CDCh) 5 9.88 (t, J= 1.6 Hz, 1H), 8.07 - 7.97 (m, 2H), 7.62 - 7.53 (m, 1H), 7.49 - 7.39 (m, 2H), 4.68 (t, J= 6.4 Hz, 2H), 2.92 (dd, J= 1.6, 6.4 Hz, 2H). Step 3: 2-[rac-(cis & trans)-4-bromotetrahydropyran-2-ylJethyl benzoate: A solution of 3-oxopropyl benzoate (500 mg, 2.81 mmol), aluminum chloride (18.7 mg, 0.140 mmol), 3-buten-l-ol (0.24 mL, 2.81 mmol) and TMSBr (0.74 mL, 5.61 mmol) in dry dichloromethane (20 mL) was stirred at r.t. for 16 hours. The reaction was quenched with water (50 mL) and extracted with dichloromethane (10 mLx3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated under reduced pressure and purified by flash chromatography (solvent gradient: 6% ethyl acetate in petroleum ether) to afford 2-[rac-(cis)-4-bromotetrahydropyran-2-yl]ethyl benzoate (210 mg, 0.670 mmol, 23.9% yield) and 2-[rac-(trans)-4-bromotetrahydropyran-2-yl]ethyl benzoate (330.0 mg, 1.053 mmol, 37.5% yield) as colorless oil. cis isomer: 'H NMR (400 MHz, CDCh) 5 8.12 - 7.97 (m, 2H), 7.62 - 7.52 (m, 1H), 7.50 - 7.38 (m, 2H), 4.49 - 4.38 (m, 2H), 4.22 - 4.10 (m, 1H), 4.02 - 3.96 (m, 1H), 3.53 - 3.42 (m, 2H), 2.36 - 2.25 (m, 1H), 2.24 - 2.16 (m, 1H), 2.08 - 2.03 (m, 1H), 1.97 - 1.91 (m, 2H), 1.88 - 1.81 (m, 1H). LCMS M / Z (M+H)+= 313.0. trans isomer: 'HNMR (400 MHz, CDCh) 5 8.09 - 8.03 (m, 2H), 7.60-7.54 (m, 1H), 7.48-7.43 (m, 2H), 4.74 (t, J= 3.2 Hz, 1H), 4.48-4.42 (m, 2H), 4.06 (tdd, J= 2.0, 8.0, 12.7 Hz, 1H), 4.01-3.94 (m, 1H), 3.92-3.80 (m, 1H), 2.14-2.03 (m, 2H), 1.98-1.88 (m, 4H). LCMS M / Z (M+H)+= 313.0. Step 4: 2-[rac-(cis)-4-azidotetrahydro-2H-pyran-2-yl]ethyl benzoate (Tail group T-6): To a solution of 2-[rac-(2S, 4R)-4-bromotetrahydropyran-2-yl]ethyl benzoate (220.0 mg, 0.700 mmol) in A,A-dimethylformamide (5 mL) was added sodium azide (140.0 mg, 2.15 mmol) slowly at 0 °C. Then the mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (25 mL) and extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine (3x10 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude racemic cis product (180 mg, 93% yield). The aqueous layer was quenched with NaClO solution. LCMS M / Z (M+H)+ = 276.1. Synthesis of 2-(4-azidotetrahydro-2H-pyran-2-yl)propyl benzoate (Tail group T-7) OBz T-7 T-7 was synthesized in a similar fashion to T-6 from 2-methylpropane-l,3-diol. Synthesis of cis-(lS)-l-[l-[3-(fluoromethyl)-3-methylsulfonyl- cyclobutyl]triazol-4-yl] ethanol (Tail group T-8) m-CPBA DCM, 0 °C, 1 h LAH THF, 0 °C, 1 h OH OTBS PAST THF, 0 °C, 2 h OTBS TBAF THF, rt, 0.5 h Step 1: tert-butyl 3-hydroxycyclobutanecarboxylate: To a solution of tert-butyl 3-oxocyclobutanecarboxylate (5 g, 29.38 mmol) in methyl alcohol (100 mL) was added NaBH4 (1.7 g, 44.94 mmol) at 0 °C. The reaction was stirred at 25 °C for 2 h. The reaction was quenched with NH4CI, then diluted with water (50 mL) and extracted with dichloromethane (100 mLx3).The organics were washed with brine ( 30 mLx2), dried over sodium sulfate, fdtered and concentrated under reduced pressure to afford crude tert-butyl 3-hydroxycyclobutanecarboxylate (5 g, 29.033 mmol, 98.8 % yield) as yellow oil. 1H NMR (400 MHz, CDCh-d) 5 4.23 -4.13 (m, 1H), 2.68 - 2.44 (m, 3H), 2.15 - 2.06 (m, 2H), 1.46 (s, 9H). Step 2: tert-butyl 3-methylsulfonyloxycyclobutanecarboxylate: To a solution of tert-butyl 3-hydroxycyclobutanecarboxylate (5 g, 29.03 mmol) and triethylamine (12.11 mL, 87.1 mmol) in dichloromethane (150 mL) was added MsCl (3.78 mL, 48.8 mmol) dropwise at 0 °C. Then the reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with ice water (50 mL) and saturated NaHCOs aqueous solution (10 mL). The mixture was extracted with dichloromethane (100 mL*3). The combined organics were washed with brine (30 mLx2), dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure to afford crude tert-butyl 3-methylsulfonyloxycyclobutanecarboxylate (7.2 g, 28.764 mmol, 99.1% yield) as a colorless oil. Tf NMR (400 MHz, CDCh-d) 5 4.97 - 4.85 (m, 1H), 3.00 (s, 3H), 2.72 - 2.61 (m, 3H), 2.57 - 2.46 (m, 2H), 1.45 (s, 9H). Step 3: tert-butyl 3-azidocyclobutanecarboxylate: To a stirred solution of tertbutyl 3-methylsulfonyloxycyclobutanecarboxylate (7.2 g, 28.76 mmol) in DMF (100 mL) was added NaNs (2.75 g, 42.3 mmol), and the mixture was stirred at 80 °C for 12 h. After cooling to 25 °C, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (100 mLx3).The organics were washed with brine (50 mLx2), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude tert-butyl 3-azidocyclobutanecarboxylate (5.6 g, 28.393 mmol, 98.7% yield) as a yellow oil. The aqueous layer was quenched with NaClO aq. solution. 'H NMR (400 MHz, CDCh-t / ) 5 2.99 (s, 1H), 2.71 - 2.60 (m, 1H), 2.56 - 2.49 (m, 2H), 2.39 - 2.23 (m, 2H), 1.45 (s, 9H). Step 4: tert-butyl 3-[4-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]cyclobutanecarboxylate: To a solution of CuSO4 (1.59 g, 7.1 mmol) in tert-butyl methyl ether (80 mL) and water (20 mL) was added tert-butyl 3-azidocyclobutanecarboxylate (5.6 g, 28.39 mmol), sodium ascorbate (1.4 g, 7.1 mmol) and tert-butyl-dimethyl-[(lS)-l-methylprop-2-ynoxy]silane (5.23 g, 28.39 mmol). The mixture was stirred at 20 °C for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mLx2). The combined organic layers were washed with brine (50 mLx2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (solvent gradient: 5% ethyl acetate in petroleum ether) to afford tertbutyl 3-14-1 (LS)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl]cyclobutanecarboxylate (7.2 g, 18.869 mmol, 66.5% yield) as a colorless oil. 'H NMR (400 MHz, CDCh-d) 5 7.41 (s, 1H), 5.18 (quin, J= 8.0 Hz, 1H), 5.10 (q, J= 6.4 Hz, 1H), 3.22 - 3.08 (m, 1H), 2.99 - 2.84 (m, 2H), 2.84 - 2.76 (m, 2H), 1.52 (s, 3H), 1.50 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.04 (s, 3H). LCMS M / Z (M+H)+ = 382.3. Step 5: tert-butyl l-methylsulfanyl-3-[4-[(lS)-l-[tert- butyl(dimethy I) silyl] oxy ethyl] triazol-1-yl] cyclobutanecarboxy late: To a solution of tert-butyl 3-[4-[( IS)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 - yl]cyclobutanecarboxylate (3.0 g, 7.86 mmol) in tetrahydrofuran (40 mL) was added LiHMDS (7.86 mL, 15.72 mmol, 2 M in hexanes) at -78 °C slowly. The mixture was stirred at -78 °C for 30 minutes before the addition of methyl methanethiosulfonate (1.62 mL, 15.72 mmol) slowly at -78 °C. The mixture was stirred at -78 °C for 1 hour. The reaction was terminated with aqueous solution of NH4CI. The resulting solution was extracted with ethyl acetate (3x10 mL), and the organic layers were washed with brine (5 mix2), dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography (solvent gradient: 50% ethyl acetate in petroleum ether) to afford tert-butyl l-methylsulfanyl-3-[4-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]cyclobutanecarboxylate (1.38 g, 3.2267 mmol, 41% yield) as a colorless oil. LCMS (ESI): [M+H]+ = 428.3. Step 6: tert-butyl l-methylsulfonyl-3-[4-[(lS)-l-[tert- butyl(dimethy I) silyl] oxy ethyl] triazol-1-yl] cyclobutanecarboxy late: To a solution of tert-butyl 1 -methylsulfanyl-3-[4-[( IS)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl]cyclobutanecarboxylate (1.38 g, 3.23 mmol) in dichloromethane (20 mL) was added 3-chloroperoxybenzoicacid (1.97 g, 9.68 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction was terminated with aqueous solution of Na2SO3 and aq. NaHCOs. The resulting solution was extracted with dichloromethane (3x10 mL), and the organic layers were washed with brine (5 mlx2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (solvent gradient: 0-25% methyl alcohol in dichloromethane) to afford tert-butyl l-methylsulfonyl-3-[4-[(lS)-l-[tert-butyl (dimethyl) silyl]oxyethyl]triazol-l-yl]cyclobutanecarboxylate (1.4 g, 3.0456 mmol, 94.4% yield) as a yellow oil. Mixture of cis and trans: 1H NMR (400 MHz, CDCh-t / ) 5 7.78 (s, 1H), 7.44 (s, 1H), 5.36 - 5.26 (m, 2H), 5.21 - 5.04 (m, 4H), 3.48 - 3.39 (m, 2H), 3.38 - 3.30 (m, 4H), 3.26 (d, J= 8.8 Hz, 2H), 3.10 (s, 3H), 3.05 (s, 3H), 1.59 (s, 9H), 1.55 (s, 9H), 1.53 (d, 7= 2.4 Hz, 3H), 1.52 (d, . / = 2.8 Hz, 3H), 0.91 (s, 18H), 0.11 (s, 6H), 0.06 (s, 6H). LCMS M / Z (M+H)+= 460.2. Step 7: [l-methylsulfonyl-3-[4-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]cyclobutyl]methanol: To a solution of tertbutyl 1 -methylsulfonyl-3-[4-[( IS)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl]cyclobutanecarboxylate (1.4 g, 3.1 mmol) in anhydrous tetrahydrofuran (20 mL) was added LiAlH4 (231 mg, 6.1 mmol) in portions. The resulting mixture was stirred at 0 °C for 1 h. The mixture was quenched by 2 N NaOH aq. solution carefully and dried with Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (070% ethyl acetate in petroleum ether) to afford ((lS,3r)-3-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -(methylsulfonyl)cyclobutyl)methanol methanol (550 mg, 1.4 mmol, 46.4% yield) as a colorless oil and ((U?,35')-3-(4-((S)-l-((rert-butyldimethylsilyl)oxy)ethyl)-12 / -l,2,3-triazol-l-yl)-l-(methylsulfonyl)cyclobutyl)methanol (450 mg, 1.2 mmol, 37.9% yield) as a colorless oil. / ram-isomer: 'HNMR (400 MHz, CDCL-T) 5 7.44 (s, 1H), 5.21 (quin, J = 8.4 Hz, 1H), 5.12 (q, J= 6.4 Hz, 1H), 4.35 -4.19 (m, 2H), 3.26 - 3.13 (m, 2H), 3.06 (s, 3H), 3.11-2.94 (m, 2H), 1.51 (d, 7= 6.4 Hz, 3H), 0.91 (s, 9H), 0.11 (s, 3H), 0.05 (s, 3H). LCMS M / Z (M+H)+ = 390. cA-isomer: 'HNMR (400 MHz, CDCh-7) 5 7.82 (s, 1H), 5.34 - 5.28 (m, 1H), 5.10 (q, J= 6.4 Hz, 1H), 4.21 (s, 2H), 3.20 - 3.06 (m, 2H), 2.98 (s, 3H), 2.92 - 2.84 (m, 2H), 1.53 (d, J= 6.4 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). LCMS M / Z (M+H)+=390. Step 8: cis-tert-butyl-dimethyl-[(lS)-l-[l-[3-(fluoromethyl)-3-methylsulfonyl-cyclobutyl]triazol-4-yl] ethoxy] silane: under nitrogen, to a solution of cA-[l-methylsulfonyl-3-[4-[( IS)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl]cyclobutyl]methanol (100 mg, 0.26 mmol) in dichloromethane (2.5 mL) was added DAST (0.14 mL, 1.03 mmol) at -78 °C. Then the reaction mixture was allowed to stir for 2 h at 25 °C. The reaction mixture was quenched with NaHCOs (a.q. 5 mL). The resulting mixture was extracted with dichloromethane (3x5 mL) and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (40% ethyl acetate in petroleum ether) to afford cA-tert-butyl-dimethyl-[(lS)-l-[l-[3-(fluoromethyl)-3-methylsulfonyl- cyclobutyl]triazol-4-yl]ethoxy]silane (35 mg, 0.0894 mmol, 34.8% yield) as a yellow oil. LCMS M / Z (M+H)+= 392.2. Step 9: cis-(lS)-l-[l-[3-(fluoromethyl)-3-methylsulfonyl-cyclobutyl]triazol-4-yl]ethanol (Tail group T-8): to a solution of fert-butyl-dimethyl-[(lS)-l-[l-[3-(fluoromethyl)-3-methylsulfonyl-cyclobutyl]triazol-4-yl]ethoxy]silane (35.0 mg, 0.09 mmol) in tetrahydrofuran (1 mL) was added TBAF (0.13 mL, 0.1300 mmol, 1 M in THF) at 0 °C. The mixture was stirred at 25 °C for 2 h. LCMS (ESI)[M+H]+= 278.1. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mLx3).The organics were washed with brine (5 mLx2), dried over sodium sulfate, fdtered and concentrated under reduced pressure to afford crude cis-{IS)-1 -[ 1 -[3-(fluoromethyl)-3-methylsulfonyl-cyclobutyl]triazol-4-yl]ethanol (24 mg, 0.0865 mmol, 96.8% yield) as a colorless oil, which was pure enough for next step. LCMS M / Z (M+H)+= 278.1. Synthesis of trans fS)-l-(l-(3-(difluoromethyl)-3-(methylsulfonyl)cyclobutyl)-lH-l,2,3-triazol-4-yl)ethan-l-ol (Tail group T-9) Step 1: trans-3-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-l-(methylsulfonyl)cyclobutane-l-carbaldehyde'. To a solution of [1-methylsulfonyl-3-[4-[( IS)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl]cyclobutyl]methanol (100.0 mg, 0.260 mmol., T-8 step 7) in dichloromethane (10 mL) was added DMP (436 mg, 1.0 mmol) at 0 °C. Then the mixture was stirred at 20 °C for 2 hours. The mixture was adjusted to pH = 7 with saturated NaHCOs solution at 0 °C, then saturated Na2SOs (2 mL) and Na2S2O3 (2 mL) were added. The mixture was stirred at r.t. for 60 min, then was extracted with dichloromethane (10 mLx3). The combined extracts were washed with brine (10 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by chromatography on silica (solvent gradient: 80% ethyl acetate in petroleum ether) to afford [1-methylsulfonyl-3-[4-[( IS)-1 -| / c / 7-butyl(dimcthyl )silyl |oxycthyl |triazol-1 -yl]cyclobutyl]methanediol (70 mg, 67.2% yield) as a colorless oil. LCMS M / Z (M+H)+= 406.1. Step 2: trans-4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-l-(3-(difluoromethyl)-3-(methylsulforiyl)cyclobutyl)-lH-l,2,3-triazole: to a mixture of trans-3 -(4-((5)-1 -(( / m-butyldimcthyl si lyl )oxy (ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -(methylsulfonyl)cyclobutane-l-carbaldehyde (70.0 mg, 0.17 mmol) in dichloromethane (8 mL) was added DAST (0.09 mL, 0.69 mmol) at -78 °C, and the mixture was stirred at 25 °C for 2 hours. The mixture was quenched by adding saturated NaHCOs (10 mL) slowly, and then extracted with dichloromethane (3 mLx2). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica (solvent gradient: 60% ethyl acetate in petroleum ether) to afford trans-4-((5)-l-((tert-butyldimethylsilyl)oxy)ethyl)-3 -(difluoromethyl)-3(methylsulfonyl)cyclobutyl)-lH-l,2,3-triazole (60 mg, 84.9% yield) as a colorless oil. LCMS M / Z (M+H)+ = 410.1. Step 3: trans-(S)-l-(l-(3-(difluoromethyl)-3-(methylsulfonyl)cyclobutyl)-lH-l,2,3-triazol-4-yl)ethan-l-ol (Tail group T-9): To a solution of trans-4-((5)- \-fiert-butyldimethylsilyl)oxy)ethyl)-3-(difluoromethyl)-3(methylsulfonyl)cyclobutyl)-lH-1,2,3-triazole (75.0 mg, 0.180 mmol) in tetrahydrofuran (8 mL) was added TBAF (0.37 mL, 0.370 mmol, 1 M in THF). The mixture was stirred at 20 °C for 2 hours. The TLC (petroleum ether / EE (25% ethanol in ethyl acetate) = 2 / 1, Rf = 0.2) indicated the reaction was completed. Water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (5 mLx2). The combined organic layers were washed with water (5 mLx2) and brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product tra«5'-(5)-l-(l-(3-(difluoromethyl)-3-(methylsulfonyl)cyclobutyl)-lH-l,2,3-triazol-4-yl)ethan-l-ol (40 mg, 74% yield) was used for next step directly without further purification. Synthesis of (S)-l-(l-((lr, 3S)-3-methyl-3-(methylsulfonyl)cyclobutyl)-lH-1,2,3-triazol-4-yl)ethan-l -ol (Tail group T-10) Step 1: trans-4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-3-(iodomethyl)-3- (methylsulfonyl)cyclobutyl)-lH-l,2,3-triazole: trara-[l-Methylsulfonyl-3-[4-[(15)-l- [tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]cyclobutyl]methanol (100.0 mg, 0.26 mmol, T-8 step 7) was dissolved in dichloromethane (4 mL), then triphenylphosphine (134.65 mg, 0.51 mmol), iodine (130.3 mg, 0.51 mmol) and imidazole (52.42 mg, 0.77 mmol) were added sequentially. The resulting mixture was stirred at 25 °C for 16 h. The mixture was quenched with ammonium chloride (10 mL) and diluted with dichloromethane (10 mL). After phase separation, the organic layer was washed with sodium thiosulfate (10 mL), water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica (solvent gradient: 50% ethyl acetate in petroleum ether) to afford trans1-4-((5)-l-((tert-butyldimethylsilyl)oxy)ethyl)-3-(iodomethyl)-3-(methylsulfonyl)cyclobutyl)-lH-l,2,3-triazole (140 mg, 0.28 mmol, 72.8% yield) as a white solid. 1HNMR(400 MHz, CDCh) 5 7.54 (s, 1H), 5.31 - 5.18 (m, 1H), 5.10 (q, J= 6.4 Hz, 1H), 3.85 (s, 2H), 3.31 - 3.20 (m, 2H), 3.20 - 3.08 (m, 2H), 3.07 (s, 3H), 1.53 (d, J= 6.4 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). LCMS M / Z (M+H)+ = 500. Step 2: trans-4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-3-(methylsulfonyl)cyclobutyl)-lH-l,2,3-triazole: A solution of trans-4-((S)-l -((tertbutyl dimethylsilyl)oxy)ethyl)-3 -(iodomethyl)-3 -(methylsulfonyl)cyclobutyl)-1H-1,2,3-triazole (120.0 mg, 0.24 mmol), 10% palladium on carbon (3.85 mg, 0.0200 mmol) and triethylamine (0.05 mL, 0.36 mmol) in methyl alcohol (1mL) was stirred under H2 (15 Psi) at 25 °C for 1 h. After filtration, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography (50% ethyl acetate in petroleum ether) to give trans-4-((5)-1 -((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-3-(methylsulfonyl)cyclobutyl)-lH-l,2,3-triazole (50 mg, 0.1338 mmol, 55.7% yield) as a colorless oil. LCMS M / Z (M+H)+ = 374. Step 3: trans-(S)-l-(3-methyl-3-(methylsulfonyl)cyclobutyl)-lH-l, 2,3-triazol-4-yl)ethanol (Tail group T-10): To a solution of trans-4-((S)-\-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-3-(methylsulfonyl)cyclobutyl)-lH-l,2,3-triazole (70.0 mg, 0.19 mmol) in tetrahydrofuran (2 mL) was added TBAF (0.28 mL, 0.28 mmol, 1 M in THF) at 0 °C . The mixture was stirred at 25 °C for 2 h. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mLx3). The organics were washed with brine ( 5 mLx2), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude trans-(S)-l-(3-methyl-3- (methylsulfonyl)cyclobutyl)-lH-l,2,3-triazol-4-yl)ethanol (48 mg, 0.1851 mmol, 98.8% yield) as a colorless oil, which was pure enough for next step. LCMS M / Z (M+H)+=260. Synthesis of (1S, 3r)-3-(4-((S)-l-hydroxyethyl)-lH-l, 2,3-triazol-l- yl)cyclobutane-l-carbonitrile (Tail group T-ll) o n3-s-f o OTBS KHCO3 ---------------► n3'" DMF / MTBE / H2O, 0 °C, 1 h sodium ascorbate, CUSO4 f-Bu0H / H20, rt, 12 h TBAF THF, rt, 1 h T-11 (1 S,3r)-3-(4-((S)-1 -hydroxy ethyl)- 1H-1,2,3-triazol-1 -yl)cyclobutane-1 -carbonitrile T-l 1 was prepared in a similar fashion as T-L Synthesis of tail group T-12 NaN- MTBE / MeCN / H2O 0 °C, 10 min N3-S-F o Step 1: sulfurazidic fluoride: To a solution of sodium azide (220 mg, 3.38 mmol) in water (1 mL) and MTBE (2 mL) was added a solution of l-(fluorosulfuryl)-2,3 -dimethyl-lH-imidazol-3-ium trifluoromethane sulfonate (650 mg, 1.97 mmol) in MeCN (1 mL) slowly at 0 °C. The mixture was stirred at 0 °C for 10 min. Then the mixture was allowed to warm to room temperature, then the organic phase was separated from the aqueous phase, and this organic phase containing sulfurazidic fluoride was used directly in the next step as a solution in MTBE without further purification. Step 2: 3-azidobicyclo[1.1.1]pentane-1 -carbonitrile: To a solution of3-aminobicyclo[ 1.1.1]pentane-1-carbonitrile hydrochloride (200 mg, 1.38 mmol) in DMF (1 mL) was added FSO2N3 (MTBE solution prepared from above step) and sat. KHCO3 aqueous solution (1 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, then the entire mixture was carried on directly to the next step without further purification. Step 3: (S)-3-(4-(l-hydroxyethyl)-lH-l, 2,3-triazol-l-yl)bicyclo[l. 1.1]pentane-1-carbonitrile T-12: To the mixture containing 3-azidobicyclo[l.l.l]pentane-l-carbonitrile (185 mg, 1.38 mmol) obtained from above step was added sodium ascorbate (54.6 mg, 0.28 mmol), CuSO4 (44 mg, 0.28 mmol) and (5)-(-)-3-butyn-2-ol (290 mg, 4.14 mmol). The mixture was stirred at 25 °C for 16 h. The reaction was then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography (25% ethyl acetate in petroleum ether) to give 3-[4-[(lS)-l-hydroxyethyl]triazol-l-yl]bicyclo[l.l.l]pentane-l-carbonitrile (T-12, 240 mg, 1.17 mmol, 85% yield) as a white solid. LCMS M / Z (M+H) 204.9. Synthesis of tail group T-13 NH4CI, HATU, DIPEA DMF, ri, 2 h HCI MeOH, rt, 1 h O 0 KHCO3 □ MF / MTBE / H2O, 0 °C, 1 h OTBS t-BuOH / H2O, rt, 16 h sodium ascorbate, CUSO4 TBAF THF, rt, 2 h Step 1: tert-butyl (4-carbamoylbicyclo[2.1.1]hexan-l-yl)carbamate: To a solution of NH4CI (177.3 mg, 3.32 mmol), 4-(tert-butoxycarbonylamino)bicyclo [2.l.l]hexane-l-carboxylic acid (400 mg, 1.66 mmol) and HATU (693.4 mg, 1.82 mmol) in DMF (6 mL) was added DIPEA (0.82 mL, 4.97 mmol). The solution was stirred for 2 h at 25 °C. The TLC (20% EE (25% ethanol in ethyl acetate) in petroleum ether, Rf = 0.5) showed the starting material was consumed and a new spot appeared. The reaction was then diluted with water and extracted with ethyl acetate. The organic layers was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (90% EE (25% ethanol in ethyl acetate) in petroleum ether) to afford tert-butyl A-(4-carbamoyl-l-bicyclo[2.1.1]hexanyl)carbamate (320 mg, 1.33 mmol, 80% yield) as a white solid. LCMS M / Z (M-56) 184.8. JHNMR(400 MHz, DMSO- J6) 5 7.32 (s, 1H), 7.15-6.71 (m, 2H), 2.00-1.85 (m, 2H), 1.69 (s, 4H), 1.48 (s, 2H), 1.37 (s, 9H). Step 2: 4-aminobicyclo [2.1. l]hexane-l-carboxamide hydrochloride: A solution of tert-butyl A-(4-carbamoyl-l-bicyclo [2.1. l]hexanyl)carbamate (320 mg, 1.33 mmol) in HCl / dioxane (4 M, 10 mL) was stirred at 25 °C for 1 h. The TLC (10% methanol in dichloromethane, Rf = 0.1) showed anew spot. The reaction mixture was concentrated under reduced pressure. The resulting residue was used for next step directly. Step 3: (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl) bicyclo[2.1.1 ]hexane-1-carboxamide: 4-[4-[(15)-l-[tert-Butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]bicyclo[2.1.l]hexane-l-carboxamide (240 mg, 0.68 mmol) was made in a similar fashion as T-12 via diazo transfer and click reactions. LCMS M / Z (M+H) 351.1. Step 4: (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl) bicyclo[2.1.1]hexane-1-carbonitrile: To a solution of 4-[4-[( 15)-1-[tert-butyl (dimethyl)silyl]oxyethyl]triazol-l-yl]bicyclo [2.1. l]hexane-l-carboxamide (220 mg, 0.63 mmol) and pyridine (0.26 mL, 3.1 mmol) in DCM (12 mL) was added TFAA (0.27 mL, 1.9 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 3 h. The reaction was then diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10% EE (25% ethanol in ethyl acetate) in petroleum ether) to afford 4-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl] triazol-l-yl]bicyclo[2.1.1]hexane-l-carbonitrile (190 mg, 0.57 mmol, 91% yield) as a white solid. 'H NMR (400 MHz, DMSO-Jd) 5 8.13 (s, 1H), 5.02 (q, J= 6.4 Hz, 1H), 2.66 (s, 2H), 2.30-2.24 (m, 2H), 2.24-2.17 (m, 4H), 1.43 (d, J= 6.4 Hz, 3H), 0.85 (s, 9H), 0.07 (s, 3H), 0.00 (s, 3H). LCMS M / Z (M+H) 333.2. Step 5: (S)-4-(4-(l-hydroxyethyl)-lH-l, 2,3-triazol-l-yl)bicyclo[2.1.1]hexane-1-carbonitrile T-13. To a solution of (5)-4-(4-( l-Hydroxycthyl)-IH-1.2.3-triazol-l-yl)bicyclo[2.1.1] hexane -1-carbonitrile (40.0 mg, 0.12 mmol) in THF (3 mL) was added TBAF (0.23 mL, 1 M in THF) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was used for next step directly. LCMS M / Z (M+H) 218.9. Synthesis of tail group T-14 NH4CI, HATU, DIPEA DMF, rt, 16 h pyridine, TFAA 0 °C, 1 h Step 1: (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-oxabicyclo[2.1. l]hexane-l-carboxylic acid: To a solution of ethyl 4-[4-[( 15)-1-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo [2.1.l]hexane-l-carboxylate (200 mg, 0.52 mmol, prepared in a similar fashion as T-12 via diazo transfer and click reactions) in THF (4 mL), MeOH (2 mL) was added Li OH (87.98 mg, 2.1 mmol) in water (1 mL). The mixture was stirred at 25 °C for 1 h. TLC (petroleum ether / ethyl acetate = 1 / 1, Rf = 0.2) showed the starting material was consumed and a new spot appeared. The reaction mixture was adjusted to pH = 2 with 1 M HCl(aq). Then the mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated to afford crude 4-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo[2.1. l]hexane-l-carboxylic acid (180 mg, 0.509 mmol, 97% yield) as a white solid. LCMS M / Z (M+H) 354.1. Step 2: (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-oxabicyclo[2.1. l]hexane-l-carboxamide: To a solution of NH4CI (54.48 mg, 1.02 mmol), 4-[4-[( 15)-1- [tert-butyl(dimethyl) silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo[2.1.1]hexane-l-carboxylic acid (180 mg, 0.51 mmol) and HATU (212.98 mg, 0.56 mmol) in DMF (4 mL) was added DIEA (0.25 mL, 1.53 mmol) and the solution was stirred for 2 h at 25 C. The reaction was then diluted with water with extracted by ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtrated and concentrated to afford 4-[4-[( 15)-1 -[tertbutyl (dimethyl)silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo [2.1.1] hexane-1-carboxamide (170 mg, 0.482 mmol, 94% yield) as a yellow solid. LCMS M / Z (M+H) 354.1. 'H NMR (400 MHz, DMSO-Je) 5 8.30 (s, 1H), 7.60-7.37 (m, 2H), 5.04 (q, J= 6.4 Hz, 1H), 4.30-4.22 (m, 2H), 2.75 (t, J= 5.2 Hz, 2H), 2.32-2.27 (m, 2H), 1.44 (d, J = 6.4 Hz, 3H), 0.86 (s, 9H), 0.08 (s, 3H), 0.02 (s, 3H). Step 3 & 4: (S)-4-(4-(l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)-2-oxabicyclo[2.1.1]hexane-l-carbonitrile: 4-[4-[( 15)-1 -hydroxyethyl]triazol-1 -yl]-2-oxabicyclo[2.1.1]hexane-l-carbonitrile (T-14, 45 mg, 0.2 mmol, 85% yield, white solid) was prepared in a similar fashion as T-13. LCMS M / Z (M+H) 220.8. Synthesis of tail group T-15 4-(4-((S)-l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)-2-oxabicyclo[2.2.1]heptane-l-carbonitrile T-15 was prepared in a similar fashion to T-13. LCMS M / Z (M+H) 234.8. Synthesis of tail group T-16 sodium ascorbate, CuSO4 t-BuOH / H2O, rt, 16 h CbzHN Pd / C, H2 MeOH, 2 h ii n3-S-F 0 KHCO3 DMF / MTBE / H2O, 0°C; 1 h OTBS DPPA, BnOH, TEA toluene, 90 °C, 16 h DMP DCM, 0°C~ rt, 2h MeNO2, KOtBu THF / LBuOH, 0 ~ rt, 1.5 h MsCI, TEA DCM -78 °C - rt, 2 h NaBH4 EtOH, 0 °C ~ rt, 1 h Fe / NH4CI EtOH / H2O, 80 °C, 1 h 5% TFA in HFIP triphosgene, EtsN DCM, 0 °C - rt, 1 h TBAF THF, 0 °C - rt, 2 h Step 1: tert-butyl 4-(((benzyloxy)carbonyl)amino)-l-(hydroxymethyl)-2-azabicyclo[2.1. l]hexane-2-carboxylate: To a solution of 2-tert-butoxycarbonyl-l-(hydroxymethyl)-2-azabicyclo [2.1.1]hexane-4-carboxylic acid (2.0 g, 7.77 mmol) in toluene (80 mL) was added benzyl alcohol (1.6 mL, 15.55 mmol), DPPA (2.5 mL, 11.66 mmol) and triethylamine (3.2 mL, 23.32 mmol). The mixture was heated to 100 C and stirred for 16 hs. The solvent was removed under reduced pressure, and the residue was purified directly by flash chromatography (30% ethyl acetate in petroleum ether) to afford the title compound (2 g, 71% yield) as a yellow oil. 'H NMR (400 MHz, CDCh) 5 7.43-7.32 (m, 5H), 5.24 (br s, 1H), 5.10 (s, 2H), 3.96 (s, 2H), 3.50 (s, 2H), 2.01 (s, 4H), 1.46 (s, 9H). LCMS [M-fBu+H]+= 306.9. Step 2: tert-butyl 4-amino-l-(hydroxymethyl)-2-azabicyclo [2.1.1] hexane-2-carboxylate: To a solution of tert-butyl 4-(benzyloxycarbonylamino)-l-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.0 g, 5.52 mmol) in methyl alcohol (80 mL) was added 10% palladium (0.6 g, 0.560 mmol). The mixture was stirred at 25 C for 1 h under hydrogen balloon (15 psi). The reaction was filtered and concentrated to afford crude title compound (1.1g, 87% yield) as yellow oil, which was carried on without further purification. 1H NMR (400 MHz, DMSO-r / e) 5 4.61 (brs, 1H), 3.80 (d, J=5.6 Hz, 2H), 3.08 (s, 2H), 2.25 (s, 2H), 1.66 (s, 2H), 1.501.42 (m, 2H), 1.39 (s, 9H). Step 3 & 4: tert-butyl 4-azido-l-(hydroxymethyl)-2-azabicyclo[2.1. l]hexane-2-carboxylate: The title compound was prepared in a similar fashion to T-12 via diazo transfer and click reactions from corresponding amine and alkyne. Step 5: tert-butyl (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-formyl-2-azabicyclo[2.1.1]hexane-2-carboxylate: To a solution of tertbutyl 4-[4-[(IS)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl] -1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.0 g, 2.28 mmol) in DCM (30 mL) was added DMP (1.93 g, 4.56 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h, then sat. Na2S2O3(aq) (20 mL) and aq. sat. NaHCOs (20 mL) were added, and the mixture was stirred at room temperature for 30 min. After phase separation, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate in petroleum ether) to afford tert-butyl 4-[4-[( 15)-1 -[tertbutyl (dimethyl)silyl]oxyethyl]triazol-1 -yl] -1 -formyl-2-azabicyclo [2.1. l]hexane-2-carboxylate (800 mg, 1.83 mmol, 80 % yield) as a colorless oil. 'H NMR (400 MHz, CDCh) 5 9.94 (s, 1H), 7.48 (s, 1H), 5.12 (q, J= 6.4 Hz, 1H), 4.01 (s, 2H), 2.66 (s, 2H), 2.39 (dd, J= 1.6, 4.4 Hz, 2H), 1.53 (d, J= 6.4 Hz, 3H), 1.50 (s, 9H), 0.92 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). LCMS M / Z (M+H) 437.2. Step 6: tert-butyl 4-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-(l -hydroxy-2-nitroethyl)-2-cizabicyclo[2.1.1 ]hexcine-2-ccirboxylate: To a solution of tert-butyl 4-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-l-formyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (800 mg, 1.83 mmol) and nitromethane (660 mg, 10.81 mmol) in THF (45 mL) and tBuOH (15 mL) was added t-BuOK (0.37 mL, 0.37 mmol, IM in THF) dropwise at 0 °C. Then the mixture was stirred at 0 °C for 1 h, then the reaction was diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (40% ethyl acetate in petroleum ether) to afford tert-butyl 4-[4-[(lS)-1 -[tert-butyl(dimethyl)silyl] oxyethyl]triazol-1 -yl] -1-(1 -hydroxy-2 -nitro-ethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (800 mg, 1.6 mmol, 88% yield) as a colorless oil. 'HNMR (400 MHz, CDCh) 5 7.48 (s, 1H), 5.44 (s, 1H), 5.13 (q, J= 6.4 Hz, 1H), 4.99-4.86 (m, 1H), 4.81-4.71 (m, 1H), 4.67-4.54 (m, 1H), 4.01-3.80 (m, 2H), 2.47 (m, J= 5.6 Hz, 2H), 2.44-2.35 (m, 1H), 2.33-2.23 (m, 1H), 1.54-1.51 (m, 12H), 0.92 (s, 9H), 0.13 (s, 3H), 0.07 (s, 3H). LCMS M / Z (M+H) 498.7. Step 7: tert-butyl (S, E)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-(2-nitrovinyl)-2-azabicyclo [2.1. l]hexane-2-carboxylate: To a solution of tert-butyl 4-[4-[( IS)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol- 1-yl] -1-(1-hydroxy-2-nitro-ethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (800 mg, 1.61 mmol) and triethylamine (0.9 mL, 6.48 mmol) in dry DCM (40 mL) was added MsCl (0.25 mL, 3.22 mmol) at -78 °C. The mixture was stirred for 1 h at -78 °C, before warming to 25 °C, and stirred for another 1 h. The reaction mixture °was quenched by saturated aq. NaHCO? and water, then extracted with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, fdtrated and concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in petroleum ether) to afford the tert-butyl 4-[4-[(IS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl] -1 -[(E)-2-nitrovinyl] -2-azabicyclo[2.1.1]hexane-2-carboxylate (720 mg, 1.50 mmol, 93% yield) as a colorless oil. 'HNMR (400 MHz, CDCh) 5 7.88 (d, J= 13.6 Hz, 1H), 7.48 (s, 1H), 7.08 (d, J= 13.6 Hz, 1H), 5.13 (q, J= 6.0 Hz, 1H), 3.97 (s, 2H), 2.61 (s, 2H), 2.51 (dd, J= 1.2, 4.4 Hz, 2H), 1.53 (d, J= 6.4 Hz, 3H), 1.47 (s, 9H), 0.92 (s, 9H), 0.13 (s, 3H), 0.07 (s, 3H). LCMS M / Z (M+H) 480.3. Step 8: tert-butyl (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-(2-nitroethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate: To a solution of the tert-butyl 4-[4-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-l-[(E)-2-nitrovinyl]-2-azabicyclo[2.1.1]hexane-2-carboxylate (720 mg, 1.5 mmol) in ethanol (50 mL) was added NaBH4 (170.36 mg, 4.5 mmol) at 0 °C. The reaction mixture was then warmed to room temperature and stirred for 1 h. The reaction was quenched with saturated aqueous NH4CI solution, and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (20% ethyl acetate in petroleum ether) to afford the title compound tert-butyl 4-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl] triazol-l-yl]-l-(2-nitroethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (640 mg, 1.3 mmol, 89% yield) as a colorless oil. Tf NMR (400 MHz, CDCh) 5 7.45 (s, 1H), 5.12 (q, J= 6.4 Hz, 1H), 4.67 (t, J= 6.4 Hz, 2H), 3.89 (s, 2H), 2.99 (t, J= 6.4 Hz, 2H), 2.42-2.25 (m, 4H), 1.52 (d, J= 6.4 Hz, 3H), 1.50 (s, 9H), 0.91 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). LCMS M / Z (M+H) 482.3. Step 9: tert-butyl (S)-l-(2-aminoethyl)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate: To a solution of tert-butyl 4-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl] -1 -(2-nitroethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (100 mg, 0.21 mmol) in ethanol (6 mL) and water (2 mL) was addedNH4CI (111 mg, 2.08 mmol) and iron (powder, 115.9 mg, 2.08 mmol) at room temperature. After cooling to 25 °C, the reaction was diluted with water and extracted with di chloromethane. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, which was carried on to the next step without purification. 1H NMR (400 MHz, CDCh) 5 8.47 (s, 2H), 7.50 (s, 1H), 5.12 (q, J= 6.4 Hz, 1H), 3.90 (s, 2H), 3.29 (s, 2H), 2.77 (s, 2H), 2.39 (s, 4H), 1.51 (d, J= 6.4 Hz, 3H), 1.47 (s, 9H), 0.91 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). LCMS M / Z (M+H) 452.3. Step 10: (S)-2-(4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-azabicyclo[2.1.1]hexan-l-yl)ethan-l-amine: A solution of tert-butyl 1-(2-aminoethyl)-4-[4-[(lS)-l-[tert-butyl(dimethyl)silyl] oxyethyl]triazol-l-yl]-2-azabicyclo[2.1.1]exane-2-carboxylate (510 mg, 1.13 mmol) in 5% TFA in HFIP (10 mL) was stirred at 20 °C for 3 hs. The reaction was diluted with water (10 mL), and the pH was adjusted to ~8 by progressively adding solid NaHCOs. The aqueous layer was extracted with DCM. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-[4-[4[(15)-1 -[tert-butyl (dimethyl)silyl] oxyethyl]triazol-1 -yl] -2-azabicyclo [2.1. l]hexan-1 - yl]ethanamine (350 mg, 1.0 mmol, 88.2% yield) as a colorless oil. 'HNMR (400 MHz, CDCh) 5 7.45 (s, 1H), 5.12 (q, J= 6.4 Hz, 1H), 3.48 (s, 2H), 3.05-2.84 (m, 2H), 2.23-2.18 (m, 3H), 2.18-2.12 (m, 1H), 2.51 (d,J= 14.0 Hz, 2H), 1.52 (d,J= 6.4 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). LCMS M / Z (M+H) 352.5. Step 11: (S)-6-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-1-yI) tetrahydro-5H-4a,6-methanopyrrolo[l,2-c]pyrimidin-l(2H)-one: To a stirred solution of 2-[4-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl] -2-azabicyclo[2.1.1]hexan-l-yl]ethanamine (350 mg, Immol) in dichloromethane (10 mL) was added triphosgene (118 mg, 0.40 mmol) at 0 °C. After 10 min, TEA (0.35 mL, 2.49 mmol) was added into the reaction mixture. The resulting mixture was stirred at 25 °C for 1.5 h, then the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (3% dichloromethane in methyl alcohol) to afford the title compound 8-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl] -4,6-diazatricyclo[6.1.1.01,6]decan-5-one (172 mg, 0.456 mmol, 45.8% yield) as a white solid. 'H NMR (400 MHz, CDCh) 5 7.47 (s, 1H), 5.13 (q, J= 6.4 Hz, 1H), 4.03-3.84 (m, 2H), 3.38 (s, 2H), 2.51 (d, J= 10.8 Hz, 2H), 2.39-2.19 (m, 4H), 1.54 (d, J= 6.4 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). LCMS M / Z (M+H) 378.2. Step 12: (S)-6-(4-(l-hydroxyethyl)-lH-l, 2,3-triazol-l-yl)tetrahydro-5H-4a, 6-methanopyrrolo[1,2-c]pyrimidin-l (2H)-one T-16: To a solution of 8-[4-[( 15)-1-[tert-butyl (dimethyl)silyl]oxyethyl]triazol- 1 -yl] -4,6-diazatricyclo[6.1.1.01,6]decan-5-one (70 mg, 0.19 mmol) in THF (8 mL) was added TBAF (0.37 mL, 0.37 mmol, 1 M in THF) at 0 °C. The mixture was stirred at 25 °C for 1 h, then the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtrated and concentrated under reduced pressure to afford crude product T-16, which was carried on to the next step without further purification. LCMS M / Z (M+H) 264.0. Synthesis of tail group T-l 7 OTBS                               OTBS                             OH Mel, NaH Step 1: (S)-6-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-methyltetrahydro-5H-4a, 6-methanopyrrolo[l,2-c]pyrimidin-l(2H)-one: To a solution of 8-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-4,6-diazatricyclo[6.1.1.01,6]decan-5-one (82.0 mg, 0.22 mmol, intermediate prepared from above reaction) in DMF (4 mL) was added NaH (9.56 mg, 0.24 mmol). The reaction was stirred for 30 min at 0 °C under nitrogen, then iodomethane (0.02 mL, 0.33 mmol) was added. The mixture was stirred at 25 °C for 2 hs under nitrogen. The reaction was quenched with NH4CI (10 mL) and diluted with water (10 mL), then the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography (30% EE (25% ethanol in ethyl acetate) in petroleum ether) to afford 8-[4-[( 15)-1 -[tertbutyl (dimethyl)silyl]oxyethyl]triazol-1 -yl] -4-methyl-4,6-diazatricyclo[6.1.1.01,6]decan-5-one (90 mg, 0.229 mmol) as a yellow solid. 'H NMR (400 MHz, CDC13) 5 7.46 (s, 1H), 5.12 (q, J= 6.0 Hz, 1H), 3.90 (s, 2H), 3.31 (t,J = 6.0 Hz, 2H), 2.97 (s, 3H), 2.46 (d, J= 7.2 Hz, 2H), 2.38-2.19 (m, 4H), 1.53 (d, J= 6.4 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). LCMS M / Z (M+H) 392.2. Step 2: (S)-6-(4-(l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)-2-methyltetrahydro-5H-4a,6-methanopyrrolo[l,2-c]pyrimidin-l(2H)-one T-17: To a solution of 8-[4[(15)-1 -| / e / 7-butyl(dimcthyl )silyl |oxycthyl | triazol-1 -yl]-4-methyl-4,6-diazatricyclo[6.1.1.01,6]decan-5-one (90.0 mg, 0.23 mmol) in THF (10 mL) was added TBAF (0.46 mL, 1 M in THF) at 0 °C. The mixture was stirred at room temperature for 1 h, then the reaction was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to afford crude product T-17 which was carried on directly to the next step without purification. LCMS M / Z (M+H) 277.9. Synthesis of tail group T-18 OTBS 5% TFA in HFIP OTBS NaBH(OAc)3, DIEA □CM, rt, 16 h rt, 4 h MeMgBr THF, -78 °C - rt, 16 h DMP DCM, rt, 1 h 3HF«Et3N THF, 50 °C, 1 h Step 1: (S)-(4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-azabicyclo[2.1.1]hexan-l-yl)metanol: A solution of tert-butyl (5)-4-(4-( l-((tert- 5     butyl dimethylsilyl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl)-1 -(hydroxymethyl)-2- azabicyclo[2.1.1]hexane-2-carboxylate (4.6 g, 10.49 mmol) in TFA (30 mL, 5% in HFIP) was stirred at 25 °C for 4 hs. The mixture was adjusted pH to 9 with saturated NaHCO? at 0°C, then the reaction was extracted with DCM. The combined organic phases were dried over sodium sulfate, fdtered and concentrated under reduced 10 pressure. The residue was purified by flash chromatography (0-10% methanol in dichloromethane) to afford the title compound (3 g, 85% yield) as yellow oil. LCMS M / Z (M+H) 339.1 Step 2: (S)-(4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-(oxetan-3-yl)-2-azabicyclo[2.1. l]hexan-l-yl)metanol: A solution of (5)-(4-(4-(1 15 ((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-azabicyclo[2.1.1]hexan-l-yl)methanol (2.5 g, 7.39 mmol), oxetan-3-one (1.6 g, 22.16 mmol) and DIEA (3.8 g, 5.15mL, 29.54 mmol) in DCM (40 mL) was stirred at 25 °C for 2 hs. Then NaBH(OAc)3 (4.7 g, 22.16 mmol) was added. The mixture was stirred at 25 °C for 16 h, then the mixture was diluted with water and extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0-2% methanol in dichloromethane) to afford the title compound (2.3g, 79% yield) as yellow oil. LCMS M / Z (M+H) 395.3 Step 3: (lS)-l-(l-(4-(hydroxymethyl)dihydro-lH,6H-7,8a- methanopyrrolo[2,1-c][1,4]' oxazin-7(8H)-yl)-lH-l,2,3-triazol-4-yl)ethan-l-ol & (7- (4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl) tetrahydro-lH,6H-7,8a-methanopyrrolo[2,1-c] [l,4]oxazin-4-yl)metanol: To a solution of (.8)-(4-(4-( l-(( / c / 7-butyldimcthylsilyl)oxy)cthyl)-l / / -1.2.3-triazol-l-yl)-2-(oxetan-3-yl)-2-azabicyclo[2.1.1]hexan-l-yl)methanol (2.3 g, 5.83 mmol) in DCM (20 mL) was added BF3 Et20 (1.5 mL, 11.66 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with sat. NH4CI (5 mL) and further adjusted pH to 8 with aq. NaHCOs. Then the mixture was extracted with ethyl acetate (50 mL><3). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0 ~ 50% EE (ethyl acetate / ethanol =3 / 1) in petroleum ether) to afford (7-(4-((5)-1 -((tert-butyldimethylsilyl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl) tetrahydro-1 / / . 6 / / -7.8a-mcthanopyrrolo| 2.1-c || 1.4 |oxazin-4-yl)mctanol (840 mg, 36.5% yield) as yellow oil. Tf NMR (400 MHz, CDCI3) 5 7.45 (s, 1H), 5.12 (q, J= 6.4 Hz, 1H), 3.99-3.93 (m, 2H), 3.75-3.67 (m, 2H), 3.65-3.54 (m, 3H), 3.07 (d, J= 8.0 Hz, 1H), 2.91-2.81 (m, 1H), 2.61-2.56 (m, 1H), 2.38 (s, 1H), 2.30-2.26 (m, 1H), 2.222.16 (m, 1H), 2.13-2.08 (m, 1H), 1.52 (d, J= 6.8 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). Additionally, TBS deprotected side product was observed in the water phase, and was obtained by lyophilization and flash chromatography (10% methanol in chloromethane) as a colorless oil (452 mg, 28% yield). This intermediate was then used for T-19. 'H NMR (400 MHz, DMSO-d6) 5 8.09 (s, 1H), 5.26 (d, J= 4.8 Hz, 1H), 4.86 4.77 (m, 1H), 4.62 (t, J= 5.6 Hz, 1H), 4.10 (q, J= 5.2 Hz, 1H), 3.95-3.84 (m, 2H), 3.54 (d, J= 11.6 Hz, 1H), 3.48-3.39 (m, 2H), 3.25-3.17 (m, 2H), 3.00 (br d, J = 8.0 Hz, 1H), 2.73-2.64 (m, 1H), 2.44-2.38 (m, 1H), 2.29-2.25 (m, 1H), 2.04 (d, J= 6.8 Hz, 1H), 1.92-1.89 (m, 1H), 1.40 (d, J= 6.4 Hz, 3H). Step 4: 7-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl) tetrahydro-lH, 6H-7,8a-methanopyrrolo [2,1-c] [1,4] oxazine-4-carbaldehyde: To a solution of (7-(4-((5)-1 -((tert-butyIdimethylsilyl)oxy)ethy 1)- 1H-1,2,3-triazol-1 -yl) tetrahydro-127,627-7,8a-methanopyrrolo[2,1-c] [l,4]oxazin-4-yl)methanol (840 mg, 2.13 mmol), TEA (2585 mg, 25.6 mmol) and DMSO (3992 mg, 51.1 mmol) in DCM (10 mL) was added PySO3(1694 mg, 10.6 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 h. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure to afford the title compound (830 mg, 99% yield, crude) as a yellow oil. Tf NMR (400 MHz, CDCh) 5 9.62 (d, J= 1.2 Hz, 1H), 7.43 (s, 1H), 5.15-5.10 (m, 1H), 4.18-4.13 (m, 1H), 4.01 (d, J= 11.6 Hz, 1H), 3.84 (d, J= 8.8 Hz, 1H), 3.78 (d, J= 11.6 Hz, 1H), 3.51-3.46 (m, 1H), 3.21-3.09 (m, 1H), 2.99-2.95 (m, 1H), 2.55-2.49 (m, 1H), 2.34-2.31 (m, 1H), 2.27-2.22 (m, 1H), 2.16-2.09 (m, 1H), 1.52 (d, J= 6.8 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). Step 5: l-(7-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2,l-c][l,4]oxazin-4-yl)ethan-l-ol: To a solution of 7-(4-((5)-l-((tert-butyldimethylsilyl) oxy)ethyl)-\H-1,2,3-triazol-1 -yl) tetrahydro-127,627-7,8a-methanopyrrolo[2,1 -c] [ 1,4]oxazine-4-carbaldehyde (830 mg, 2.1 mmol) in THF (12 mL) was added MeMgBr (2.1 mL, 6.31mmol, 3 M) at -78 °C. The mixture was slowly warm to 25 °C and stirred for 16 h. The reaction was then quenched with NH4CI (10 mL) and diluted with water (10 mL), then extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0-60% ethyl acetate in petroleum ether) to afford the title compound (483 mg, 56 % yield) as a yellow oil. LCMS M / Z (M+H) 409.2. Step 6: l-(7-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2,1-c] [1,4] oxazin-4-yl)ethcin-l-one: To a solution of 1 -(7-(4-((5)-1 -((tert-butyldimethy 1 silyl)oxy)ethyl)-127-1,2,3 -triazol-1 - yl)tetrahydro-127,627-7,8a-methanopyrrolo[2,1 -c] [ 1,4]oxazin-4-yl)ethan-1 -ol (483 mg, 1.18 mmol) in DCM (8 mL) was added DMP (752 mg, 1.77 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h, and then fdtered, the fdtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (50% ethyl acetate in petroleum ether) to afford the title compound (357 mg, 74% yield) as a yellow oil. LCMS M / Z (M+H) 407.3. Step 7: 2-(7-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2,1-c][1,4]bxazin-4-yl)propan-2-ol: To a stirring solution of l-(7-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-127-l,2,3-triazol-1 -yl)tetrahydro-127,627-7,8a-methanopyrrolo [2,1 -c] [ 1,4] oxazin-4-yl)ethan-1 -one (357 mg, 0.88 mmol) in THF (5 mL) was added MeMgBr (1.5 mL, 4.5mmol, 3 M) at -78 °C. The mixture was slowly warm to 25 °C and stirred for 4 h. The mixture was quenched with NH4CI (10 mL) and diluted with water (5 mL), then extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (318 mg, 86% yield, crude) as a yellow oil. LCMS M / Z (M+H) 423.1. Step 8: (7-(4-((R)-l-((l, 4-dihydro-2H-pyrano[3,4-c]quinolin-9-y I) oxy) ethyl)-1H-1,2,3-triazol-l-yl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2,1-c] [1,4]oxazin-4-yl)methyl methane sulfonate T-18: To a solution of 2-(7-(4-((5)-1-((tert-butyl dimethylsilyl)oxy)ethyl)- 127-1,2,3 -triazol-1 -yl)tetrahydro- 127,627-7,8a-methanopyrrolo[2,l-c][l,4]oxazin-4-yl)propan-2-ol (303 mg, 0.72 mmol) in THF (5 mL) was added 3HF -EtsN (2 mL) at 0 °C. The mixture was stirred at 50 °C for 1 h. The mixture was adjusted pH to 9 with saturated NaHCO? at 0 °C. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (10% methanol in chloromethane) to afford the title compound T-18 (164 mg, 74% yield) as colorless oil. LCMS M / Z (M+H) 309.2. Synthesis of tail group T-19 Step 1: l-(l-(4-(hydroxymethyl)dihydro-lH, 6H-7,8a-methanopyrrolo[2,l-e] [1,4] oxazin-7(8H)-yl)-lH-l ,2,3-triazol-4-yl)ethan-l-one: To a solution of l-[l-[5-(hydroxymethyl)-3-oxa-6-azatricyclo [6.1.1.01,6]decan-8-yl] triazol-4-yl]ethanol (422 mg, 1.51 mmol, intermediate prepared from above step) in DCM (10 mL) was added MnO2(1.96 g, 22.6 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h, and then fdtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (10% methanol in dichloromethane) to afford l-[l-[5-(hydroxymethyl)-3-oxa-6-azatricyclo[6.1.1,01,6]decan-8-yl]triazol-4-yl]ethanone (299 mg, 1.074 mmol, 71% yield) as a white solid. LCMS M / Z (M+H) 278.2. Step 2: l-(l-(4-(((tert-butyldimethylsilyl)oxy)methyl)dihydro-lH,6H-7,8a-methanopyrrolo[2,1-c][1,4]' oxazin-7(8H)-yl)-lH-l,2,3-triazol-4-yl)ethan-l-one: To a mixture of imidazole (219.4 mg, 3.22 mmol) and l-[l-[5-(hydroxymethyl)-3-oxa-6-azatricyclo[6.1.1.01,6]decan-8-yl]triazol-4-yl]ethanone (299 mg, 1.07 mmol) in DCM (8 mL) was added TBSC1 (242.9 mg, 1.61 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h, then was quenched with saturated sodium bicarbonate(aq) (5 mL). The resulting solution was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in petroleum ether) to afford l-[l-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-oxa-6-azatricyclo[6.1.1.01,6]decan-8-yl]triazol-4-yl]ethanone (384 mg, 0.978 mmol, 91% yield) as a colorless oil. LCMS M / Z (M+H) 393.2. Step 4: (lS)-l-(l-(4-(((tert-butyldimethylsilyl)oxy)methyl)dihydro-lH, 6H- 7,8a-methanopyrrolo[2,1-c][1,4]oxazin-7(8H)-yl)-lH-l,2,3-triazol-4-yl)ethan-l-ol T-19: Under H2 (15 Psi) atmosphere, a mixture of t-BuOK (16 mg, 0.14 mmol), RuC12[(R)-xylbinap][(R)-daipen](44.18 mg, 0.04 mmol) and 1-[ 1-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-oxa-6-azatricyclo[6.1.1.01,6]decan-8-yl]triazol-4-yl]ethanone (284 mg, 0.72 mmol) in 2-propanol (8 mL) was stirred at 25 °C for 16 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (40% EE (33% ethanol in ethyl acetate) in petroleum ether) to afford (15)-l-[l-[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-oxa-6-azatricyclo[6.1.1.01,6]decan-8-yl]triazol-4-yl]ethanol (T-19, 260 mg, 0.66 mmol, 91% yield) as a yellow solid. LCMS M / Z (M+H) 395.3. Synthesis of tail group T-20 CK N ----------> / -PrOH, rt, 16 h TsCI, tBuOK -------► THF, 0°C, 1 h Step 1: (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxamide: To a mixture of [4-[4[(15)-1 -| / c / 7-butyl(dimcthyl )silyl |oxycthyl | triazol-1 -yl]-2-azabicyclo[2.1. l]hexan-1 -yl]methanol (300 mg, 0.89 mmol) in 2-propanol (8 mL) was added trimethylsilyl isocyanate (0.17 mL, 1.24 mmol) at 0 °C. The reaction was stirred at 25 °C for 3 h, then the reaction was diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the tittle compound (330 mg, crude product) as white solid. LCMS (ESI): [M+H]+= 382.1. Step 2: (S)-6-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-tosyltetrahydro-3H,5H-6,7a-methanopyrrolo[l,2-c]imidazol-3-one: To a solution of 4- [4-[( 15)-1 -[tert-butyl (dimethyl)silyl] oxyethyl]triazol-1 -yl] -1 -(hydroxymethyl)-2- azabicyclo[2.1.1]hexane-2-carboxamide (330 mg, 0.86 mmol) in THF (6 mL) was added / BuOK (291.15 mg, 2.59 mmol). The resulting mixture was stirred at 0 °C for 30 min, then TsCl (247.34 mg, 1.3 mmol) was added. The mixture was stirred at 0 °C for 30 min. The organic solvent was then removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0-10% methanol in dichloromethane) to afford the tittle compound (180 mg, 40% yield) as yellow oil. LCMS: [M+H]+= 518.3 Step 3: (S)-6-(4-(1 -hydroxyethyl)- 1H-1,2,3-triazol-l-yl)-2-tosyltetrahydro-3H,5H-6, 7a-methanopyrrolo[l,2-c]imidazol-3-one T-20: To a solution of7-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-3-(p-tolylsulfonyl)-3,5-diazatricyclo[5.1.1.01,5]nonan-4-one (160 mg, 0.31 mmol) in THF (3 mL) was added TBAF (0.62 mL, 0.62 mmol, 1 M in THF) at 0 °C. The mixture was diluted with water and extracted by ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5% methanol in ethyl acetate) to afford the tittle compound (T-20, 120 mg, 96.2% yield) as a white solid, which was pure enough for next step. LCMS (ESI): [M+H]+= 404.1. Synthesis of tail group T-21 lah , THF, 0 °C, 16 h 5% TFA in HFIP rt, 2 h DCM, 0°C, 1 h Step 1: tert-butyl (2R,4R)-4-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-1,2,3-triazol-l-yl)-2-(hydroxymethyl) pyrrolidine-1-carb oxy late: To a solution of (ISAR)-1 -(tert-butoxycarbonyl)-4-(4-((S)-1 -((tert-butyldimethylsilyl) oxy)ethyl)- IH-l,2,3-triazol-l-yl)pyrrolidine-2-carboxylic acid (460.0 mg, 1.04 mmol, prepared in a similar fashion as T-12 via diazo transfer and click reactions) in THF (1 mL) was added LiAlH4 (59.43 mg, 1.57 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 h. The reaction was quenched with 2 M NaOH (2 mL) and stirred for 15 min, then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product as a colorless oil. LCMS M / Z (M+H) 427.3. Step 2: ((2R, 4R)-4-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)pyrrolidin-2-yl) methanol: A solution of tert-butyl (2 / ?.4 / ?)-4-(4-((.S)-l-((tert-butyldimethylsilyl)oxy)ethyl)- IH-1,2,3 -triazol-1 -yl)-2-(hydroxymethyl)pyrrolidine-l-carboxylate (410.0 mg, 0.96 mmol) in TFA (10 mL, 5% in HFIP) was stirred at 25 °C for 2 h. The reaction was quenched by sat. NaHCO3(aq) solution (8 mL). The resulting solution was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (4% methanol in dichloromethane) to afford ((2 / / .4 / / )-4-(4-((.8)-1 -(( / c / 7-butyldimethylsilyl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl)pyrrolidin-2-yl)methanol (108 mg, 0.33 mmol, 34% yield) as a colorless oil. LCMS M / Z (M+H) 327.2. Step 3: l-((2R,4R)-4-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-(hydroxymethyl) pyrrolidin-l-yl)-2-chloroethan-l-one: To a solution of ((2 / / ,47 / )-4-(4-((5)-1 -((tert-buty Idimethyl si lyl )oxy )ethy 1)- 1H-1,2,3 -triazol-1 -yl)pyrrolidin-2-yl)methanol (108.0 mg, 0.33 mmol) and triethylamine (0.14 mL, 0.99 mmol) in dichloromethane (3 mL) was added chloroacetyl chloride (0.03 mL, 0.36 mmol) at 0 °C. Then the mixture was stirred at 0 °C for 1 h, then was concentrated under reduced pressure and purified by flash chromatography (0.3% methanol in dichloromethane) to afford I-((2 / / .4 / / )-4-(4-((.8)-1-(( / 677-butyldimethylsilyl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-2-(hydroxymethyl)pyrrolidin-1 -yl)-2-chloroethan-l-one (30 mg, 0.074 mmol, 22.5% yield) as a yellow oil. LCMS M / Z (M+H) 403.2. Step 4: (7R,8aR)-7-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH-pyrrolo[2,l-c][1,4]oxazin-4(3H)-one To a solution of 1- ((2 / ?,4 / ?)-4-(4-((S)-1 -(( / m-biityldimcthyl silyl )oxy )cthy I)- IH-1,2,3 -triazol-1 -yl)-2-(hydroxymethyl)pyrrolidin-l-yl)-2-chloroethan-l-one (30.0 mg, 0.07mmol) in THF (1 mL) was added NaH (6.0 mg, 0.15 mmol) at 0 °C. The reaction was allowed to warm to 25 °C and stirred for 16 h. The reaction was then quenched with NH4Cl(aq) (10 ml), and extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (20% EE (25% ethanol in ethyl acetate) in petroleum ether) to afford (lR$aR)-l-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)- IH-1,2,3 -triazol-1 -yl)tetrahydro-1 H-pyrrolo [2,1 -c] [ 1,4] oxazin-4(3 / / )-onc (20 mg, 0.055 mmol, 73.3% yield) as a colorless oil. LCMS M / Z (M+H) 367.2. Step 5: (7R,8aR)-7-(4-((S)-l-hydroxyethyl)-lH-l, 2,3-triazol-l -yl)tetrahydro-lH-pyrrolo[2,1-c][1,4]oxazin-4(3H)-one T-21: To a solution of (7RftaR)-!-(4-((5)-1-(( / c / 7-buty Idimcthy Isi lyl )oxy )cthy I)- IH-1,2,3 -triazol-1 -yl)tetrahydro-1 H-py rrolo [2,1 -c][l,4]oxazin-4(3E7)-one (20.0 mg, 0.05 mmol) in THF (1 mL) was added TBAF (0.11 mL, 0.11 mmol) at 0 °C, then the mixture was allowed to warm to 25 °C and stirred for Ih. The reaction was concentrated under reduced pressure. The residue was purified by flash chromatography (5% methanol in dichloromethane) to afford (1R, ^aR)-!-(4-((5)-1 -hydroxyethyl)- IH-1,2,3-triazol-1 -yl)tetrahydro-1 H-pyrrolo [2,1-c][l,4]oxazin-4(327)-one (T-21, 13 mg, 0.052 mmol, 94.4% yield) as a colorless oil. LCMS M / Z (M+H) 253 .2. Synthesis of tail group T-22 Eto' ., ,, OTBS ,CO2Et Pd / C, H2, 15 psi N- NBoc MeOH, rt, 2 h 5% TFA in HFIP rt, 1 h EtONa, EtOH reflux, 6 h TBAF THF, 0 °C ~ rt, 2 h Step 1: tert-butyl(S,E)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-(3-ethoxy-3-oxoprop-l-en-l-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate: To a mixture of ethyl 2-(diethoxyphosphoryl)acetate (0.12 mL, 0.6 mmol) in THF (1 mL) was added sodium hydride (9 mg, 0.2 mmol) at 0 °C. The resulting solution was stirred for 30 min at 0 °C, then tert-butyl l-formyl-4-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-azabicyclo[2.1.1]hexane-2-carboxylate (200 mg, 0.5 mmol, intermediate prepared from above step) in THF (2 mL) was added at 0 °C. The reaction was stirred for 1 h at 0 °C, then the reaction was quenched by saturated NH4Cl(aq), diluted with water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate, then the combined organic layers were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (20% ethyl acetate in petroleum ether) to afford tert-butyl (5, / :)-4-(4-( I -(( / 677-butyldimethylsilyl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -(3 -ethoxy-3 -oxoprop -1 -en-1 -yl)-2-azabicyclo[2.1. l]hexane-2-carboxylate (70 mg, 0.14 mmol, 30.2% yield) as a colorless oil. LCMS M / Z (M+H) 507. Step 2: tert-butyl (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-(3-ethoxy-3-oxopropyl)-2-azabicyclo[2.1.1]hexcine-2-ccirboxylate: To a solution of tert-butyl4-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-l-[(E)-3-ethoxy-3-oxo-prop-l-enyl]-2-azabicyclo[2.1.l]hexane-2-carboxylate (190.0 mg, 0.37 mmol) in methyl alcohol (3 mL) was added Pd / C (40.71 mg, 10% pure), The mixture was stirred at 25 °C under H2 (15 Psi) for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford crude tert-butyl (5)-4(4-( 1 -((tert-butyldimethylsilyl)oxy)ethyl)-I / / -1,2.3-triazol-1 -yl)-1 -(3 -ethoxy-3 -oxopropyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (60 mg, 0.12 mmol, 31.5% yield) as a colorless oil. LCMS M / Z (M+H) 509. Step 3: ethyl (S)-3-(4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-azabicyclo[2.1.1]hexan-l-yl) propanoate: A solution of tert-butyl 1-(3-ethoxy-3-oxo-propyl)-4-[4-[( 15)-1 -[tert-butyl (dimethyl)silyl]oxyethyl]triazol-1 -yl]-2-azabicyclo[2.1.1]hexane-2-carboxylate (160.0 mg, 0.31 mmol) in 5% TFA in HFIP (5 ml) was stirred at 25 °C for 2 h then the reaction was quenched with NaHCOstaq) (5 mL). The resulting solution was extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (2% methanol in dichloromethane) to afford ethyl (5)-3-(4-(4-(1-(( / c / 7-biityldimcthylsilyl)oxy)cthyl)-1 / / -1,2.3-triazol-1 -yl)-2-azabicyclo|2.1. l]hexan-l-yl)propanoate (40 mg, 0.1 mmol, 31.1% yield) as a colorless oil. LCMS M / Z (M+H) 409.3. Step 4: (S)-2-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl) tetrahydro-lH,5H-2,7a-methanopyrrolizin-5-one: To a solution of ethyl 3-[4-[4-[l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-azabicyclo[2.1.1] hexan-l-yl] propanoate (60 mg, 0.15 mmol) in ethanol (6 mL) was added EtONa (30 mg, 0.45mmol) at 25 °C. The mixture was stirred at 80 °C for 2h, then concentrated under reduced pressure. The residue was purified by flash chromatography (0~2% methanol in dichloromethane) to afford (5)-2-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-1.2.3-tri azol-1-yl)tctrahydro-1 / / .5 / / -2.7a-mcthanopyrrolizin-5-onc (30mg,0.0827mmol, 56.4% yield) as a yellow oil. LCMS M / Z (M+H) 363.1. Step 6: (S)-2-(4-(l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH,5H- 2,7a-methanopyrrolizin-5-one T-22: To a solution of 7-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-5-azatricyclo[5.1.1.01,5]nonan-4-one (10 mg, 0.03 mmol) in THF (1 mL) was added TBAF (0.06 mL, 0.06 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h, then the reaction was quenched by water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (5)-2-(4-(l-hydroxyethyl)-12 / -l,2,3-triazol-l-yl) tetrahydro-I / / .5 / / -2.7a-methanopyrrolizin-5-one ( T-22, 7 mg, 0.03 mmol, 93.8% yield) as a yellow oil. The crude product was carried on to the next step without further purification. LCMS M / Z (M+H) 249.1 Synthesis of tail group T-23 Step 1: 2-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-6-methyltetrahydro-lH,5H-2,7a-methanopyrrolizin-5-one: To a mixture of 7-(4-((15)1 -(tert-butyl(dimethyl)silyl] oxyethyl]triazol-1 -yl] -5 -azatricyclo [5.1.1.01,5]nonan-4-one (60 mg, 0.17 mmol, intermediate prepared from above step) in toluene (3 mL) was added LDA (0.1 mL, 0.19 mmol) at -78 °C. The resulting solution was stirred for 0.5 h at -78 °C, then MeOTf (0.02 mL, 0.20 mmol) in toluene (0.5 mL) was added dropwise. The mixture was stirred at -78 °C for 3 h, then quenched with saturated NH4Cl(aq), diluted with water, and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0-20% EE (30% ethanol in ethyl acetate) in petroleum ether) to afford 7-(4-((15)-1-(^ / -butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-3-methyl-5-azatricyclo[5.1.1,01,5]nonan-4-one (48 mg, 0.13 mmol, 77% yield) as a colorless oil. LCMS M / Z (M+H) 377.3. 'H NMR (400 MHz, CDC13)5 = 7.45 (s, 1H), 5.12 (q, 7= 6.4 Hz, 1H), 3.893.76 (m, 2H), 2.89-2.78 (m, 1H), 2.61 (t, J= 6.4 Hz, 1H), 2.51-2.44 (m, 2H), 2.322.21 (m, 2H), 1.89(7=7.6, 13.6 Hz, 1H), 1.53 (d, 7= 6.4 Hz, 3H), 1.32 (d,7=7.6 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). Step 2: 2-(4-((S)-l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)-6-methyltetrahydro-lH,5H-2, 7a-methanopyrrolizin-5-one T-23: To a solution of 3-methyl-7-[4-[(15)-l-(tert-butyl(dimethyl)silyl] oxyethyl]triazol-1 -yl] -5 -azatricyclo [5.1.1.01,5]nonan-4-one (48.0 mg, 0.13 mmol) in THF (3 mL) was added TBAF (0.25 mL, 0.25 mmol) at 0 °C. The resulting solution was stirred for 2 h at 25 °C, then the reaction was concentrated under reduced pressure. The residue was purified by flash chromatography (0-5% methanol in dichloromethane) to afford crude 3-methyl-7-[4-[(15)-1 -hydroxyethyl]triazol-1 -yl] -5 -azatricyclo [5.1.1.01,5]nonan-4-one (T-23, 3 0 mg, 0.1 Imrnol, 89.7% yield) as a yellow oil. LCMS M / Z (M+H) 263.2. Synthesis of tail group T-24 Step 1: 6-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2fluorohexahydro-3H-pyrrolizin-3-one To a mixture of 7-(4-(( 15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl]-5-azatricyclo[5.1.1.01,5]nonan-4-one (50 mg, 0.14 mmol) in THF (2 mL) was added LiHMDS (0.15 mL, 0.15 mmol) at -78 °C. The resulting solution was stirred for 0.5 h at -78 °C, then NFSI (48 mg, 0.15 mmol) in THF (0.5 mL) was added dropwise. The mixture was stirred at -78 °C for 1 h, then was quenched with saturated NH4Cl(aq) (2 mL), diluted with water and extracted with 5 ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography [0-20% EE (30% ethanol in ethyl acetate) in petroleum ether] to afford 3-fluoro-7-[4-[( 15)-1 -[tert-butyl (dimethyl)silyl]oxyethyl]triazol-1 -yl]-5-azatricyclo[5.1.1.01,5]nonan-4-one (25 mg, 0.07 mmol, 47.6% yield) as a colorless 10 oil. LCMS M / Z (M+H) 381.3. Step 2: 6-fluoro-2-(4-((S)-l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH,5H-2, 7a-methanopyrrolizin-5-one T-24: To a solution of 3-fluoro-7-[4-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol- 1-yl]-5-azatricyclo [5.1.1.0 l,5]nonan-4-one (35 mg, 0.09 mmol) in THF (2 mL) was added TBAF (0.18 mL, 0.18 mmol) at 0 °C. 15 The resulting solution was stirred at 25 °C for 2 h, then the reaction was concentrated under reduced pressure. The residue was purified by flash chromatography (0-5% methanol in dichloromethane) to afford 3-fluoro-7-[4-[(lS)-l-hydroxyethyl]triazol-l-yl]-5-azatricyclo[5.1.1.01,5]nonan-4-one (T-24, 18 mg, 0.07mmol, 73.5% yield) as a yellow oil. LCMS M / Z (M+H) 267.2. Synthesis of tail group T-25 MePPhjBr, n-BuLi THF, -78 °C~rt, 4h OTBS 1) 9-BBN, 0 °C ~ rt, 16 h 2) NaOH, H2O2, 0 °C ~ 50 °C, 1 h DMP DOM, rt, 2 h O (EtO)2PXxCO2Et NaH THF, 0 °C - rt, 4 h Pd / C, H2 MeOH, rt, 4 h OH Step 1: tert-butyl (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-vinyl-2-azabicyclo[2.1.1]hexane-2-carboxylate: Under nitrogen, to a solution of MePPh3Br (2.5 g, 6.9 mmol) in THF (10 mL) was added n-BuLi (2.8 mL, 6.9 mmol) at -78 °C. The mixture was stirred at 0 °C for 1 h, then tert-butyl 4-[4-[(1S)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl] -1 -formyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (1500 mg, 3.4 mmol) in THF (6 mL) was added for 10 min at -78 °C. The mixture was stirred at 25 °C for 4 h, then was quenched by saturated NH4Cl(aq), diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10% ethyl acetate in petroleum ether) to afford the title compound (1020 mg, 68.3% yield) as a colorless oil. 'H NMR (400 MHz, CDCh-J) 7.47 (s, 1H), 6.60 (dd, J= 10.8, 17.2 Hz, 1H), 5.30-5.20 (m, 2H), 5.13 (q, J= 6.4 Hz, 1H), 3.91 (s, 2H), 2.49-2.43 (m, 2H), 2.41-2.36 (m, 2H), 1.53 (d, J= 6.4 Hz, 3H), 1.48 (s, 9H), 0.92 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). LCMS M / Z (M+H) 435.4. Step 2: tert-butyl (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-(2-hydroxyethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate: To a solution of tert-butyl 4-[4-[( 15)-l-[tert-butyl(dimethyl)silyl] oxyethyl]triazol-l-yl]-l- vinyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (1020 mg, 2.4 mmol) in THF (20 mL) was added 9-BBN (33 mL, 16.4 mmol) at 0 °C. The reaction was stirred for 16 h at 25 °C, then water (16 mL) was added at 0 °C, then after 15 minutes NaOH (5 mL, 1 M) was added over 15 minutes. The resulting mixture was then heated to 50 °C, and water (12) was added. The resulting mixture was stirred for 0.5 h at 50 °C, then the mixture was quenched by the addition of the saturated aqueous Na2SO3(aq)at 0 °C. The mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0-40% ethyl acetate in petroleum ether) to afford the title compound (952 mg, 89.6% yield) as a colorless oil. 1HNMR(400 MHz, CDCh-d) 7.47 (s, 1H), 5.14 (q, J= 6.4 Hz, 1H), 3.90-3.85 (m, 4H), 2.57 (t, J= 6.0 Hz, 2H), 2.37 (s, 4H), 1.53 (d, J= 6.4 Hz, 3H), 1.49 (s, 9H), 0.92 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H). LCMS M / Z (M+H) 453.2. Step 3: tert-butyl (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-(2-oxoethyl)-2-azabicyclo[2.1. l]hexane-2-carboxylate: To a solution of tert-butyl 4-[4-[( IS)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol- 1-yl] -1 -(2-hydroxyethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (952 mg, 2.1 mmol) in dichloromethane (20 mL) was added DMP (2230 mg, 5.26 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h, then the mixture was quenched by saturated Na2SO3(aq) (20 mL) and Na2S2O3(aq) (20 mL). The mixture was stirred at room temperature for 30 min, then diluted with water and extracted with dichloromethane. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (558 mg, 58.9% yield) as a colorless oil. 'H NMR (400 MHz, CDCh+O 9.85 (s, 1H), 7.48 (s, 1H), 5.14 (q, J= 6.4 Hz, 1H), 3.90 (s, 2H), 3.32 (s, 2H), 2.47 (s, 4H), 1.54 (d, J= 6.4 Hz, 3H), 1.47 (s, 9H), 0.92 (s, 9H), 0.13 (s, 3H), 0.06 (s, 3H). LCMS M / Z (M+H) 451.2. Step 4, 5, 6, 7 & 8: (8)-2-(4-(1-hydroxyethyl)-! H-1,2,3-triazol-I-yl)tetrahydro-1H-2,8a-methanoindolizin-5 (6H)-one O The title compound was prepared as a colorless oil in a similar fashion to T-22 to afford T-25. Synthesis of tail group T-26 Step 1: (S)-(4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-oxabicyclo[2.1. l]hexan-l-yl)methanol: To a solution of ethyl 4-[4-[(15)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo[2.1.1]hexane-l-carboxylate (110 mg, 0.29 mmol, synthesized in a similar fashion to T-23) in THF (4 mL) at 0 °C was added LiAlH4 (33 mg, 0.9 mmol) in portions. The mixture was stirred at room temperature for 1 h, then the mixture was quenched with water (0.1 mL) and 15% NaOH(aq). The mixture was filtered, and the filtrate was then concentrated under reduced pressure. The residue was purified by flash chromatography (0-60% ethyl acetate in petroleum ether) to afford [4-[4-[( 15)-1-[tert-butyl (dimethyl)silyl]oxyethyl]triazol- 1 -yl] -2-oxabicyclo[2.1. l]hexan-1 -yl]methanol (70 mg, 0.21 mmol, 71.5% yield) as a white solid. 'H NMR (400 MHz, CDCh) 5 7.60 7.40 (m, 1H), 5.11 (q, J= 6.4 Hz, 1H), 4.22 (s, 2H), 3.95 (s, 2H), 2.38-2.31 (m, 4H), 1.51 (d, J= 6.4 Hz, 3H), 0.90 (s, 9H), 0.11 (s, 3H), 0.05 (s, 3H). LCMS [M+H]+ 340.2. Step 2: (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-oxabicyclo[2.1.1] hexane-1-carbaldehyde: DMP (99.9 mg, 0.24 mmol) was added to a solution of [4-[4-[(lR)-l-[tert- butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo[2.1.1]hexan-l-yl]methanol (40 mg, 0.12 mmol) in DCM (4 ml) at 0 °C, then the mixture was stirred at 25 °C for 2 h. The reaction was quenched with sat. aq NaHCO? and sat. aq Na^S^Ch and allowed to stir for 1 h before diluting with brine and DCM. The mixture was filtered and then the layers separated. The aqueous portion was further extracted with DCM and the combined organic extracts dried over sodium sulfate and concentrated under reduced pressure to give crude 4-[4-[(lR)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo[2.1.1]hexane-l-carbaldehyde (30 mg, 0.09 mmol, 75.4 % yield) as a yellow oil, which was carried on to the next step without further purification. 'H NMR (400 MHz, CDCh) 5 9.91 (s, 1H), 7.50 (s, 1H), 5.12 (q, J= 6.4 Hz, 1H), 4.38-4.33 (m, 1H), 4.32-4.18 (m, 1H), 2.80-2.70 (m, 1H), 2.61-2.41 (m, 2H), 2.40-2.29 (m, 1H), 1.52 (d, J= 6.4 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.05 (s, 3H). LCMS [M+H]+= 356. Step 3: (S)-4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-l-(l-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-lH-l,2,3-triazole: To a solution of 4-[4-[( 15)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo[2.1.1]hexane-l-carbaldehyde (30 mg, 0.09 mmol) in DCM (0.5 mL) was added DAST (0.04 mL, 0.3 mmol) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C, then the reaction was diluted with water and extracted by DCM. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (50 % ethyl acetate in petroleum ether) to give tert-butyl-dimethyl-[(15)-l-[l-[l-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl]triazol-4-yl]ethoxy]silane (20 mg, 0.06 mmol, 62.6 % yield) as a colorless oil. LCMS [M+H]+ 360. Step 4: (S)-l-(l-(l-(difluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-lH-l, 2,3-triazol-4-yl)ethanol T26: To a mixture of tert-butyl-dimethyl-[( 15)-1 -[l-[ 1-(difluoromethyl)-2-oxabicyclo [2.1.1]hexan-4-yl]triazol-4-yl]ethoxy]silane (20 mg, 0.06 mmol) in THF (1 mL) was added TBAF (0.08 mL, 0.08 mmol, 1 M in THF) at 0 °C. The mixture was stirred at room temperature for 0.5 h, then the reaction was diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10 % methanol in DCM) to afford (15)-l-[l-[l-(difluoromethyl)-2-oxabicyclo[2.1. l]hexan-4-yl]triazol-4-yl]ethanol (T-26, 10 mg, 0.04 mmol, 73.3% yield) as a colorless oil. LCMS [M+H]+246. Synthesis of tail group T-27 Step 1: (S)-2-(4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-azabicyclo[2.1.1]hexan-l-yl)ethan-l-ol: A solution of tert-butyl 4-[4-[( 15)-1-[tert-butyl(dimethyl)silyl] oxyethyl]triazol-1 -yl] -1 -(2-hydroxyethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (327 mg, 0.7 mmol, intermediate prepared from above step) in TFA (4 mL, 5% in HFIP) was stirred for 3 h at 25 °C. The pH was then adjusted to 8 with saturated NaHCO3(aq) at 0 °C. The mixture was extracted with dichloromethane, and the combined organic phases were dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography (0-10% methanol in chloromethane) to afford the tittle compound (221 mg, 86.8% yield) as a white solid. LCMS M / Z (M+H) 353.2. Step 2: (S)-6-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl) tetrahydro-lH,5H-4a,6-methanopyrrolo[l,2-c][ 1,3]oxazin-1-one: To a stirred solution of 2-[4-[4-[(15)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl]-2-azabicyclo[2.1.1]hexan-l-yl]ethanol (70 mg, 0.2 mmol) in dichloromethane (7 mL) was added triethylamine (0.08 mL, 0.6 mmol) at 0 °C. After 10 min, triphosgene (23.57 mg, 0.08 mmol) was added to the reaction. The resulting mixture was stirred at 25 °C for 1.5 h, then concentrated under reduced pressure. The residue was purified by flash chromatography [40% EE (25% ethyl alcohol in ethyl acetate) in petroleum ether] to afford the tittle compound (40 mg, 53.2% yield) as a colorless oil. LCMS M / Z (M+H) 379.2. Step 3: (S)-6-(4-(l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH,5H-4a,6-methanopyrrolo [1,2-c][ 1,3]oxazin-1-one T-27: To a solution of 8-[4-[( 15)-1 -| / crt-buty l(dimcthy I )si lyl | oxyethyl]triazol-1 -yl] -4-oxa-6-azatricyclo [6.1.1.01,6] decan-5-one (40 mg, 0.1 mmol) in THF (1 mL) was added TBAF (0.21 mL, 0.21 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h, then the reaction was concentrated under reduced pressure. The residue was purified by flash chromatography (0-10% methanol in ethyl acetate) to afford the tittle compound (T-27, 27 mg, 96.7% yield) as a colorless oil. LCMS M / Z (M+H) 265.2. Synthesis of tail group T-28 Step 1: (S)-l-(4-(4-(1 -((tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-l-(2-hydroxyethyl)-2-azabicyclo[2.1.1]hexan-2-yl)-2-chloroethanone: To a solution of 2-[4-[4-[( IS)-1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol-1 -yl]-2-azabicyclo[2.1.1]hexan-l-yl]ethanol (100.0 mg, 0.28 mmol, intermediate prepared from above step) and triethylamine (0.08 mL, 0.57 mmol) in dichloromethane (3 mL) was added chloroacetyl chloride (0.02 mL, 0.23 mmol) dropwise at 0 °C. The mixture was stirred for 1 h at 0 °C, then was concentrated under reduced pressure. The residue was purified by flash chromatography (0-5% methanol in dichloromethane) to afford 2-chloro-l-[l-(2-hydroxyethyl)-4-[4-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-azabicyclo[2.1.1]hexan-2-yl]ethanone (73 mg, 0.17 mmol, 60% yield) as a white solid. LCMS M / Z (M+H) 429.2. Step2: (S)-8-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl) tetrahydro-lH-8,9a-methanopyrrolo [1,2-d] [1,4] oxazepin-5(2H)-one: To a solution of 2-chloro-1 -[ 1 -(2-hydroxyethyl)-4-[4-[( IS)-1 -[tert-butyl (dimethyl)silyl]oxyethyl]triazol-l-yl]-2-azabicyclo[2.1.l]hexan-2-yl]ethanone (40.0 mg, 0.09 mmol) in THF (4 mL) was added t-BuOK (15.69 mg, 0.14 mmol) at 25 °C. The reaction was stirred at 25 °C for 1 h, then concentrated under reduced pressure. The residue was purified by flash chromatography [0-55% EE (25% ethanol in ethyl acetate) in petroleum ether] to afford (5)-8-(4-( l-((tert-butyldimethylsilyl)oxy)ethyl)-\H- 1,2,3-triazol-1 -yl)tetrahydro-7H-8,9a-methanopyrrolo[ 1,2-d] [ 1,4] oxazepin-5 (4 / / )-one (17 mg, 0.043 mmol, 46.4% yield) as a white solid. LCMS M / Z (M+H) 393.3. Step 3: (S)-8-(4-(l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH-8,9a-methanopyrrolo[1,2-d][1,4]oxazepin-5(2H)-one T-28: To a solution of 9-[4-[(lS)-l-[tert-butyl(dimethyl)silyl] oxyethyl]triazol-1 -yl] -4-oxa-7 -azatricyclo[7.1.1.01,7]undecan-6-one (17.0 mg, 0.04 mmol) in THF (1 mL) was added TBAF (0.09 mL, 0.09 mmol, 1 M in THF) at 0 °C. The resulting solution was stirred for 2 h at 25 °C, then concentrated under reduced pressure. The residue was purified by flash chromatography (0-10% methanol in dichloromethane) to afford 9-[4-[(lS)-l-hydroxyethyl]triazol-l-yl]-4-oxa-7-azatricyclo[7.1.1.01,7]undecan-6-one (T-28, 10 mg, 0.036 mmol, 83% yield) as a yellow oil. LCMS M / Z (M+H) 279.3. Synthesis of tail group T-29 l-(l-(3-(difluoromethyl)bicyclo [1.1.1]pentan-l-yl)-lH-l, 2,3-triazol-4-yl)ethan-l-ol, T-29 was prepared in a similar fashion to T-l. Synthesis of tail group T-30 CO2^Bu MePPh3Br, t-BuOK THF, -78°C~rt, 3 h l2, NaHCO3 MTBE / H2O, rt, 16h KOAc DMSO, 90 °C, 16 h EtONa EtOH, rt, 16 h DAST DCM, rt, 1 h 5% TFA in HFIP rt, 2 h 1) DPPA, BnOH toluene, 85 °C, 16 h 2) Pd(OH)2, H2 (45 psi), rt, 16 h n F-S-N3 0 DMF / MeCN, rt, 1 h OH Step 1: tert-butyl 3-methylenecyclobutane-l-carboxylate: To a solution of t-BuOK (88 mL, 88 mmol) in THF (300 mL) was added methyl triphenylphosphonium bromide (31.5 g, 88.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then tert-butyl 3-oxocyclobutane-1-carboxylate (10 g, 58.8 mmol) in THF (50 mL) was added to the mixture over 10 min at 0 °C. The mixture was stirred at 25 °C for 3 h, then quenched with saturated NH4Cl(aq). The mixture was diluted with water and ethyl acetate and thee aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (10% ethyl acetate in petroleum ether) to give the tittle compound (2500 mg, 25.3% yield) as a colorless oil. 'H NMR (400 MHz, CDCh) 5 4.79 (quin, J = 2.4 Hz, 2H), 3.08-2.74 (m, 5H), 1.46 (s, 9H). Step 2: tert-butyl l-(2-(benzyloxy)-l-hydroxyethyl)-3-methylenecyclobutane-l-carboxylate: Tert-butyl 3-methylenecyclobutanecarboxylate (5.3 g, 31.5 mmol) was dissolved in THF (200 mL), then at -78 °C, LDA (23.63 mL, 2 M in THF, 47.26 mmol) was added dropwise. The mixture was stirred at -78 °C for 1 h, then benzyl oxyacetaldehyde (8.9 mL, 63.0 mmol) was added dropwise, and the reaction was stirred at -78 °C for 1 h. The reaction was quenched with saturated NH4Cl(aq) (50 mL) and water (100 mL), and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10% ethyl acetate in petroleum ether) to give the tittle compound (6500 mg, 64.8% yield) as a colorless oil. 1HNMR(400 MHz, CDCh) 5 7.35-7.28 (m, 2H), 7.27-7.17 (m, 3H), 4.83-4.72 (m, 2H), 4.53 (s, 2H), 4.00 (s, 1H), 3.51-3.45 (m, 1H), 3.45-3.38 (m, 1H), 3.04-2.98 (m, 2H), 2.90 (d, J= 2.0 Hz, 2H), 2.66 (dd, J= 1.6, 16.0 Hz, 1H), 1.44 (s, 9H). Step 3: tert-butyl 3-((benzyloxy) methyl)-l-(iodomethyl)-2-oxabicyclo [2.1. l]hexane-4-carboxylate: To a solution of iodine (10.4 g, 40.8 mmol) in tert-butyl methyl ether (120 mL) and water (50 mL) were added NaHCO? (3.4 g, 40.8 mmol) and tert-butyl 1 -(2-benzyloxy-l-hydroxy-ethyl)-3-methylenecyclobutanecarboxylate (6.5 g, 20.4 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h, then the excess iodine was neutralized with a saturated solution of sodium thiosulfate(aq). After phase separation, the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (10% ethyl acetate in petroleum ether) to give the tittle compound (6600 mg, 72.8% yield) as a colorless oil. 1H NMR (400 MHz, CDCh) 5 7.45-7.27 (m, 5H), 4.64-4.52 (m, 2H), 4.36 (t, J= 5.6 Hz, 1H), 3.693.56 (m, 2H), 3.42 (s, 2H), 2.11-2.07 (m, 1H), 2.07-2.00 (m, 1H), 1.99-1.92 (m, 2H), 1.44 (s, 9H). Step 4: tert-butyl l-(acetoxymethyl)-3-((benzyloxy)methyl)-2-oxabicyclo [2.1. l]hexane-4-carboxylate: To a solution of AcOK (2.2 g, 22.3 mmol) in dimethyl sulfoxide (70 mL) was added tert-butyl 3-(benzyloxymethyl)-l-(iodomethyl)-2-oxabicyclo[2.1.1]hexane-4-carboxylate (6.6 g, 14.9 mmol). The mixture was stirred at 90 °C for 16 hs. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the tittle compound (4500 mg, 80.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCh) 5 7.39-7.27 (m, 5H), 4.67-4.49 (m, 2H), 4.37-4.33 (m, 1H), 4.33-4.23 (m, 2H), 3.72-3.64 (m, 1H), 3.64-3.55 (m, 1H), 2.09 (s, 3H), 2.08-1.99 (m, 2H), 1.97-1.91 (m, 2H), 1.40 (s, 9H). Step 5: tert-butyl 3-((benzyloxy)methyl)-l-(hydroxymethyl)-2-oxabicyclo [2.1. l]hexane-4-carboxylate: To a solution of tert-butyl 1-(acetoxymethyl)-3-(benzyloxymethyl)-2-oxabicyclo[2.1. l]hexane-4-carboxylate (4.5 g, 12.0 mmol) in ethanol (80 mL) was added EtONa (1.2 g, 17.9 mmol) in portions at 5-10 °C. The mixture was then stirred at 25 °C for 16 h. The mixture was then diluted with saturated NH4C(aq), and the mixture was stirred for 5 min at 25 °C. The resulting precipitate was fdtered and washed with ethyl acetate. The fdtrate was dried over sodium sulfate, fdtered and concentrated under reduced pressure to give the crude tittle compound (3500 mg, 87.6% yield) as brown oil. 'H NMR (400 MHz, CDCh) 5 7.39-7.27 (m, 5H), 4.64 (d, J= 12.4 Hz, 1H), 4.55 (d, J= 12.4 Hz, 1H), 4.34 (dd, J= 4.4, 6.9 Hz, 1H), 3.88-3.74 (m, 2H), 3.69 (dd, J= 4.0, 10.4 Hz, 1H), 3.56 (dd, J= 12, 10.4 Hz, 1H), 2.07-2.00 (m, 2H), 1.96-1.88 (m, 2H), 1.41 (s, 9H). Step 6: tert-butyl 3-((benzyloxy)methyl)-l-(fluoromethyl)-2-oxabicyclo [2.1. l]hexane-4-carboxylate: To a solution of tert-butyl 3-(benzyloxymethyl)-l-(hydroxymethyl)-2-oxabicyclo [2.1.1]hexane-4-carboxylate (500 mg, 1.5 mmol) in DCM (10 mL) was added DAST (0.8 mL, 6.0 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h, then quenched with aq. NaHCO3(aq). The resulting mixture was extracted with ethyl acetate, and the combined organics were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography [0-15% EE (ethanol: ethyl acetate=l:3) in petroleum ether] to afford tert-butyl 3-(benzyloxymethyl)-1-(fluoromethyl)-2-oxabicyclo[2.1.1]hexane-4-carboxylate (300 mg, 0.89 mmol, 59.6% yield) as a white solid. Step 7: 3-((benzyloxy)methyl)-l-(fluoromethyl)-2-oxabicyclo[2.1.1]hexane-4-carboxylic acid: A solution of tert-butyl 3-(benzyloxymethyl)-l-(fluoromethyl)-2-oxabicyclo[2.1. l]hexane-4-carboxylate (300 mg, 0.9 mmol) in 5% TFA in HFIP (10 ml) was stirred at 25 °C for 2 h, then concentrated under reduced pressure. The residue was purified by flash chromatography (50% ethyl acetate in petroleum ether) to give 3-(benzyloxymethyl)-l-(fluoromethyl)-2-oxabicyclo[2.1. l]hexane-4-carboxylic acid (200 mg, 0.71 mmol, 80% yield) as a colorless oil. 'H NMR (400 MHz, CHLOROFORM-d) 5 = 7.36-7.28 (m, 5H), 4.65 (s, 1H), 4.63-4.56 (m, 2H), 4.53 (s, 1H), 4.44 (t, J= 5.6 Hz, 1H), 3.76-3.69 (m, 2H), 2.28 (d, J= 7.0 Hz, 1H), 2.17-2.07 (m, 3H). Step 8: (4-amino-l-(fluoromethyl)-2-oxabicyclo[2.1.1]hexan-3-yl)methanol: A solution of 3-(benzyloxymethyl)-l-(fluoromethyl)-2-oxabicyclo[2.1. l]hexane-4-carboxylic acid (150 mg, 0.54 mmol), DPPA (0.15 mL, 0.7 mmol), TEA (0.11 mL, 0.8 mmol) and BnOH (0.11 mL, 1.1 mmol) in toluene (5 mL) was stirred at 85 °C for 16 h, thendiluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by flash chromatography (20% ethyl acetate in petroleum ether) to afford benzyl A-[3-(benzyloxymethyl)-l-(fluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl]carbamate (168 mg, 0.44 mmol, 81.4% yield) as a colorless oil. LCMS [M+H] 386.1. To a solution of benzyl A-[3-(benzyloxymethyl)-l-(fluoromethyl)-2-oxabicyclo [2.1. l]hexan-4-yl]carbamate (100.0 mg, 0.26 mmol) in methyl alcohol (2 mL) was added Pd(OH)2 (200.39 mg, 0.29 mmol). The reaction mixture was stirred at 25 °C for 16 h under H2 (45 Psi). After filtration and concentration, crude [4-amino-l-(fluoromethyl)-2-oxabicyclo[2.1. l]hexan-3-yl]methanol (40 mg, 0.24 mmol, 95.7% yield) was obtained as a colorless oil. LCMS M / Z (M+H) 162.1. Step 9: (4-azido-l-(fluoromethyl)-2-oxabicyclo[2.1. l]hexan-3-yl)methanol T-30: To a solution of [4-amino-l-(fluoromethyl)-2-oxabicyclo[2.1.1]hexan-3-yl]methanol (40 mg, 0.24 mmol) in DMF (1 mL) was added sulfurazidic fluoride (MTBE solution prepared from above step) and sat. KHCO3 aqueous solution (1 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, then the whole mixture was carried on directly to next step without further purification. Example 1: (IS,3s)-1 -(difluoromethyl)-3-(4-(( / ?)-1 -((2,4-dihydro- 1H-pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)cyclobutanol To a mixture ofPBus (173. 5 mg, 0.86 mmol), 2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-ol H-l (43.14 mg, 0.21 mmol) and l-(difluoromethyl)-3-[4-[(lS)-l-hydroxyethyl]triazol-l-yl] cyclobutanol T-4 (50.0 mg, 0.21 mmol) in THF (1 mL) was added a solution of TMAD (147.66 mg, 0.86 mmol) in DCM (0.5 mL) under nitrogen 5 atmosphere at 0 °C. The mixture was then stirred at r.t. for 1 hour. The solvent was removed under reduced pressure. Then the resulting residue was purified by reverse phase chromatography (acetonitrile 30-60% / 0.1% NH4OH in water) to afford (1S,3 s)-1 -(difluoromethyl)-3-(4-(( / ?)-1 -((2,4-dihydro-1 / / -py rano [3,4-c] quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)cyclobutanol (32.8 mg, 0.078 mmol, 36.4% yield) 10 as a white solid. Tf NMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.34 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.44 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 6.29 (s, 1H), 6.15 (t, J= 56.0 Hz, 1H), 5.92 - 5.85 (m, 1H), 4.84 (s, 2H), 4.81 - 4.73 (m, 1H), 4.10 -3.96 (m, 2H), 3.17 - 3.06 (m, 1H), 3.05 - 2.96 (m, 1H), 2.96 - 2.86 (m, 2H), 2.61 (s, 2H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H)+ = 417.2. 15           Examples 2-12: the following compounds were synthesized using methods and procedures similar to those used in Example 1 using appropriate starting materials and synthetic intermediates: No. Structure Compound Name 2 XX Th 1J n=N (U?,3r)-3-(4-((R)-l-((2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl)-1 -methylcyclobutanecarbonitrile 3 / 0 A. / z (IS, 3s)-3-(4-((R)-1-((2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl)-1 -methylcyclobutanecarbonitrile 4 XX IL Hj^3 LI n«n 3 - [4-[(1R)-1 -[(1,1 -dideuterio-2,4-dihydropyrano[3,4-c] quinolin-9-yl)oxy] ethyl]triazol-1 -yl] cyclobutanecarbonitrile No. Structure Compound Name 5 YY (I n=n'       oh l-methyl-3-[4-[(lR)-l-[(5-methyl-2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yl)oxy] ethyl]triazol-1 -yl] cyclobutanol 6 .0. riY IJ Y^n-O"cn N=n' 3-[4-[(l / ?)-l-[(5-methyl-2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yl)oxy]ethyl]triazol-l-yl] cyclobutanecarbonitrile 7 .0. \ H j T 0^^ A^o-n N=N 3-[4-[(lR)-l-[(5-fluoro-2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yl)oxy]ethyl]triazol-l-yl] cyclobutanecarbonitrile 8 Til If T ^TY-O^n N=n' 3-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-1 -yl] cyclobutanecarbonitrile 9 Til X J *Y^\ Z\A°F n=n 9-[( 1R)-1 -[ 1 -[3-(difluoromethyl)-3-methylsulfonyl-cyclobutyl]triazol-4-yl]ethoxy]-2,4-dihydro-lH-pyrano[3,4-c]quinoline 10 Til N X T F / \£''' / ° ( \r■ ■ \y*sC^ n=n 9-[(lR)-l-[l-[3-(fluoromethyl)-3-methylsulfonyl-cyclobutyl]triazol-4-yl]ethoxy]-2,4-dihydro-lH-pyrano[3,4-c]quinoline No. Structure Compound Name 11 9-[( 1R)-1 -[ 1 -(3 -methyl-3 -methylsulfonyl-cyclobutyl)triazol-4-yl]ethoxy]-2,4-dihydro-lH-pyrano[3,4-c]quinoline 9-[( I / ?)-1 -[ 1 -[3-(fluoromethyl)-3-methylsulfonyl-cyclobutyl]triazol-4-yl]ethoxy]-2,4-dihydro-lH-pyrano[3,4-c]quinoline Analyticla data for compounds of Examples 2-12 is provided in the table below: No. NMR MS1 2 'HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.38 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.43 (d, J= 2.4 Hz, 1H), 7.38 (dd, J= 2.8, 9.2 Hz, 1H), 5.91 (q, J= 6.4 Hz, 1H), 5.36 - 5.29 (m, 1H), 4.83 (s, 2H), 4.15 -3.93 (m, 2H), 3.16-2.96 (m, 4H), 2.71 - 2.64 (m, 2H), 1.71 (d,J= 6.4 Hz, 3H), 1.56 (s, 3H). 390.2 3 'HNMR (400 MHz, DMSO-Je) 5 8.45 (s, 1H), 8.44 (s, 1H)„ 7.88 (d, J= 9.2 Hz, 1H), 7.44 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.91 (q, 7=6.4 Hz, 1H), 5.41-5.33 (m, 1H), 4.83 (s, 2H), 4.11 -3.97 (m, 2H), 3.15-2.95 (m, 4H), 2.72-2.65 (m, 2H), 1.72 (d, J= 6.4 Hz, 3H), 1.59 (s, 3H). 390.3 4 'HNMR (400 MHz, CDCh) 5 = 8.45 (s, 1H), 8.06 (s, 1H), 7.55 (s, 1H), 7.43 (s, 2H), 5.83 (q, J= 6.4 Hz, 1H), 5.24 - 5.18 (m, 1H), 4.94 ( s, 2H), 4.21 - 4.05 (m, 2H), 3.42 - 3.30 (m, 1H), 3.19 - 3.06 (m, 2H), 3.04 - 2.94 (m, 2H), 1.81 (d, J= 6.4 Hz, 3H). 378.0 5 'HNMR (400 MHz, DMSO-7?) 5 8.27 (s, 1H), 7.79 (d, J= 9.1 Hz, 1H), 7.40 (d, J= 2.7 Hz, 1H), 7.34 (dd, J= 9.1, 2.7 Hz, 1H), 5.87 (q, J= 6.4 Hz, 1H), 5.27 (s, 1H), 4.76 (d, J= 3.7 Hz, 3H), 4.01 (td, J= 5.7, 2.6 Hz, 2H), 3.08 (dt, J= 17.5, 5.6 Hz, 1H), 2.97 (dt, J= 17.5, 5.6 Hz, 1H), 2.55 (dd, J= 10.8, 7.8 Hz, 4H), 2.42 (s, 3H), 1.70 (d, J= 6.4 Hz, 3H), 1.30 (s, 3H). 395.1 6 'HNMR (400 MHz, DMSO-7?) 5 8.35 (s, 1H), 7.78 (d, J= 9.1 Hz, 1H), 7.40 (d, 7 = 2.7 Hz, 1H), 7.33 (dd. J = 9.1, 2.7 Hz, 1H), 5.88 (q, 7= 6.4 Hz, 1H), 5.40 (pd, 7= 8.0, 1.3 Hz, 1H), 4.77 (s, 2H), 4.00 (tt, 7= 8.4, 4.2 Hz, 2H), 3.53 (ttd, 7= 9.5, 4.9, 1.3 Hz, 1H), 3.12 - 3.02 (m, 1H), 3.04 - 2.92 (m, 1H), 2.95 - 2.77 (m, 4H), 2.42 (s, 3H), 1.70 (d, 7= 6.4 Hz, 3H). 390 7 'HNMR (400 MHz, DMSO-Je) 5 8.36 (s, 1H), 7.75 (d, 7= 9.1 Hz, 1H), 7.49 (d,7= 2.8 Hz, 1H), 7.44 (dd,7= 9.1, 2.7 Hz, 1H), 5.92 (q, 7= 6.4 Hz, 1H), 5.40 (pd, 7= 7.9, 1.3 Hz, 1H), 4.77 (s, 2H), 4.05 (td, 394.0 No. NMR MS1 J =5.7, 1.9 Hz, 2H), 3.54 (ttd, 7=9.5,4.9, 1.2 Hz, 1H), 3.20 - 2.98 (m, 2H), 2.98 - 2.80 (m, 4H), 1.71 (d, J= 6.4 Hz, 3H). 8 'HNMR (400 MHz, DMSO-rie) 5 8.49 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 9.1 Hz, 1H), 7.44 (d, J= 2.7 Hz, 1H), 7.39 (dd, J= 9.1, 2.7 Hz, 1H), 5.91 (q, J= 6.4 Hz, 1H), 5.20 - 5.07 (m, 1H), 4.84 (s, 2H), 4.05 (td, J= 5.8, 3.1 Hz, 2H), 3.27 (dt, J= 10.0, 9.0 Hz, 1H), 3.16 - 3.01 (m, 1H), 3.04 - 2.90 (m, 1H), 2.94 - 2.78 (m, 4H), 1.72 (d, J= 6.4 Hz, 3H). 376.1 9 'HNMR (400 MHz, DMSO-de) 5 8.44 (s, 1H), 8.37 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.43 (d, J= 2.8 Hz, 1H), 7.38 (dd, J= 2.8, 9.2 Hz, 1H), 6.67 (t, J= 54.8 Hz, 1H), 5.93 (q, J= 6.4 Hz, 1H), 5.26 (quin, J = 8.4 Hz, 1H), 4.84 (s, 2H), 4.13 - 3.92 (m, 2H), 3.19 (s, 3H), 3.17 -2.97 (m, 6H), 1.72 (d, J= 6.4 Hz, 3H). 479.1 10 'HNMR (400MHz, CDCh) 5 = 8.44 (s, 1H), 8.13 - 7.94 (m, 1H), 7.54 (s, 1H), 7.37 (d, J= 9.2 Hz, 1H), 7.33 (s, 1H), 5.83 (q, J= 6.4 Hz, 1H), 5.26 - 5.13 (m, 1H), 5.05 (d, J= 53.6 Hz, 2H), 4.92 (d, J= 9.6 Hz, 2H), 4.27 - 4.02 (m, 2H), 3.33 - 2.88 (m, 9H), 1.81 (d, J= 6.8 Hz, 3H). 461.1 11 'HNMR (400 MHz, CDCh) 5 8.44 (s, 1H), 7.98 (d, J= 9.2 Hz, 1H), 7.51 (s, 1H), 7.36 (d, J =9.2 Hz, 1H), 7.31 (s, 1H), 5.82 (q, . / =6,4 Hz, 1H), 5.12 (quin, J= 8.4 Hz, 1H), 4.91 (s, 2H), 4.30 - 3.99 (m, 2H), 3.29 -3.26 (m, 2H), 3.20 - 3.07 (m, 2H), 2.96 - 2.87 (m, 2H), 2.85 (s, 3H), 1.80 (d, 7= 6.8 Hz, 3H), 1.78 (s, 3H). 443.1 12 'HNMR (400 MHz, DMSO-de) 5 = 8.44 (s, 1H), 8.29 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.44 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.94 (d, J= 6.4 Hz, 1H), 5.43 - 5.30 (m, 1H), 5.07 (d, J= 53.6 Hz, 2H), 4.83 (s, 2H), 4.12 - 3.97 (m, 2H), 3.17 - 3.07 (m, 2H), 3.06 -2.99 (m, 2H), 2.97 (s, 3H), 2.80 - 2.72 (m, 2H), 1.72 (d, J= 6.4 Hz, 3H). 461 1 LCMS M / Z (M+H) Examples 13 and 14: Synthesis of ((l / ?,3r)-3-(4-(( / ?)-l-((2,4-dihydro-lH-pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -methylcyclobutyl)methanol (Example 13) and ((lS,3s)-3-(4-((J?)-l-((2,4-dihydro-lH- 5      pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 - methylcyclobutyl)methanol (Example 14) 13                  14 To a mixture of ( / ?)-mcthyl 3-(4-(1-((2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-methylcyclobutanecarboxylate as a mixture of cis and trans isomers (126 mg, 0.3 mmol, prepared in a similar fashion to Example 1 via Mitsunobu reaction from H-l and T-3) in THF (2 mL) at 0 °C was added LiAlH4 (11.3 mg, 0.3 mmol) in portions, and the mixture was stirred at r.t. for 1 h. The reaction was quenched by 2 N aq. NaOH solution. Then after filtration, the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (acetonitrile 128% / 0.2% formic acid in water) to afford [l-methyl-3-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]cyclobutyl]methanol (80 mg, 0.20 mmol, 68% yield) as a white solid. Then this mixture of cis and trans isomers was further separated by SFC (Column: Chiralcel OD-3 150*4.6mm I.D., 3um, Mobile phase: A: CO2 B:methanol (0.05% DEA), Gradient: from 5% to 40% of B in 4 min and from 40% to 5% of B in 0.2min,then hold 5% of B for 1.8 min, Flow rate: 2.5mL / min, Column temp.: 35 °C) to afford ((lR,3r)-3-(4-((R)-l-((2,4-dihydro-lH-pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -methylcyclobutyl)methanol (Compound 13; 26.5 mg, 0.07 mmol, 31% yield) and ((lS,3s)-3-(4-((R)-l-((2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-methylcyclobutyl)methanol (Compound 14; 24.3 mg, 0.06 mmol, 30% yield). Compound 13: 'H NMR (400 MHz, DMSO-Je) 5 8.45 (s, 1H), 8.28 (s, 1H), 7.91 (d, J =9.2 Hz, 1H), 7.44 (d, J =2.4 Hz, 1H), 7.39 (dd, J = 2.4, 9.2 Hz, 1H), 5.91 (q, 7= 6.4 Hz, 1H), 5.15 (q,7=8.5 Hz, 1H), 4.85 - 4.83 (m, 2H), 4.83 - 4.79 (m, 1H), 4.11 - 4.01 (m, 2H), 3.25 (d, J= 5.5 Hz, 2H), 3.15 - 3.06 (m, 1H), 3.04 - 2.95 (m, 1H), 2.46 - 2.40 (m, 2H), 2.16 - 2.08 (m, 2H), 1.72 (d, J= 6.4 Hz, 3H), 1.16 (s, 3H). LCMS M / Z (M+H)+ = 395.3. Compound 14: 'H NMR (400 MHz, DMSO-ok) 5 8.45 (s, 1H), 8.39 (s, 1H), 7.91 (d, J= 9.2 Hz, 1H), 7.44 (d, J= 2.4 Hz, 1H), 7.39 (dd, J= 2.4, 9.2 Hz, 1H), 5.90 (q, J= 6.4 Hz, 1H), 5.09 - 4.98 (m, 1H), 4.90 (t, J= 5.3 Hz, 1H), 4.84 (s, 2H), 4.09 - 4.02 (m, 2H), 3.36 (d, J= 5.4 Hz, 2H), 3.17 - 3.05 (m, 1H), 3.05 - 2.95 (m, 1H), 2.46 - 2.40 (m, 2H), 2.22 - 2.16 (m, 2H), 1.72 (d, J= 6.4 Hz, 3H), 1.13 (s, 3H). LCMS M / Z (M+H)+= 395.3. Example 15: (lR,3r)-3-(4-((R)-1 -((2,4-dihydro-1 H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -tri azol-1 -yl)cyclobutanecarbonitrile t-BuOH / H2O, rt, 12 h sodium ascorbate, CuSO4 To a solution of 9-[(lR)-l-methylprop-2-ynoxy]-2,4-dihydro-lH-pyrano[3,4-c]quinoline (H-2, 151.4 mg, 0.6 mmol), cupric sulfate (19 mg, 0.12 mmol) and sodium ascorbate (24 mg, 0.12 mmol) in water (1 ml) and t-BuOH( 1 ml) was added the directly used solution of trans-3-azidocyclobutanecarbonitrile (73.0 mg, 0.6 mmol, made in a similar fashion to Til). The mixture was stirred at rt for 16 hours. The mixture was diluted with water (8 mL). The aqueous layer was extracted with EtOAc (5 mLx3). The combined organic layer was washed with brine (8 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-40% EE(25% ethanol in EtOAc) in petroleum, Rf = 0.4) to give 160 mg of 3-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl] cyclobutanecarbonitrile as a white solid. LCMS (10-80CD / 3min): RT = 1.575 min, [M+H]+ 376.1 1HNMR(400 MHz, DMSO-d6) 5: 8.44 (s, 1H), 8.36 (s, 1H), 7.87 (d, J= 9.2 Hz, 1H), 7.42 (d, J= 2.8 Hz, 1H), 7.37 (dd, J= 9.2, 2.8 Hz, 1H), 5.91 (q, J= 6.4 Hz, 1H), 5.45 - 5.35 (m, 1H), 4.83 (s, 2H), 4.09 -3.98 (m, 2H), 3.56 - 3.49 (m, 1H), 3.11 - 2.97 (m, 2H), 2.95 -2.82 (m, 4H), 1.71 (d, J = 6.4 Hz, 3H). LCMS M / Z [M+H]+ 376. Examples 16-37: the compounds were synthesized using methods and procedures similar to those used in Example 15 using appropriate starting materials and synthetic intermediates. Chemical structures and chemical names of compounds of Examples 16-37 are summarized in the table below: No. Example Compound Name 16 / =\ o— / (lS,3s)-3-(4-((R)-l-((2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -(trifluoromethyl)cyclobutanol 17 £ - I (lS,3s)-3-(4-((R)-l-((2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -methylcyclobutanol 18 rii jTT A^n-O n=n' V-7 (R)-9-( 1-(1 -(tetrahydro-2H-pyran-4-yl)- 1H-1,2,3-triazol-4-yl)ethoxy)-2,4-dihydro-lH-pyrano[3,4-c] quinoline 19 .o. Th jj JTNT^S=O N=N       'b SFC Method E Second peak on SFC 4-(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4- c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)- 2-methyltetrahydrothiophene 1,1 -dioxide 20 .0. Tpii 1J O^^ ^?C'NA?s=o N SFC Method B Second peak on SFC 3 -(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)tetrahydrothiophene 1,1 -dioxide 21 Vo / \ / V o' o (R)-4-(4-(l-((2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)tetrahydro-2H-thiopyran 1,1-dioxide No. Example Compound Name 22 Til 1J N—\ 1 N'N SFC Method A First peak on SFC 3 -(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)cyclopentane-1 -carbonitrile 23 Ci 9-(( 1R)-1 -(1 -(3 -fluorotetrahydro-2H-pyran-4-yl)-lH-l,2,3-triazol-4-yl)ethoxy)-l,4-dihydro-2H-pyrano [3,4-c] quinoline 24 Nl. / p n=n y-7 F 9-(( 1R)-1 -(1 -(3 -fluorotetrahydro-2H-pyran-4-yl)-lH-l,2,3-triazol-4-yl)ethoxy)-l,4-dihydro-2H-pyrano [3,4-c] quinoline 25 .0. Pll Z^N If T .OH N"\ A N=n'        ON SFC Method C First peak on SFC 4-(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4- c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-2-hydroxy cyclopentane-1 -carbonitrile 26 .0. pil JTY o^^ 3-[4-[(15)-l-(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methylcyclobutanol 27 .0. Lil A.N Xj HO nA Tf n=n A 2-(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4- c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)- 4,4-difluorocyclopentan-l-ol No. Example Compound Name 28 rii Xj HQ F rT-Xh n=n (1 S,5R)-5 - [4-[ (1R)-1 -(2,4-dihydro- IH-pyrano [3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -2,2-difluoro-cyclopentanol 29 Th N X T N—(  3 n=n HC> SFC Method AB Second peak on SFC (4-(4-((R)-1-((1,4-dihydro-2H-pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 - yl)tetrahydro-2H-pyran-2-yl)methanol 30 Th n £T ,9 / —s=o N—\T N=N / SFC Method N Second peak on SFC 3 -(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4- c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)- 4-methyltetrahydrothiophene 1,1 -dioxide 31 ,o. Th £ T o^^   .o n-XX / N=n'       V SFC Method G Third peak on SFC 4-(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4- c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-l-(2-methylcyclopropyl)pyrrolidin-2-one 32 Th r r ?£ N=n     \ SFC Method AC First peak on SFC 4-(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4- c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)- 2-methyltetrahydro-2H-thiopyran 1,1 -dioxide No. Example Compound Name 33 .CL Th N=n     \ SFC Method AC Second peak on SFC 4-(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4- c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)- 2-methyltetrahydro-2H-thiopyran 1,1 -dioxide 34 .cl Th r r IT n£ n=n     \ SFC Method AC Third peak on SFC 4-(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4- c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)- 2-methyltetrahydro-2H-thiopyran 1,1 -dioxide 35 .CL Th r r ?T r^s? N=n     \ SFC Method AC Fourth peak on SFC 4-(4-(( / ?)-1 -((1,4-dihydro-2H-pyrano [3,4- c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)- 2-methyltetrahydro-2H-thiopyran 1,1 -dioxide 36 .Ck Til 1J —\ s=° N=N' 0 SFC Method B First peak on SFC ( / ?)-3-(4-(( / ?)-l-((2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)tetrahydrothiophene 1,1 -dioxide 37 .0. PH J 1          o Z\ 11 T n—C / —s— 1     / X / 11 N'n       0 9-[( 1R)-1 -[ 1 -(3 -methylsulfonylcyclobutyl)triazol-4-yl]ethoxy]-2,4-dihydro-lH-pyrano[3,4- c] quinoline Analyticla data for compounds of Examples 16-37 is provided in the table below: No. NMR MS1 16 'HNMR (400 MHz, DMSO-Je) 5 8.43 (s, 1H), 8.33 (s, 1H), 7.87 (d, J= 9.2 Hz, 1H), 7.43 (d, J= 2.8 Hz, 1H), 7.37 (dd, J= 2.8, 9.2 Hz, 1H), 6.98 (s, 1H), 5.92 (q,J=6.4Hz, 1H), 4.96 - 4.85 (m, 1H), 4.83 (s, 2H), 4.09 - 3.97 (m, 2H), 3.13 - 2.96 (m, 4H), 2.77 (s, 2H), 1.71 (d, J=6.4Hz, 3H). 435.2 17 'HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.29 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.43 (d, J= 2.8 Hz, 1H), 7.38 (dd, J= 2.8, 9.2 Hz, 1H), 5.90 (q, J= 6.4 Hz, 1H), 5.29 (s, 1H), 4.83 (s, 2H), 4.80 - 4.69 (m, 1H), 4.11 - 3.97 (m, 2H), 3.15 - 2.91 (m, 2H), 2.58 - 2.52 (m, 4H), 1.71 (d, 7= 6.4 Hz, 3H), 1.30 (s, 3H). 381.3 18 'HNMR (400 MHz, DMSO-Je) 5 8.48 (s, 1H), 8.35 (s, 1H), 7.89 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 7.42 (dd, J= 2.8, 9.2 Hz, 1H), 5.91 (q, J = 6.4 Hz, 1H), 4.84 (s, 2H), 4.78 - 4.65 (m, 1H), 4.09 -4.02 (m, 2H), 3.94 (d, J= 10.4 Hz, 2H), 3.50 - 3.44 (m, 1H), 3.50 -3.44 (m, 1H), 3.16-2.96 (m, 2H), 2.05 - 1.93 (m, 4H), 1.72 (d, J= 6.4 Hz, 3H). 381.0 19 'HNMR (400MHz, DMSO-Je) 5 8.44 (s, 1H), 8.40 (s, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.43 (d, J= 2.4 Hz, 1H), 7.38 (dd, J= 2.8, 9.2 Hz, 1H), 5.93 (q, J= 6.4 Hz, 1H), 5.48 - 5.39 (m, 1H), 4.84 (s, 2H), 4.13 -3.98 (m, 2H), 3.90 (dd, J= 8.8, 13.6 Hz, 1H), 3.54 (dd, J= 8.8, 13.6 Hz, 1H), 3.45 - 3.42 (m, 1H), 3.11 - 2.95 (m, 2H), 2.86 (td, J= 6.4, 12.8 Hz, 1H), 2.26-2.09 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H), 1.26 (d, J = 6.8 Hz, 3H). 429.2 20 'HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1 H), 8.42 (s, 1 H), 7.88 (d, J= 9.2 Hz, 1 H), 7.43 (d, J= 2.4 Hz, 1 H), 7.39 (dd, J= 2.4, 9.2 Hz, 1H), 5.93 (q, J= 6.4 Hz, 1H), 5.51 - 5.44 (m, 1H), 4.84 (s, 2H), 4.08 -4.00 (m, 2H), 3.82 - 3.79 (m, 1H), 3.62 - 3.60 (m, 1H), 3.46 - 3.38 (m, 1H), 3.31 - 3.25 (m, 1H), 3.13 - 2.96 (m, 2H), 2.75 - 2.62 (m, 1H), 2.64 - 2.56 (m, 1H), 1.72 (d, J= 6.4 Hz, 3H). 415.2 21 'HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.43 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.43 (d, J= 2.4 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.90 (q, J= 6.4 Hz, 1H), 4.98 - 4.86 (m, 1H), 4.84 (s, 2H), 4.04 (t, J= 6.0 Hz, 2H), 3.46 - 3.39 (m, 2H), 3.21 - 3.18 (m, 2H), 3.14 -3.05 (m, 1H), 3.04 -2.93 (m, 1H), 2.45-2.31 (m, 4H), 1.72 (d, J= 6.4 Hz, 3H). 429.3 22 'HNMR (400 MHz, CDCh) 5 = 8.44 (s, 1H), 8.04 (d, J= 9.2 Hz, 1H), 7.53 (s, 1H), 7.38 (dd, J=2.4, 9.2 Hz, 1H), 7.33 (s, 1H), 5.81 (q, J= 6.4 Hz, 1H), 5.05 - 4.96 (m, 1H), 4.91 (s, 2H), 4.16 - 4.12 (m, 1H), 3.29 - 3.20 (m, 1H), 3.18 - 2.95 (m, 2H), 2.67 - 2.57 (m, 1H), 2.56 -2.49 (m, 1H), 2.48 -2.38 (m, 2H), 2.21 -2.18 (m, 1H), 2.16 -2.06 (m, 1H), 1.80 (d, J= 6.4 Hz, 3H). 390.0 23 'HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.34 (s, 1H), 7.91 -7.83 (m, 1H), 7.46 - 7.41 (m, 1H), 7.41 - 7.37 (m, 1H), 5.95 - 5.89 (m, 1H), 5.15-4.86 (m, 2H), 4.83 (s, 2H), 4.10 - 3.97 (m, 4H), 3.76 - 399.3 No. NMR MS1 3.51 (m, 2H), 3.18-2.92 (m, 2H), 2.45 - 2.35 (m, 1H), 1.98 (dd, J= 3.2, 12.6 Hz, 1H), 1.74 (d, J= 6.4 Hz, 3H). 24 'HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.34 (s, 1H), 7.95 -7.82 (m, 1H), 7.44 (d, J= 2.4 Hz, 1H), 7.40 (dd, J= 2.4, 9.1 Hz, 1H), 5.98 - 5.86 (m, 1H), 5.18 - 4.86 (m, 2H), 4.84 (s, 2H), 4.12 - 3.94 (m, 4H), 3.79 - 3.52 (m, 2H), 3.19 - 2.91 (m, 2H), 2.46 - 2.35 (m, 1H), 2.07 - 1.93 (m, 1H), 1.74 (d, J= 6.4 Hz, 3H). 399.3 25 'HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.33 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.43 (d, J= 2.4 Hz, 1H), 7.38 (dd, J= 2.8, 8.8 Hz, 1H), 5.90 (q, 7= 6.4 Hz, 1H), 5.84 (d, 7= 5.6 Hz, 1H), 5.16-5.06 (m, 1H), 4.84 (s, 2H), 4.39 - 4.28 (m, 1H), 4.09 - 4.00 (m, 2H), 3.20 -3.05 (m, 2H), 3.04 - 2.94 (m, 1H), 2.62 - 2.56 (m, 1H), 2.45 - 2.39 (m, 2H), 1.93 - 1.89 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H). 406.2 26 'HNMR (400 MHz, DMSO-Je) 5 8.45 (s, 1H), 8.29 (s, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.44-7.37 (m, 2H), 5.93-5.88 (m, 1H), 5.28 (s, 1H), 4.84 (s, 2H), 4.80-4.74 (m, 1H), 4.06-4.03 (m, 2H), 3.14-2.96 (m, 2H), 2.52-2.53 (m, 4H), 1.72 (d, J = 6.4 Hz, 3H), 1.30 (s, 3H). 381.1 27 n / a 417 28 n / a 417 29 1HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.34 (s, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.44 (d, J = 2.7 Hz, 1H), 7.39 (dd, J = 9.1, 2.7 Hz, 1H), 5.89 (q, J = 6.4 Hz, 1H), 4.86 - 4.70 (m, 2H), 4.12 - 3.96 (m, 2H), 3.56 - 3.31 (m, 2H), 3.16 - 2.93 (m, 2H), 2.11 - 1.87 (m, 2H), 1.86 (s, 3H), 1.8- 1.59 (m, 4H). 411 30 'HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.32 (s, 1H), 7.90 -7.78 (m, 1H), 7.39 (d, J= 1.% Hz, 2H), 5.94 (q, J= 6.4 Hz, 1H), 5.50 (dt, J= 8.8, 4.4 Hz, 1H), 4.83 (s, 2H), 4.04 (td, J= 5.8, 2.0 Hz, 2H), 3.80 (qd, J= 14.6, 6.2 Hz, 2H), 3.36 (dd, J= 12.8, 6.4 Hz, 1H), 3.14 -2.86 (m, 4H), 1.73 (d, J= 6.4 Hz, 3H), 0.57 (d, J= 6.7 Hz, 3H). 429 31 n / a 434 32 1HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.40 (s, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.53 - 7.22 (m, 2H), 5.92 (q, J = 6.4 Hz, 1H), 4.97 (tt, J = 7.1, 3.8 Hz, 1H), 4.84 (s, 2H), 4.05 (td, J = 5.8, 1.6 Hz, 2H), 3.40 - 3.32 (m, 2H), 3.24 - 2.91 (m, 3H), 2.72 - 2.52 (m, 2H), 2.38 (ddt, J = 13.9, 8.5, 3.8 Hz, 1H), 2.23 (ddd, J = 13.5, 8.6, 3.7 Hz, 1H), 1.73 (d, J = 6.4 Hz, 3H), 1.31 (d, J = 7.0 Hz, 3H). 433 33 'HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.40 (s, 1H), 7.88 (d, J= 9.1 Hz, 1H), 7.45 - 7.36 (m, 2H), 5.92 (q, J= 6.4 Hz, 1H), 4.97 (tt, J= 7.1, 3.8 Hz, 1H), 4.84 (s, 2H), 4.05 (td, J= 5.8, 1.8 Hz, 2H), 3.36 (ddd, J= 14.6, 7.6, 3.8 Hz, 2H), 3.23 - 2.92 (m, 3H), 2.68 - 2.51 (m, 2H), 2.40 (tt, 7=9.9,4.1 Hz, 1H), 2.23 (ddd, 7= 13.7, 8.8, 3.7 Hz, 1H), 1.73 (d, 7= 6.4 Hz, 3H), 1.29 (d, J = 7.0 Hz, 3H). 433 34 'HNMR (400 MHz, DMSO-7?) 5 8.44 (s, 1H), 8.42 (s, 1H), 7.88 (d, 7= 9.1 Hz, 1H), 7.46 - 7.36 (m, 2H), 5.89 (q, 7= 6.4 Hz, 1H), 5.04 -4.90 (m, 1H), 4.84 (s, 2H), 4.05 (td, 7= 5.8, 1.7 Hz, 2H), 3.55 - 3.38 (m, 2H), 3.30 - 3.22 (m, 1H), 3.10 (dt, 7= 17.5, 5.6 Hz, 1H), 2.99 (dt, 433 No. NMR MS1 J= 17.6, 5.8 Hz, 1H), 2.46-2.28 (m, 3H), 2.18 (q, J= 12.6 Hz, 1H), 1.71 (d, 7= 6.4 Hz, 3H), 1.17 (d, J= 6.8 Hz, 3H). 35 'HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.42 (s, 1H), 7.88 (d, J= 9.0 Hz, 1H), 7.47 - 7.34 (m, 2H), 5.89 (q, J= 6.4 Hz, 1H), 5.06 -4.88 (m, 1H), 4.84 (s, 2H), 4.05 (td, J= 5.7, 2.6 Hz, 2H), 3.48 (dddd, J= 19.3, 17.0, 9.3, 4.2 Hz, 2H), 3.27 (dt,7= 14.4, 3.6 Hz, 1H), 3.10 (dt,7= 17.5, 5.7 Hz, 1H), 2.99 (dt,7= 17.5, 5.7 Hz, 1H), 2.45-2.27 (m, 3H), 2.19(q,7= 12.6 Hz, 1H), 1.71 (d,7=6.4 Hz, 3H), 1.18(d,7 = 6.8 Hz, 3H). 433 36 'HNMR (400 MHz, DMSO-7?) 5 8.44 (s, 1H), 8.42 (s, 1H), 7.88 (d, 7= 9.2 Hz, 1H), 7.43 (d, 7= 2.8 Hz, 1H), 7.39 (dd, 7= 2.8, 9.2 Hz, 1H), 5.93 (q, 7= 6.4 Hz, 1H), 5.54 - 5.42 (m, 1H), 4.84 (s, 2H), 4.09 -4.00 (m, 2H), 3.81 (dd, 7= 8.0, 13.6 Hz, 1H), 3.59 (dd, 7= 7.2, 13.6 Hz, 1H), 3.47 - 3.35 (m, 2H), 3.13 - 2.96 (m, 2H), 2.79 - 2.71 (m, 1H), 2.61 - 2.57 (m, 1H), 1.72 (d, 7= 6.4 Hz, 3H). 415.2 37 1H NMR (400 MHz, DMSO) 5 8.43 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 9.1 Hz, 1H), 7.44 (d, J = 2.8 Hz, 1H), 7.39 (dd, J = 9.1, 2.7 Hz, 1H), 5.92 (q, J = 6.4 Hz, 1H), 5.33 - 5.20 (m, 1H), 4.84 (s, 2H), 4.12 -3.99 (m, 3H), 3.10 (dt, J = 17.6, 5.7 Hz, 1H), 3.05 - 2.96 (m, 1H), 3.01 (s, 3H), 2.94 (dd, J = 8.4, 6.3 Hz, 4H), 1.72 (d, J = 6.4 Hz, 3H). 429 1 LCMS M / Z (M+H). Example 38: Synthesis of 9-((R)-l-(l-((ls,3S)-3-methoxy-3-methylcyclobutyl)- 1H-1,2,3-triazol-4-yl)ethoxy)-1,4-dihydro-2H-pyrano[3,4- NaH, Mel THF To a solution of3-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]-l-methyl-cyclobutanol (30 mg, 0.079 mmol, Example 17) in tetrahydrofuran (0.5 mL) was added sodium hydride (6.3 mg, 0.16 mmol, 60 mass% in mineral oil) at 0 °C. The resulting mixture was allowed to stir at 0 °C for 10 min 10 before iodomethane (22.4 mg, 0.16 mmol) was added. Then the reaction was allowed to stir at 25 °C for 5 h. After that, the reaction mixture was quenched with saturated NaHCO? aqueous solution and extracted with isopropyl acetate and dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (20-60% acetonitrile in water with 0.1% ammonium hydroxide) to afford the title compound (11.2 mg, 36% yield) as a white solid. 'H NMR (400 MHz, DMSO-r / e) 5 8.44 (s, 1H), 8.32 (s, 1H), 7.87 (d,7=9.1Hz, 1H), 7.44 (d, 7=2.7 Hz, 1H), 7.38 (dd, 7= 9.1, 2.7 Hz, 1H), 5.89 (q, 7= 6.4 Hz, 1H), 4.89 (q,7=8.3 Hz, 1H), 4.83 (s, 2H), 4.05 (td, 7= 5.7, 2.7 Hz, 2H), 3.12 (s, 3H), 3.16 - 3.04 (m, 1H), 2.99 (dt, 7 = 17.7, 5.7 Hz, 1H), 2.57-2.51 (m, 4H), 1.72 (d, 7= 6.4 Hz, 3H), 1.34 (s, 3H). LCMS M / Z (M+H) 395.2. Example 39: 2-((25, 4R)-4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin- 9-yl)oxy)ethyl)-1H-1,2,3 -tri azol-1 -yl)tetrahydro-2H-pyran-2-yl)ethan-1 -ol Step 1: 2-((cis)-4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)tetrahydro-2H-pyran-2-yl)ethyl benzoate was prepared in a similar fashion to Compound 15, using azide intermediate T-6. 1H NMR (400 MHz, DMSO-de) 5: 8.44 (s, 1H), 8.35 (s, 1H), 7.97 (d, 7= 8.4 Hz, 2H), 7.88 (d, 7= 9.2 Hz, 1H), 7.70 - 7.62 (m, 1H), 7.57 - 7.48 (m, 2H), 7.44 (d, 7= 2.8 Hz, 1H), 7.39 (dd, 7= 2.8, 9.2 Hz, 1H), 5.90 (q, 7= 6.4 Hz, 1H), 4.93 - 4.69 (m, 3H), 4.47 -4.25 (m, 2H), 4.17 -3.92 (m, 3H), 3.76 - 3.60 (m, 1H), 3.53 (brt,7= 11.2 Hz, 1H), 3.17-2.93 (m, 2H), 2.17 (br d,7= 12.4 Hz, 1H), 2.04 - 1.99 (m, 1H), 1.98 - 1.87 (m, 3H), 1.80 - 1.73 (m, 1H), 1.72 (d, 7= 6.4 Hz, 3H). LCMS M / Z (M+H)+ = 529.2. Step 2: 2-((cA)-4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)tetrahydro-2H-pyran-2-yl)ethan-1 -ol (Compound 39 in above scheme): To a solution of 2-[4-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]tetrahydropyran-2-yl]ethyl benzoate (210.0 mg, 0.400 mmol) in methyl alcohol (20 mL) was added K2CO3 (219.6 mg, 1.59 mmol) at 25 °C. The mixture was diluted with water (20 mL) and ethyl acetate (10 mL). After phase separation, the aqueous layer was further extracted with ethyl acetate (10 mLx2). The combined organic layers were washed with brine (10x2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile 1-28% / 0.2% formic acid in water) to afford 2-((cA)-4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl)tetrahydro-2H-pyran-2-yl)ethan-1 -ol (140 mg, 83% yield) as a colorless oil. 1-((1,4-dihydro-2H-pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-2H-pyran-2-yl)ethan-l-ol (140.0 mg, 0.260 mmol) was further separated by chiral SFC (Column: Chiralpak AD-3 50x4.6mm I.D., 3 pm. Mobile phase: A: CO2 B: iso-propanol (0.05% DEA). Gradient: from 5% to 40% of B in 2 min and hold 40% for 1.2 min, then 5% of B for 0.8 min, Flow rate: 4 mL / min Column temp.: 35 °c) to give 2-((cA)-4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl)tetrahydro-2H-pyran-2-yl)ethan-1 -ol (49 mg, 0.114 mmol, 43.1% yield, second peak) as a white solid. 'H NMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.35 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.44 (d, J= 2.4 Hz, 1H), 7.39 (dd, J= 2.4, 9.2 Hz, 1H), 5.89 (q, J= 6.4 Hz, 1H), 4.83 (s, 2H), 4.79 - 4.61 (m, 1H), 4.42 (t, J= 5.2 Hz, 1H), 4.13 - 4.02 (m, 2H), 3.98 (dd, 7=3.6, 11.6 Hz, 1H), 3.61-3.52 (m, 1H), 3.51 -3.41 (m, 3H), 3.17-2.94 (m, 2H), 2.08 (d, J= 12.4 Hz, 1H), 2.03 - 1.95 (m, 1H), 1.94 - 1.82 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H), 1.67 - 1.50 (m, 3H). LCMS M / Z (M+H)+ = 425.2. Examples 40 and 41: (S)-2-((2R,45)-4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl)tetrahydro-2H-pyran-2-yl)propan-l-ol (Example 40) and (R)-2-((2R,4S)-4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl)tetrahydro-2H-pyran-2-yl)propan-l-ol (Example 41) Examples 40 and 41 were synthesized in a similar fashion to Example 39 from H-2 and T-7 via two chiral SFC separations. C-l is known R configuration, the stereochemistry of C-2, C-3 and C-4 are arbitrarily assigned. The relative configuration of C-2 and C-3 is cis, which was confirmed by 2D NMR. First chiral SFC separation: Column: Chiralpak AD-3 150x4.6 mm I.D., 3 pm. Mobile phase: 40% of methanol (0.05% DEA) in CO2. Flow rate: 2.5 mL / min Column temp.: 35 °C. (S)-2-((2RAS)-4-(4-((R)-1 -((1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-2H-pyran-2-yl)propan-l-ol (21.9 mg, 0.0499 mmol, 17.5% yield, Compound 40, first peak) was obtained as a white solid. Other three peaks were overlapped and were separated successfully by second chiral SFC separation. Second chiral SFC separation: Column: Cellulose 2 150x4.6mm I.D., 5um Mobile phase: A: CO2 B: methanol (0.05% DEA). Isocratic: 40% B Flow rate: 2.5 mL / min. Column temp.: 35 °c (R)-2-((2R,4S)-4-(4-((R)-1-((1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl)tetrahydro-2H-pyran-2-yl)propan-l-ol (18.1 mg, 0.0303 mmol, 13.3% yield, Compound 41, first peak) was obtained as a white solid. Compound 40: 1H NMR (400 MHz, DMSO-r / e) 5 = 8.44 (s, 1H), 8.37 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.48 - 7.33 (m, 2H), 5.89 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.83 -4.74 (m, 1H), 4.45 (t, J= 5.2 Hz, 1H), 4.08 - 3.98 (m, 3H), 3.51 - 3.43 (m, 2H), 3.36 - 3.24 (m, 2H), 3.14 - 3.05 (m, 1H), 3.04 - 2.93 (m, 1H), 2.05 - 1.95 (m, 2H), 1.88 (dd, 7=4.8, 12.4 Hz, 1H), 1.81 - 1.74 (m, 1H), 1.72 (d, J= 6.4 Hz, 3H), 1.62 - 1.53 (m, 1H), 0.86 (d, J= 6.8 Hz, 3H). LCMS M / Z (M+H)+ = 439.1. Compound 41: T1 NMR (400 MHz, DMSO-Je) 5 = 8.44 (s, 1H), 8.36 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.44 (d, J= 2.0 Hz, 1H), 7.40 (s, 1H), 5.89 (q, J= 6.4 Hz, 1H), 4.83 (s, 2H), 4.83 - 4.62 (m, 1H), 4.41 (t, J= 5.2 Hz, 1H), 4.07 - 3.97 (m, 3H), 3.52 - 3.46 (m, 2H), 3.44 (m, 2H), 3.14 - 3.05 (m, 1H), 3.04 - 2.93 (m, 1H), 2.24 - 1.93 (m, 3H), 1.93 - 1.83 (m, 1H), 1.71 (d, J =6.4 Hz, 3H), 1.69-1.61 (m, 1H), 0.82 (d, J= 6.8 Hz, 3H).LCMS M / Z (M+H)+ = 439.1. Example 42: (R)-4-(4-( 1-((1,4-dihydro-2H-pyrano[3,4-c] quinolin-9- yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)bicyclo[2.1.1]hexane-l-carbonitrile To a mixture ofPBus (148 mg, 0.73 mmol), 2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-ol H-l (36.8 mg, 0.18 mmol) and 4-[4-[(15)-l-hydroxyethyl]triazol-l-yl]bicyclo[2.1.1]hexane-l-carbonitrile T-13 (40.0 mg, 0.18 mmol) in THF (3 mL) was added a solution of TMAD (126 mg, 0.73 mmol) in DCM (1 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred 2 h. The mixture was then concentrated under reduced pressure, and the residue was purified by flash chromatography [30% EE (25% ethanol in ethyl acetate) in petroleum] to afford 70 mg of the title compound. Then the compound was further purified by reverse phase chromatography (acetonitrile 30-60% 0.1% NH4OH in water) to afford 4-[4-[(1R)-1 -(2,4-dihydro-1 H-pyrano[3,4-c]quinolin-9-yloxy)ethyl ]triazol-1 -yl]bicyclo[2.1. l]hexane-l-carbonitrile (28.4 mg, 0.07 mmol, 38.2% yield) as a white solid. 'HNMR (400 MHz, DMSO-Je) 5 8.48 (s, 1H), 8.44 (s, 1H), 7.88 (d, 7=9.2 Hz, 1H), 7.46 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.92 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.17 3.93 (m, 2H), 3.17-2.90 (m, 2H), 2.64 (s, 2H), 2.29-2.23 (m, 2H), 2.23-2.15 (m, 4H), 1.71 (d, J= 6.4 Hz, 3H). LCMS [M+H]+ = 402.4. Examples 43-58: the compounds were synthesized using methods and procedures similar to those used in Example 42 using appropriate starting materials and synthetic intermediates. No. Structure Compound Name 43 .Ck (ll 1 J n~n (7?)-4-(4-(l-((l,4-dihydro-277-pyrano [3,4-c]quinolin-9-yl)oxy)ethyl) - 1H-1,2,3 -triazol-1 -yl)-2-oxabicyclo[2.1. l]hexane -1-carbonitrile 44 .0. 111 N it T N- n=N Peak 2 on SFC Method P 4-(4-(( / ?)-l-((l,4-dihydro-2H-pyrano[3,4-c] quinolin- 9-yl) oxy) ethyl)-1 / / -1.2.3-triazol-l-yl)-2- oxabicyclo[2.2. l]heptane-1 -carbonitrile 45 .0. n N 1J o^^ n-n     Y o ( / ?)-6-(4-(l-((l,4-dihydro-227-pyrano[3,4-c] quinolin-9-yl)oxy) ethyl)-1 / / -1,2.3-triazol-1 -yl) tctrahydro-5 / / -4a,6-methanopyrrolo [l,2-c]pyrimidin-1 (2 / / )-onc 46 XL ri' AX If T O"^5^ N-n     Y 0 ( / ?)-6-(4-(l-((l,4-dihydro-227-pyrano[3,4-c] quinolin- 9-yl)oxy) ethyl)- 1H-1,2,3 -triazol-1 -yl)-2-mcthyltctrahydro-5 / / -4a.6-mcth anopyrrolo[ 1,2-c]pyrimidin-l (227)-one 47 .0. fll A^N X J ~U / oh AN > T n—\S< .o n=n Peak 1 on SFC Method Q 2-(7-(4 - ((J?) -1 -((1,4-dihydro-227-pyrano[3,4-c] quinoline-9-yl) oxy) ethyl)- 1H-1,2,3 -triazol- 1-yl) tetrahydro-127,627-7,8a-methanopyrrolo[2,1 -c][ 1,4] oxazin-4-yl) propan-2-ol No. Structure Compound Name 48 .o. rii Jl J -T0H T N-t\ n N=N Peak 2 on SFC Method Q 2-(7-(4-((R)-1 -((1,4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl)oxy) ethyl)-1 / / -1,2,3 -triazol-1 -yl) tetrahydro-1H. 6 / / -7.8a-mcthanopyrrolo| 2.1 -c][ 1,4] oxazin-4-yl) propan-2-ol 49 XX Tn N=N (JR, 8aR)-7-(4-((R)-1 -((1,4-dihydro-2 / / -py rano [3,4-c]quinolin-9-yl)oxy) ethyl)- IH-1,2,3 -triazol-1 -yl) tetrahydro-1 / / -pyrrolo [2,1 -c] [ 1,4] oxazin-4(3 / / )-onc 50 Th J T **1^N \>N-V n=n        xb (R)-2-(4-(l-((l,4-dihydro-22 / -pyrano[3,4-c]quinolin- 9-yl)oxy)ethyl)-1H-1,2,3 -tri azol-1 -yl)tetrahydro- (H, 5H-2,7a-methanopyrrolizin-5-one 51 Til 1 T N \>N-T^ n=n        xb Peak 2 on SFC Method R 2-(4-((R)-l-((l,4-dihydro-22 / -pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-12 / -1,2,3 -tri azol-1 -yl)-6-mcthyltctrahydro-1 / / .5 / / -2.7«-mcth anopyrrolizin-5-one 52 .0. rii X T 0^^ F n=n       V 0 Peak 1 on SFC Method Q 2-(4-((R)-l-((l,4-dihydro-22 / -pyrano[3,4-c] quinolin- 9-yl)oxy) ethyl)- IH-1,2,3 -triazol-1 -yl)-6- fluorotctrahydro-1 / / .5 / / -2.7a-mcthanopyrrolizin-5-onc No. Structure Compound Name 53 pll 0 Peak 2 on SFC Method Q 2-(4-(( / ?)-l-((l,4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl) oxy) ethyl)-127-l,2,3-triazol-l-yl)-6-fluorotetrahydro-lH,5H-2,7a-methanopyrrolizin-5- one 54 Th a.n T             F n^n         f ( / ?)-9-( 1-( 1-(3-(difluoromethyl) bicyclo [1.1.1] pentan-1 -yl)- 1H-1,2,3 -triazol-4-yl) ethoxy)-1,4-dihydro-2H-pyrano[3,4-c] quinoline 55 XX PH jO^ F o               \ \3> n~n (R)-9-( 1-(1-(1 -(difluoromethyl)-2-oxabicyclo [2.1.1] hcxan-4-yl)-1 / / -1,2,3-triazol-4-yl) ethoxy)-1,4-dihydro-2 / / -pyrano [3,4-c] quinoline 56 XX Th zA / N 1J n~n     y 0 ( / ?)-8-(4-(l-((2,4-dihydro-l / / -pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)-1H-1,2,3 -triazol-1 -yl) tetrahydro- 1H-8,9a-methanopyrrolo[l,2-aQ [1,4] oxazcpin-5(2 / / )-onc 57 XX Th A J n-n     X 0 ( / ?)-6-(4-(l-((l,4-dihydro-227-pyrano [3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3 -triazol-1 -yl) tctrahydro-127,527-4a,6-methanopyrrolo [1,2-c] [1,3] oxazin-lone No. Structure Compound Name 58 .0. n T nAaL ) N'N (J?)-2-(4-(l-((l,4-dihydro-2H-pyrano [3,4-c]quinolin-9-yl) oxy) cthyl)-l / / -l.2.3-triazol-l-yl) tetrahydro-1 / / -2,8a-methanoindolizin-5(6H)-one Analyticla data for compounds of Examples 43-58 is provided in the table below: No. NMR MS1 43 'H NMR (400 MHz, DMSO-d6) 5 8.58 (s, 1H), 8.45 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.45 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.96 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.21 (s, 2H), 4.10 - 3.96 (m, 2H), 3.14 - 3.05 (m, 3H), 3.04 - 2.92 (m, 1H), 2.61 - 2.57 (m, 2H), 1.72 (d, J =6.4 Hz, 3H). 404.2 44 'HNMR (400 MHz, DMSO-d6) 5 8.50 (s, 1H), 8.45 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.45 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.93 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.17 (d, J= 6.4 Hz, 1H), 4.11 - 4.01 (m, 3H), 3.15 - 2.94 (m, 2H), 2.89 - 2.77 (m, 2H), 2.35 -2.19 (m, 4H), 1.72 (d, J= 6.4 Hz, 3H). 418.3 45 >HNMR (400 MHz, DMSO-d6) 5 8.54 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.47 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.4, 9.2 Hz, 1H), 6.39 ( s, 1H), 5.93 (m, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.19 - 3.94 (m, 2H), 3.71 (s, 2H), 3.17 - 2.89 (m, 4H), 2.44 (s, 2H), 2.16 (d, J= 5.2 Hz, 2H), 2.11 -2.06 (m, 2H),1.73 (d, . / = 6.4 Hz, 3H). 447.1 46 'HNMR (400 MHz, DMSO-d6) 5 8.54 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 7.39 (dd, J= 2.4, 9.2 Hz, 1H), 5.93 (q, J= 6.2 Hz, 1H), 4.84 (s, 2H), 4.10 - 3.98 (m, 2H), 3.72 (s, 2H), 3.22 (t, J= 6.0 Hz, 2H), 3.15 - 2.97 (m, 2H), 2.78 (s, 3H), 2.43 (s, 2H), 2.21 - 2.13 (m, 4H), 1.73 (d, J= 6.4 Hz, 3H). 461.1 47 'HNMR (400MHz, DMSO-d6) 5 5.47 - 8.43 (m, 2H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.91 (q, J= 6.8 Hz, 1H), 4.84 (s, 2H), 4.31 (s, 1H), 4.12 - 3.95 (m, 2H), 3.88 - 3.72 (m, 2H), 3.54 - 3.40 (m, 2H), 3.35 (s, 1H), 3.18 - 3.05 (m, 2H), 3.04 - 2.91 (m, 1H), 2.60 (dd, J= 3.2, 10.4 Hz, 1H), 2.39 - 2.33 (m, 1H), 2.20 (d, J =6.0 Hz, 1H), 2.02 (d, J =6.4 Hz, 1H), 1.93 - 1.86 (m, 1H), 1.72 (d, J =6.4 Hz, 3H), 1.14- 1.01 (m, 6H). 492.3 48 'HNMR (400MHz, DMSO-d6) 5 8.46 - 8.43 (m, 2H), 7.88 (d, J= 8.8 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.91 (q, J= 6.0 Hz, 1H), 4.84 (s, 2H), 4.31 (s, 1H), 4.12 - 3.97 (m, 2H), 3.87 - 3.74 (m, 2H), 3.51 - 3.42 (m, 2H), 3.35 (s, 1H), 3.17 - 3.05 (m, 2H), 3.04 - 2.92 (m, 1H), 2.60 (dd, J= 3.6, 10.8 Hz, 1H), 2.38 - 2.32 (m, 1H), 2.20 (d, . / = 6.4 Hz, 1H),2.O1 (d, J = 6.8 Hz, 1H), 1.94 -1.87 (m, 1H), 1.72 (d, J= 6.4 Hz, 3H), 1.14-1.03 (m, 6H). 492.3 49 >HNMR (400 MHz, DMSO-Je) 5 = 8.44 (s, 1H), 8.40 (s, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.43 - 7.41 (m, 1H), 7.41 - 7.36 (m, 1H), 5.91 (q, 436.1 No. NMR MS1 7= 6.4 Hz, 1H), 5.36 (dd, 7= 7.6, 9.6 Hz, 1H), 4.83 (s, 2H), 4.164.14 (m, 1H), 4.13 -4.09 (m, 1H), 4.08 - 4.01 (m, 2H), 3.98 - 3.88 (m, 2H), 3.83 (d, 7= 7.6 Hz, 2H), 3.44 - 3.38 (m, 1H), 3.14-3.04 (m, 1H), 3.04 - 2.93 (m, 1H), 2.58 - 2.54 (m, 1H), 2.12 - 2.00 (m, 1H), 1.71 (d, J =6.4 Hz, 3H). 50 'HNMR (400 MHz, DMSO-Je) 5 = 8.54 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.93 (q, J= 6.4 Hz, 1H), 4.83 (s, 2H), 4.10 - 3.95 (m, 2H), 3.70 (s, 2H), 3.14 - 2.94 (m, 2H), 2.56 - 2.51 (m, 4H), 2.17 (d, J= 5.6 Hz, 2H), 2.15 - 2.10 (m, 2H), 1.72 (d, J= 6.4 Hz, 3H) 432.1 51 'HNMR (400 MHz, DMSO-d6) 5 = 8.53 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.47 (d, J= 2.8 Hz, 1H), 7.39 (7= 2.8, 9.2 Hz, 1H), 5.94 (d, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.10 - 4.00 (m, 2H), 3.76 -3.69 (m, 2H), 3.15 - 3.06 (m, 1H), 3.04 - 2.94 (m, 1H), 2.75 - 2.65 (m, 1H), 2.62 (d, J= 5.6 Hz, 1H), 2.55 (s, 1H), 2.43 - 2.35 (m, 1H), 2.20 -2.11 (m, 2H), 1.81 - 1.75 (m, 1H), 1.74- 1.70 (m, 3H), 1.14 (d, J= 7.2 Hz, 3H) 446.1 52 'HNMR (400 MHz, DMSO-d6) 5 = 8.56 (s, 1H), 8.45 (s, 1H), 7.89 (d, J= 9.2 Hz, 1H), 7.47 (d, J= 2.0 Hz, 1H), 7.40 (d, J= 9.2 Hz, 1H), 5.95 (q, J= 6.4 Hz, 1H), 5.50 - 5.20 (m, 1H), 4.84 (s, 2H), 4.05 (t, J= 5.6 Hz, 2H), 3.95 - 3.87 (m, 1H), 3.86 - 3.75 (m, 1H), 3.17 - 2.95 (m, 2H), 2.81 -2.70 (m, 1H), 2.67(7=6.4, 12.0 Hz, 2H), 2.38 -2.26 (m, 1H), 2.26 - 2.15 (m, 2H), 1.73 (d, J= 6.4 Hz, 3H) 450.1 53 'HNMR (400 MHz, DMSO-d6) 5 = 8.56 (s, 1H), 8.45 (s, 1H), 7.89 (d, J= 9.2 Hz, 1H), 7.47 (d, J= 2.4 Hz, 1H), 7.39 (7= 2.4, 9.2 Hz, 1H), 5.95 (d,7= 6.4 Hz, 1H), 5.45 - 5.24 (m, 1H), 4.84 (s, 2H), 4.05 (s, 2H), 3.94 - 3.87 (m, 1H), 3.81 (d, 7= 9.2 Hz, 1H), 3.17 - 2.95 (m, 2H), 2.81 - 2.70 (m, 1H), 2.67 (t, 7= 6.8 Hz, 2H), 2.38 - 2.26 (m, 1H), 2.25 - 2.16 (m, 2H), 1.73 (d, 7= 6.4 Hz, 3H) 450.1 54 'H NMR (400MHz, DMSO-d6) Shift = 8.44 (d, 7= 2.4 Hz, 2H), 7.88 (d, 7= 9.2 Hz, 1H), 7.45 (d, 7= 2.8 Hz, 1H), 7.38 (dd, 7= 2.8, 9.2 Hz, 1H), 6.52 - 6.16 (m, 1H), 5.92 (q, 7= 6.4 Hz, 1H), 4.84 (s, 2H), 4.09 -4.01 (m, 2H), 3.15-2.95 (m, 2H), 2.43 (s, 6H), 1.71 (d, 7= 6.4 Hz, 3H). 413.2 55 'H NMR (400MHz, CHLOROFORM-d) 5 = 8.45 (s, 1H), 7.99 (d, 7 = 9.2 Hz, 1H), 7.64 (s, 1H), 7.40 - 7.34 (m, 1H), 7.33 (s, 1H), 6.23 -5.88 (m, 1H), 5.85 (q, 7= 6.4 Hz, 1H), 4.91 (s, 2H), 4.27 (s, 2H), 4.21 - 4.01 (m, 2H), 3.19 - 2.95 (m, 2H), 2.55 (t,7= 5.6 Hz, 2H), 2.44 -2.35 (m, 2H), 1.81 (d, 7= 6.8 Hz, 3H). 429.0 56 'H NMR (400MHz, DMSO-de) 5 8.56 (s, 1H), 8.45 (s, 1H), 7.88 (d, 7 = 9.2 Hz, 1H), 7.47 (d, 7= 2.4 Hz, 1H), 7.40 (dd, 7= 2.8, 9.2 Hz, 1H), 5.95 (q,7= 6.4 Hz, 1H), 4.84 (s, 2H), 4.18 (s, 2H), 4.09 - 3.99 (m, 2H), 3.85 (s, 2H), 3.80 (t,7= 6.0 Hz, 2H), 3.15 - 3.06 (m, 1H), 3.05 - 2.96 (m, 1H), 2.49 - 2.44 (m, 4H), 2.30 - 2.21 (m, 2H), 1.73 (d, 7= 6.4 Hz, 3H). 462.3 57 'HNMR (400MHz, DMSO-7,) 5 8.57 (s, 1H), 8.45 (s, 1H), 7.89 (d, J = 9.6 Hz, 1H), 7.47 (s, 1H), 7.40 (d, 7= 10.0 Hz, 1H), 5.94 (d, 7= 6.0 Hz, 1H), 4.84 (s, 2H), 4.18 (s, 2H), 4.05 (s, 2H), 3.84 (s, 2H), 3.17 - 448.2 No. NMR MS1 3.07 (m, 1H), 3.03 (s, 1H), 2.55 (s, 2H), 2.30 (s, 2H), 2.23 (s, 2H), 1.73 (d, J=6.4Hz, 3H). 58 'H NMR (400MHz, DMSO-J6) 8.54 (s, 1H), 8.45 (s, 1H), 7.89 (d, J= 9.2 Hz, 1H), 7.47 (d, J= 2.4 Hz, 1H), 7.40 (dd, J= 2.4, 9.2 Hz, 1H), 5.94 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.05 (t, J= 5.2 Hz, 2H), 3.80 (s, 2H), 3.17 - 3.06 (m, 1H), 3.05 - 2.94 (m, 1H), 2.48 - 2.45 (m, 2H), 2.23-2.16 (m, 4H), 2.03 - 1.96 (m, 2H), 1.73 (d, J= 6.4 Hz, 5H) 446.3 'LCMS M / Z (M+H). Examples 43-58: the compounds were synthesized using methods and procedures similar to those used in Example 42 using appropriate starting materials and synthetic intermediates. Example 59: 1 -(3-(4-(( / / )-1 -((1,4-dihydro-2H-pyrano[3.4-c|quinolin-9- yl)oxy)ethyl)-1 / 7-1,2,3-tri azol-1-yl)bicy clo[ 1. 1. l]pentan-l-yl)ethan-l-ol Step 1: (R)-3-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)bicyclo[l.l.l]pentane-l-carbonitrile: The title compound was prepared in a similar fashion as Example 42 by Mitsunobu reaction between H-l and T-12 Step 2: (R)-l-(3-(4-(l-((l, 4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)bicyclo[l. 1.1]pentan-l-yl)ethan-l-one A solution of 3-[4-[(l / ?)-l-(2,4-dihydro-l / / -pyrano[3,4-c]quinolin-9-yloxy)ethyl] triazol-1-yl]bicyclo[l.l.l]pentane-l-carbonitrile (60 mg, 0.15 mmol) in THF (4 mL) was added methyllithium (6.8 mg, 0.31 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h and then allowed to warm to room temperature and stirred at 25 °C for 3 h. HC1 (10%, 0.65 ml) was added and the mixture was stirred at 25 °c for 3 h, then diluted with water and adjusted to pH = 7 with saturated aqueous sodium bicarbonate solution. The aqueous was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was used next step directly. LCMS M / Z (M+H) 405.1. Step 3: l-(3-(4-((R)-l-((l ,4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)bicyclo[l. 1.1]pentan-1-y I) ethan-l-ol: To a solution of l-[3-[4-[(U?)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy) ethyl] triazol-l-yl]-l-bicyclo [1.1.1] pentanyl] ethanone (60 mg, 0.15 mmol) in MeOH (4mL) was added NaBH4 (12 mg, 0.32 mmol) at 0 °C, and the mixture was stirred for 0.5 h. The reaction was quenched with saturated aqueous NH4CI (0.5 mL), then concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (acetonitrile 30-60% 0.1%NH4OH in water) to afford l-[3-[4-[(17?) -1 -(2,4-dihydro- IH-pyrano [3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -bicyclo[l.l.l]pentanyl] ethanol (21.5 mg, 0.05 mmol, 35%yield) as a white solid. 'H NMR (400 MHz, DMSO<L) 5 8.44 (s, 1H), 8.36 (s, 1H), 7.87 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 7.38 (dd, J= 2.8, 9.2 Hz, 1H), 5.90 (q, J= 6.4 Hz, 1H), 4.83 (s, 2H), 4.68 (d, 7= 4.4 Hz, 1H), 4.13-3.97 (m, 2H), 3.87 - 3.73 (m, 1H), 3.16-2.92 (m, 2H), 2.19-2.14 (m, 3H), 2.13 - 2.07 (m, 3H), 1.71 (d, J= 6.4 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H). LCMS M / Z (M+H) 407.1. Example 60 & 61 (7-(4-((R)-l-((5-methyl-l,4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2,l-c] [1,4] oxazin-4-yl)methanol Peak 1 Peak 2 Step 1: 4-(((tert-butyldimethylsilyl)oxy)methyl)-7-(4-((R)-l-((5-methyl-l,4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)-lH-l ,2,3-triazol-1-yI) tetrahydro-1H,6H-7,8a-methanopyrrolo [2,1 -c] [1,4] oxazine: tert-Butyl-dimethyl-[[8-[4-[(U?)-l-[(5-methyl-2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yl)oxy]ethyl]triazol-l-yl]-3-oxa- 6-azatricyclo[6.1.1.01,6]decan-5-yl]methoxy]silane was prepared as a yellow oil in a similar fashion as Example 42 by Mitsunobu reaction between H-l and T-19. Step 2: (7-(4-((R)-l-((5-methyl-l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH,6H-7,8a-methanopyrrolo[2,l-c][l,4]oxazin-4-yl)methanol To a solution of tert-butyl-dimethyl-[[8-[4-[(I / ?)-1- [(5-methyl-2,4-dihydro-177-pyrano [3,4-c] quinolin-9-yl) oxy] ethyl] triazol- 1-yl]-3-oxa-6-azatricyclo [6.1.1.01,6]decan-5-yl]methoxy]silane (261 mg, 0.44 mmol) in THF (12 mL) was added TBAF (0.88 mL, 0.88 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h, then was diluted with water and extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure and purified by flash chromatography (10% methyl alcohol in ethyl acetate) to afford the title compound 200 mg as a white solid, which was further purified by reverse phase chromatography (acetonitrile 1-28% 0.2% formic acid in water) to afford the racemic title compound 147 mg as a white solid. The racemate was separated by SFC: (Column: ChiralPak AD-3 150x4.6 mm I.D., 3 pm; Mobile phase: A: CO2 B: ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 2.5mL / min) to give Peak 1 (7-(4-((R)-1 -((5 -methyl-1,4-dihydro-2H-py rano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl)tetrahydro-I / / . 6 / / -7.8a-mcthanopyrrolo[2,1 -c] [ 1,4]oxazin-4-yl)methanol (57.3 mg, 0.12 mmol, 38% yield) as a white solid. 'H NMR (400 MHz, DMSO-r / e) 5 8.44 (s, 1H), 8.29 (s, 1H), 7.79 (d, J= 9.2 Hz, 1H), 7.42 (d, J= 2.4 Hz, 1H), 7.34 (dd, J= 2.0, 9.2 Hz, 1H), 5.88 (q, J= 6.4 Hz, 1H), 4.77 (s, 2H), 4.60 (s, 1H), 4.07 - 3.96 (m, 2H), 3.93 - 3.82 (m, 2H), 3.53 (d, J= 11.6 Hz, 1H), 3.44 (d, J= 4.4 Hz, 1H), 3.40 (d, J= 8.0 Hz, 2H), 3.21 - 3.17 (m, 1H), 3.15 - 3.05 (m, 1H), 3.02 - 2.94 (m, 2H), 2.67 (s, 1H), 2.42 (s, 3H), 2.27 (d, J= 6.4 Hz, 1H), 2.04 (d, J= 6.8 Hz, 1H), 1.91 (dd, J= 6.0, 9.6 Hz, 1H), 1.71 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 478.3. And peak 2 (7-(4-((R)-l-((5-methyl-l,4-dihydro-227-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl)tetrahydro-177,677-7,8a-methanopyrrolo [2,1-c][l,4]oxazin-4-yl)methanol (49.5 mg, 0.10 mmol, 33% yield) as a white solid. 'H NMR (400 MHz, DMSO-^) 5 8.44 (s, 1H), 7.79 (d, J= 9.2 Hz, 1H), 7.43 (d, J= 2.8 Hz, 1H), 7.34 (dd, J= 2.8, 9.2 Hz, 1H), 5.88 (q, J= 6.4 Hz, 1H), 4.77 (s, 2H), 4.59 (t, J=5.6 Hz, 1H), 4.08 -3.95 (m, 2H), 3.92 - 3.83 (m, 2H), 3.53 (d,J= 11.6 Hz, 1H), 3.47 - 3.38 (m, 2H), 3.24 - 3.12 (m, 2H), 3.11 - 3.03 (m, 1H), 3.02 - 2.92 (m, 2H), 2.67 (m, J= 3.6, 6.8 Hz, 1H), 2.42 (s, 3H), 2.39 (d, J= 6.8 Hz, 1H), 2.27 (d, J= 6.4 Hz, 1H), 2.04 (d, J= 6.8 Hz, 1H), 1.92 (dd, J= 6.0, 9.6 Hz, 1H), 1.71 (d, J = 6.4 Hz, 3H). LCMS M / Z (M+H) 478.3. Example 62: (R)-6-(4-(l-((l, 4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl) oxy)ethyl)-lH-l, 2,3-triazol-l-yl)tetrahydro-3H, 5H-6,7a-methanopyrrolo[l ,2-c] imidazol-3-one Step 1: (R)-6-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3-triazol-l-yl)-2-tosyltetrahydro-3H, 5H-6,7a-methanopyrrolo[l, 2-c]imidazol-3-one: The tittle compound was prepared as a colorless oil in a similar fashion as Example 42 by Mitsunobu reaction between H-l and T-20. Step 2: (R)-6-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3-triazol-l-yl)tetrahydro-3H, 5H-6,7a-methanopyrrolo[l, 2-c] imidazol-3-one: To a solution of 7-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl] triazol-l-yl]-3-(p-tolylsulfonyl)-3,5-diazatricyclo[5.1.1.01,5]nonan-4-one (30 mg, 0.05 mmol) in dioxane (1 ml) was added H2SO4 (20 mg, 0.2 mmol) at 25 °C. The resulting mixture was stirred at 50 °C for 0.5 h, then the mixture pH was adjusted to 7 with NaOH(aq) (IM). The reaction was diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (water (0.2%FA)-ACN) to afford the tittle compound (4.7 mg, 21.3% yield) as a white solid. 'H NMR (400 MHz, DMSO-J6) 5 8.55 (s, 1H), 8.45 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.47 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 6.74 (s, 1H), 5.94 (q, J = 6.4 Hz, 1H), 4.84 (s, 2H), 4.10 - 4.00 (m, 2H), 3.58 (s, 2H), 3.40 (s, 2H), 3.15 - 2.93 (m, 2H), 2.53 (d, J = 5.6 Hz, 2H), 2.23 (d, J = 5.2 Hz, 2H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 433.3. Example 63: (R)-9-(l-(1-(1 -(fluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)- 1H-1,2,3-triazol-4-yl)ethoxy)-2,4-dihydro-lH-pyrano[3,4-c] quinoline Step 1: 4-azido-l-(fluoromethyl)-2-oxabicyclo[2.1.1]hexane: To a solution of l-(fluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-amine hydrochloride (50 mg, 0.3 mmol) in DMF (1 mL) was added sulfurazidic fluoride (MTBE solution prepared from above step) and sat. KHCO3 aqueous solution (1 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The whole mixture was carried on directly to next step without further purification. Step 2: (R)-9-(l-(l-(l-(fluoromethyl)-2-oxabicyclo[2.1.1]hexan-4-yl)-lH-1,2,3-triazol-4-yl)ethoxy)-2,4-dihydro-lH-pyrano[3,4-c]quinolone: To the mixture containing 4-azido-l-(fluoromethyl)-2-oxabicyclo[2.1.1]hexane obtained from the previous step was added 9-[( l / ?)-l-mcthylprop-2-ynoxy|-2.4-dihydro-l / / -pyrano|3.4-c]quinoline H-2 (272 mg, 0.3 mmol), CuSO4 (11.7 mg, 0.07 mmol) and sodium ascorbate (14.5 mg, 0.07 mmol). The mixture was stirred at room temperature for 16 h, then was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water (0.2%FA)-ACN) to afford the title compound (40 mg, 33.3% yield) as a white solid. 'HNMR (400 MHz, DMSO-de) 5 8.56 (s, 1H), 8.45 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.50 7.43 (m, 1H), 7.39 (dd, J= 2.4, 9.2 Hz, 1H), 5.95 (q, J= 6.0 Hz, 1H), 4.84 (s, 2H), 4.78 (s, 1H), 4.66 (s, 1H), 4.14 (s, 2H), 4.09 3.98 (m, 2H), 3.16 2.95 (m, 2H), 2.48 2.43 (m, 2H), 2.21 (d, J= 5.2 Hz, 2H), 1.73 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H)411.2. Examples 64-90: the compounds were synthesized using methods and procedures similar to those used in Example 63 using appropriate starting materials and synthetic intermediates. No. Structure Name 64 .o. Tn N=N (J?)-9-( 1-( 1-(1 -methyl-2-oxabicyclo [2.1.1] hexan-4-yl)- 1H-1,2,3 -triazol-4-yl) ethoxy)-2,4-dihydro-IH-pyrano [3,4-c] quinoline 65 Y       __ OH n—\7 N=n' (4-(4-( 1 -((2,4-dihydro-1 H-pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl) bicyclo[2.2. l]heptan-l-yl)methanol 66 .0. 111 IJ T            oh N—O ' N=N ( / ?)-(3 -(4-( 1 -((1,4-dihydro-2H-py rano [3,4-c] quinolin-9-yl) oxy) ethyl)-1 / / -1.2.3-triazol-l-yl) bicyclo [1.1.1] pentan-1-yl) methanol 67 JX Til CT / --\ 0H n—TT— N=n' V-o Peak 1 on SFC Method Q [4-[4-[( 1R)-1 -(2,4-dihydro-1 H-pyrano [3,4-c]quinolin-9-yloxy)ethyl] triazol-1-yl] -2-oxabicyclo [2.2.1] heptan-l-yl] methanol 68 o p cfy / A vV\= / ( / ?)-4-(4-( 1 -((1,4-dihydro-2H-pyrano [3,4-c] quinolin-9-yl)oxy) cthyl)-l / / -l.2.3-triazol-l-yl)-2-thiabicyclo [2.1.1] hexane 2,2-dioxide 69 [(4-[4-[( 17?)-1 -(2,4-dihydro-1 H-pyrano [3,4-c] quinolin-9-yloxy) ethyl]triazol-l-yl]-l-(fluoromethyl)-2-oxabicyclo [2.1.1] hexan-3-yl] methanol No. Structure Name .0. Til o^^ iyN-<4 n-n ru OH Peak 1 on SFC Method S 70 .0. Th IJ J\^\ a~T^f n=n y OH Peak 2 on SFC Method S [(4-[4- [( 1R)-1 -(2,4-dihydro-1 H-pyrano [3,4-c] quinolin-9-yloxy) ethyl]triazol-l-yl]-l-(fluoromethyl)-2-oxabicyclo [2.1.1] hexan-3-yl] methanol 71 th X J N—^S*0 n=n b (R)-4-(4-( 1 -((5 -methyl-1,4-dihydro-2H- pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-l,2,3-triazol-l-yl)-2- thiabicyclo[2.1. l]hexane 2,2-dioxide 72 0. Lil yvN O-^^ OH (peak 1) (4-(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4-c]quinolin-9-yl)oxy)ethyl)- \H-1,2,3-triazol-1 -yl)-1 -methyl-2- oxabicyclo[2.1. l]hexan-3-yl)methanol 73 Til flN OH (peak 2) (4-(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4-c]quinolin-9-yl)oxy)ethyl)- \H-1,2,3-triazol-1 -yl)-1 -methyl-2- oxabicyclo[2.1. l]hexan-3-yl)methanol No. Structure Name 74 5 N=N (R)-9-( 1-(1 -(2-oxaspiro [3,3]heptan-6-yl)-1 / / -1,2,3 -triazol-4-yl)ethoxy)-1,4-dihydro-2 / / -py rano | j. 4-c] quinoline 75 .0. Th / T n=N (S)-9-( 1-(1 -(2-oxaspiro [3,3]heptan-6-yl)-1 / / -1,2,3 -triazol-4-yl)ethoxy)-1,4-dihydro-2 / / -py rano | j. 4-c] quinoline 76 .0. rii m r t n=n Peak 1 on SFC Method Y N-( 1-(1 -(2-oxaspiro [3.3]heptan-6-yl)-1 / / -l,2,3-triazol-4-yl)ethyl)-2,4-dihydro-l / / -pyrano[3,4-c] quinol in-9-amine 77 PH r y HN^5^ ^nXX)0 n'N Peak 2 on SFC Method Y N-( 1-(1 -(2-oxaspiro [3.3]heptan-6-yl)-1 / / -l,2,3-triazol-4-yl)ethyl)-2,4-dihydro-l / / -pyrano[3,4-c] quinol in-9-amine 78 / ° T Ho z V= /   _ / O I 6-[4-[ 1 -(2,4-dihydro- l / / -pyrano [3,4-c]quinolin-9-yloxy)ethyl]triazol-1 -yl]spiro[3.3]heptan-2-ol No. Structure Name 79 .0. |f fl ^^0      OH N—< X / N=N v Peak 1 on SFC Method C 6-(4-((R)-1 -((2,4-dihydro-1 / / -pyran o 15.4-c]quinolin-9-yl)oxy)ethyl)- \H-1,2,3-triazol-1 -y 1) spi ro [ 3.3 ] heptan-1 -ol 80 .0. PH 1J l" N—J N=N Peak 1 on SFC Method Z 9-((lR)-l-(l-(6-oxaspiro[3.4]octan-2-yl)-\H-1,2,3 -triazol-4-yl)ethoxy)-2,4-dihydro-1 / / -py rano 15.4-c\ quinoline 81 .0. Il N A J z\A~0 N—\XJ n^n Peak 1 on SFC Method Y 9-((lR)-l-(l-(6-oxaspiro[3.4]octan-2-yl)-1H-1,2,3 -triazol-4-yl)ethoxy)-2,4-dihydro-1 / / -py rano 15.4-c] quinoline 82 z°\ r \ V ° \ 9-(( lR)-l-(l-(3 -oxabicyclo [3.1.0]hexan-6-yl)- 1H-1,2,3-triazol-4-yl)ethoxy)-2,4-dihydro-1 / / -pyrano 15.4-c]quinolone No. Structure Name 83 o— / 9-[(lR)-l-[l-[(lR,5S)-6,6-difluoro-3-bicyclo [3.1.0]hexanyl]triazol-4-yl]ethoxy] -2,4-dihydro-1 H-py rano [3,4-c]quinoline 84 -- Q5’ o Ci x° \ 9- [ 1 - [ 1 -(2-oxabicyclo [2.2.1] heptan-4-yl)triazol-4-yl] ethoxy] -2,4-dihydro- \H-pyrano [3,4-c] quinoline 85 ,0. PH n 1 J n=n Peak 3 on SFC Method C 5-(4-((R)-1 -((2,4-dihydro- IH-pyrano [3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3- triazol-1 -yl)bicyclo [2.2.1] heptan-2-ol 86 .0. [Il N X T N=N Mix of Peak 1 & 2 on SFC Method V 5-(4-((R)-1 -((2,4-dihydro- IH-pyrano [3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3- triazol-1 -yl)bicyclo [2.2.1] heptan-2-ol 87 ro o-\ €^¾ 9-[l-[l-(2,5 -dioxaspiro [3.4] octan-7-yl)triazol-4-yl] ethoxy] -2,4-dihydro- 1H-pyrano [3,4-c] quinoline No. Structure Name 88 pH Jf T v n-\A / N=n' 5-methyl-9-[(lR)-l-[l-(2- oxaspiro[3.3]heptan-6-yl)triazol-4-yl]ethoxy]-2,4-dihydro- lH-pyrano[3,4-c] quinoline 89 n r y n-\ / n N=n        ' 0H Methyl 5 -(4-((R)-1-((1,4-dihydro-2 / / -pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-l,2,3-triazol-l-yl)spiro[2.3]hexane-l-carboxylate 90 o I Methyl 5 -(4-((R)-1-((1,4-dihydro-2 / / -pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-l,2,3-triazol-l-yl)spiro[2.3]hexane-l-carboxylate Analyticla data for compounds of Examples 64-90 is provided in the table below: No. NMR m / z 64 'HNMR (400 MHz, DMSO-^) 5 8.50 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.93 (q, J= 6.8 Hz, 1H), 4.84 (s, 2H), 4.05 (s, 4H), 3.15 - 2.95 (m, 2H), 2.34 (dd, J= 2.8, 6.0 Hz, 2H), 2.11 - 2.06 (m, 2H), 1.72 (d, J = 6.4 Hz, 3H), 1.45 (s, 3H) 393.1 65 'HNMR (400 MHz, DMSO-Je) 5 8.44 (s, 1H), 8.33 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.4, 9.2 Hz, 1H), 5.89 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.63 (s, 1H), 4.09 - 4.00 (m, 2H), 3.46 (s, 2H), 3.15 - 3.06 (m, 1H), 3.04 - 2.94 (m, 1H), 2.03 (t, J= 6.4Hz, 4H), 1.87 (s, 2H), 1.83 - 1.75 (m, 2H), 1.72 (d, J= 6.4 Hz, 3H), 1.46 - 1.38 (m, 2H) 421.2 66 1HNMR(400MHz, CHLOROFORM-d) Shift = 8.46 - 8.39 (m, 1H), 8.42 (s, 1H), 7.97 (d, 7= 8.8 Hz, 1H), 8.10-7.85 (m, 1H), 7.54 (s, 1H), 7.57 - 7.51 (m, 1H), 7.42 - 7.32 (m, 2H), 5.82 (q, J= 6.4 Hz, 1H), 4.96 - 4.83 (m, 2H), 4.19 - 4.06 (m, 2H), 3.85 (s, 2H), 3.16 -2.98 (m, 2H), 2.31 (s, 6H), 1.79 (d, 7= 6.6 Hz, 3H). 393.3 No. NMR m / z 67 'HNMR (400 MHz, DMSO-de) 5 = 8.46 (d, J= 8.0 Hz, 2H), 7.93 -7.86 (m, 1H), 7.50 - 7.36 (m, 2H), 5.92 (q, J= 6.4 Hz, 1H), 4.93 -4.87 (m, 1H), 4.85 (s, 2H), 4.11 - 3.91 (m, 4H), 3.67 - 3.52 (m, 2H), 3.16 - 2.96 (m, 2H), 2.31 - 2.14 (m, 4H), 2.03 - 1.92 (m, 1H), 1.73 (d, J= 6.4 Hz, 3H), 1.72 - 1.65 (m, 1H). 423.3 68 XHNMR (400 MHz, DMSO-de) 5 = 8.55 (s, 1H), 8.45 (s, 1H), 7.89 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 7.39 (dd, J= 2.8, 9.1 Hz, 1H), 5.95 (q, . / = 6.4 Hz, 1H), 4.84 (s, 2H), 4.12-4.08 (m, 1H), 4.08 -4.02 (m, 2H), 3.79 (s, 2H), 3.14 (td, J= 2.0, 4.0 Hz, 2H), 3.11 - 2.97 (m, 2H), 2.66 - 2.59 (m, 2H), 1.72 (d, J= 6.4 Hz, 3H). 423.1 69 'HNMR (400MHz, DMSO-de) 5 = 8.45 (d, J= 3.6 Hz, 2H), 7.88 (d, J= 9.2 Hz, 1H), 7.57 - 7.30 (m, 2H), 5.92 (q, J= 6.4 Hz, 1H), 4.83 (s, 2H), 4.80-4.71 (m, 2H), 4.63 (s, 1H), 4.28 (t, J= 5.2 Hz, 1H), 4.11 -3.96 (m, 2H), 3.65 - 3.44 (m, 2H), 3.19 - 2.92 (m, 2H), 2.45 - 2.39 (m, 2H), 2.39 - 2.31 (m, 2H), 1.72 (d, J= 6.4 Hz, 3H). 441.1 70 'HNMR (400MHz, DMSO-de) 5 = 8.45 (d, J= 3.6 Hz, 2H), 7.88 (d, J= 9.2Hz, 1H), 7.44 (d, J= 2.4 Hz, 1H), 7.40 (dd, J= 2.4, 9.2 Hz, 1H), 6.03 - 5.82 (m, 1H), 4.84 (s, 2H), 4.80 - 4.72 (m, 2H), 4.63 (s, 1H), 4.30 (t, J= 4.8 Hz, 1H), 4.05 (s, 2H), 3.55 - 3.43 (m, 2H), 3.20 -2.89 (m, 2H), 2.45 - 2.40 (m, 2H), 2.40 - 2.35 (m, 2H), 1.72 (d, J= 6.4 Hz, 3H) 441.1 71 1HNMR(400 MHz, DMSO) 5 8.53 (s, 1H), 7.80 (d, J= 9.1 Hz, 1H), 7.43 (d, J= 2.7 Hz, 1H), 7.34 (dd, J= 9.1, 2.7 Hz, 1H), 5.91 (q, J= 6.4 Hz, 1H), 4.77 (s, 2H), 4.08 (t, J= 3.9 Hz, 1H), 4.01 (td, J= 5.7, 2.4 Hz, 2H), 3.78 (t, J= 1.6 Hz, 2H), 3.13 (ddt, J= 6.2, 4.1, 1.9 Hz, 2H), 3.11 - 2.95 (m, 2H), 2.66 - 2.57 (m, 2H), 2.42 (s, 3H), 1.70 (d, J = 6.4 Hz, 3H). 441 72 XHNMR (400 MHz, DMSO) 5 8.44 (s, 1H), 8.38 (s, 1H), 7.88 (d, J= 9.0 Hz, 1H), 7.48 - 7.32 (m, 2H), 5.91 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.66 (t, J= 5.5 Hz, 1H), 4.19 (dd, J= 5.7, 4.5 Hz, 1H), 4.04 (td, J= 5.7, 3.0 Hz, 2H), 3.52 - 3.38 (m, 2H), 3.09 (dt, J= 17.6, 5.8 Hz, 1H), 2.99 (dt, J= 17.6, 5.7 Hz, 1H), 2.41-2.15 (m, 4H), 1.71 (d, J= 6.4 Hz, 3H), 1.42 (s, 3H). 423 73 XHNMR (400 MHz, DMSO) 5 8.44 (s, 1H), 8.38 (s, 1H), 7.88 (d, J= 9.1 Hz, 1H), 7.45 - 7.31 (m, 2H), 5.91 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.66 (t, J= 5.5 Hz, 1H), 4.20 (dd, J= 5.7, 4.5 Hz, 1H), 4.05 (td, J= 5.8, 2.1 Hz, 2H), 3.44 (tdd, J= 11.9, 8.8, 5.0 Hz, 2H), 3.09 (dt, J = 17.7, 5.9 Hz, 1H), 2.99 (dt, J= 17.7, 5.8 Hz, 1H), 2.26 (ddt, J= 17.8, 10.8, 3.4 Hz, 4H), 1.71 (d, . / = 6.4 Hz, 3H), 1.42 (s, 3H). 423 74 'HNMR (400 MHz, DMSO-d6) 5 8.44 (s, 1H), 8.34 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 2.8 Hz, 1H), 7.37 (dd, J = 2.8, 9.2 Hz, 1H), 5.89 (q, J = 6.4 Hz, 1H), 4.99 - 4.95 (m, 1H), 4.83 (s, 2H), 4.65 (s, 2H), 4.54 (s, 2H), 4.08 - 4.00 (m, 2H), 3.14 - 2.92 (m, 2H), 2.86 -2.76 (m, 2H), 2.68 - 2.65 (m, 2H), 1.70 (d, J = 6.4 Hz, 3H). 393.4 75 'HNMR (400 MHz, DMSO-d6) 5 8.45 (s, 1 H), 8.36 (s, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 7.43 (d, J = 2.8 Hz, 1 H), 7.38 (dd, J = 2.8, 8.8 Hz, 1 H), 5.89 (q, J = 6.4 Hz, 1 H), 4.97 (q, J = 8.0 Hz, 1 H), 4.83 (s, 2 H), 4.65 (s, 2 H), 4.54 (s, 2 H), 4.09-4.00 (m, 2 H), 3.13-3.06 (m, 1 393.2 No. NMR m / z H), 3.02-2.95 (m, 1 H), 2.86-2.78 (m, 2 H), 2.68-2.62 (m, 2 H), 1.70 (d, J =6.8 Hz, 3 H) 76 'HNMR (400 MHz, DMSO-d6) 5 8.19 (s, 1H), 8.04 (s, 1H), 7.66 (d, J =8.8 Hz, 1H), 7.20-7.17 (m, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.53 (d, J = 7.2 Hz, 1H), 4.98 - 4.90 (m, 1H), 4.85 - 4.77 (m, 3H), 4.64 (s, 2H), 4.53 (s, 2H), 4.07 - 3.94 (m, 2H), 2.97 - 2.92 (m, 1H), 2.83 -2.73 (m, 3H), 2.68 - 2.60 (m, 2H), 1.55 (d, J = 6.4 Hz, 3H) 392.3 77 'HNMR (400 MHz, DMSO-d6) 5 8.19 (s, 1H), 8.04 (s, 1H), 7.66 (d, J =8.8 Hz, 1H), 7.20-7.17 (m, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.53 (d, J = 7.2 Hz, 1H), 4.98 - 4.90 (m, 1H), 4.88 - 4.75 (m, 3H), 4.64 (s, 2H), 4.53 (s, 2H), 4.09 - 3.95 (m, 2H), 2.97 - 2.92 (m, 1H), 2.86 -2.73 (m, 3H), 2.69 - 2.58 (m, 2H), 1.55 (d, J= 6.4 Hz, 3H) 392.3 78 ND 407 79 'HNMR (400 MHz, DMSO-d6) 5 8.44 (s, 1H), 8.28 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.40 - 7.34 (m, 1H), 5.89 (q, J = 6.4 Hz, 1H), 5.16 (d, J = 5.6 Hz, 1H), 5.02 (quin, J = 8.4 Hz, 1H), 4.83 (s, 2H), 4.04 (s, 2H), 3.79 (q, J= 6.8 Hz, 1H), 3.18 - 2.95 (m, 2H), 2.79 - 2.65 (m, 1H), 2.43 - 2.29 (m, 1H), 2.05 - 1.93 (m, 1H), 1.83 - 1.74 (m, 1H), 1.71 (d, J= 6.4 Hz, 3H), 1.65 - 1.51 (m, 2H), 1.29 - 1.11 (m, 1H) 407.3 80 'HNMR (400 MHz, chloroform- d) 5 8.44 (s, 1H), 8.08 - 7.91 (m, 1H), 7.55 (s, 1H), 7.43 - 7.29 (m, 2H), 5.87 - 5.76 (m, 1H), 5.03 -4.93 (m, 1H), 4.90 (s, 2H), 4.17 - 4.09 (m, 2H), 3.91 - 3.82 (m, 2H), 3.76 (s, 2H), 3.16 - 2.96 (m, 2H), 2.74 - 2.55 (m, 4H), 2.11 - 2.03 (m, 2H), 1.80 (d, J = 6.4 Hz, 3H) 407.3 81 ND 407.3 82 'HNMR (400 MHz, DMSO-d6) 5 8.44 (s, 1H), 8.29 (s, 1H), 7.87 (d, J= 9.2 Hz, 1H), 7.42 (d, J= 2.8 Hz, 1H), 7.37 (dd, J= 2.8, 9.2 Hz, 1H), 5.89 (q, J= 6.4 Hz, 1H), 4.83 (s, 2H), 4.11-4.01 (m, 2H), 3.98 (d, J= 8.8 Hz, 2H), 3.69 (d, J= 2.0 Hz, 2H), 3.67 (s, 1H), 3.15 - 2.94 (m, 2H), 2.47 (s, 2H), 1.70 (d, J= 6.4 Hz, 3H) 379.3 83 ND 413 84 ND 393 85 'HNMR (400 MHz, DMSO-d6) 5 = 8.44 (s, 1H), 8.25 (s, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.38 - 7.35 (m, 2H), 5.92 - 5.84 (m, 1H), 4.83 (s, 2H), 4.78 - 4.71 (m, 1H), 4.66 (d, J= 3.6 Hz, 1H), 4.10 - 3.99 (m, 2H), 3.69 - 3.63 (m, 1H), 3.15 - 2.90 (m, 2H), 2.67 - 2.50 (m, 1H), 2.14 - 2.02 (m, 2H), 1.84 - 1.62 (m, 5H), 1.44 - 1.36 (m, 1H), 1.20 -1.11 (m, 1H), 1.05 - 0.95 (m, 1H) 407.3 86 'HNMR (400 MHz, DMSO-d6) 5 = 8.44 (s, 1H), 8.24 (s, 1H), 7.87 (d, J= 8.8 Hz, 1H), 7.42 - 7.35 (m, 2H), 5.87 (q, J = 6.4 Hz, 1H), 4.83 (s, 2H), 4.80 - 4.64 (m, 2H), 4.07 - 4.00 (m, 2H), 3.73 - 3.65 (m, 1H), 3.12 - 2.94 (m, 2H), 2.50 - 2.46 (m, 1H), 2.14 - 2.03 (m, 2H), 1.79 - 1.65 (m, 5H), 1.40-1.39 (m, 1H), 1.20-1.12 (m, 1H), 1.04 -0.95 (m, 1H) 407.3 87 ND 409 No. NMR m / z 88 1H NMR (400 MHz, DMSO) 5 8.32 (s, 1H), 7.78 (d, J = 9.1 Hz, 1H), 7.39 (d, 2=2.7 Hz, 1H), 7.33 (dd, J = 9.1, 2.7 Hz, 1H), 5.85 (q, J= 6.4 Hz, 1H), 4.97 (p, J= 8.2 Hz, 1H), 4.77 (s, 2H), 4.65 (s, 2H), 4.54 (s, 2H), 4.00 (td, J= 5.7, 3.0 Hz, 2H), 3.14 - 2.90 (m, 2H), 2.87 -2.75 (m, 2H), 2.65 (ddd, J= 12.8, 8.2, 3.9 Hz, 2H), 2.42 (s, 3H), 1.69 (d, J= 6.4 Hz, 3H). 407 89 'H NMR (400 MHz, DMSO) 5 8.44 (s, 1H), 8.39 (s, 1H), 7.88 (d, J= 9.1Hz, 1H), 7.45 (d, J= 2.7 Hz, 1H), 7.39 (dd, J= 9.1, 2.7 Hz, 1H), 5.90 (q, J = 6.4 Hz, 1H), 5.24 (p, J = 7.9 Hz, 1H), 4.84 (s, 2H), 4.53 (t, J = 5.2 Hz, 1H), 4.05 (td, J = 5.7, 2.8 Hz, 2H), 3.52 (dt, J = 10.9, 5.3 Hz, 1H), 3.16 - 2.96 (m, 3H), 2.78 - 2.55 (m, 3H), 2.49 - 2.44 (m, 1H), 1.73 (d, J = 6.4 Hz, 3H), 1.02 (tt, J = 8.7, 5.5 Hz, 1H), 0.61 (dd, J = 8.8, 5.1 Hz, 1H), 0.25 (t, J = 5.3 Hz, 1H). 407 90 'HNMR (400 MHz, DMSO) 5 8.44 (s, 1H), 8.39 (s, 1H), 7.88 (d, J = 9.1Hz, 1H), 7.45 (d, J =2.7 Hz, 1H), 7.39 (dd, J = 9.1, 2.7 Hz, 1H), 5.90 (q, J = 6.4 Hz, 1H), 5.24 (p, J = 7.9 Hz, 1H), 4.84 (s, 2H), 4.53 (t, J = 5.2 Hz, 1H), 4.05 (td, J = 5.7, 2.8 Hz, 2H), 3.52 (dt, J = 10.9, 5.3 Hz, 1H), 3.21 - 2.92 (m, 3H), 2.77 - 2.55 (m, 3H), 2.47 (dd, J = 8.2, 3.0 Hz, 1H), 1.73 (d, J = 6.4 Hz, 3H), 1.02 (tt, J = 8.5, 5.5 Hz, 1H), 0.61 (dd, J = 8.8, 5.1 Hz, 1H), 0.25 (t, J = 5.4 Hz, 1H). 407 Example 91: (R)-(4-(4-(l-((2,4-dihydro-lH-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)-\H-1,2,3 -triazol-1 -yl)-2-oxabi cyclo [2.1. l]hexan-l-yl)methanol Step 1: (R)-(4-(4-(l-((2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)- 5     1H-1,2,3-triazol-l-yl)-2-oxabicyclo[2.1.1]hexan-l-yl)methanol: To a solution of ethyl 4-[4-[(1R)-1 -(2,4-dihydro- IH-pyrano [3,4-c]quinolin-9-yloxy) ethyl]triazol-1 -yl] -2-oxabicyclo[2.1. l]hexane-l-carboxylate (110 mg, 0.24 mmol, prepared in a similar fashion to Example 63 via diazo transfer and click reactions) in THF (3 mL) was added LAH (13.9 mg, 0.4 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hs. The 10 reaction was quenched with 2 N NaOH(aq). After filtration and concentration, the resulting residue was purified by reverse phase chromatography (water (0.2%FA)-ACN) to afford the title compound (46.2 mg, 44.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-de) 5 8.56 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.47 (d, J = 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.93 (q, J= 6.4 Hz, 1H), 4.83 (s, 2H), 4.09 (s, 2H), 4.07 - 4.00 (m, 2H), 3.66 (s, 2H), 3.59 - 3.47 (m, 1H), 3.15 - 3.05 (m, 1H), 3.04 -2.94 (m, 1H), 2.41 -2.34 (m, 2H), 2.11 -2.05 (m, 2H), 1.73 (d, 7= 6.4 Hz, 3H). LCMS M / Z (M+H) 409.1. Example 92: (R)-(4-(4-( 1-((1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl) oxy)ethyl)-lH-l, 2,3-triazol-l-yl)bicyclo[2.1.1]hexan-l-yl)methanol The title compound was prepared in a similar fashion as Example 91 via diazo transfer, click reaction and reduction. 'H NMR (400 MHz, DMSO-de) 5 = 8.44 (s, 1H), 8.39 (s, 1H), 7.89 (d, J= 9.2 Hz, 1H), 7.47 (d, J= 2.8 Hz, 1H), 7.33 - 7.28 (m, 1H), 5.92 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.67 (t, J= 5.6 Hz, 1H), 4.04 - 3.91 (m, 2H), 3.51 - 3.42 (m, 2H), 3.08 - 2.98 (m, 1H), 2.96 - 2.86 (m, 1H), 2.14 - 2.06 (m, 2H), 1.92 (s, 2H), 1.73 (d, J= 6.4 Hz, 3H), 1.62 - 1.57 (m, 4H). LCMS [M+H] 407.1. Example 93: [4-[4-[(lR)-l-[(5-methyl-2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yl)oxy]ethyl] triazol-l-yl]-2-oxabicyclo [2.1.1]hexan-l-y I] methanol The title compound was prepared in a similar fashion as Example 91 via diazo transfer, click reaction and reduction. 'H NMR (400 MHz, DMSO) 5 8.53 (s, 1H), 7.79 (d, J= 9.1 Hz, 1H), 7.43 (d, J= 2.8 Hz, 1H), 7.34 (dd, J= 9.1, 2.7 Hz, 1H), 5.90 (q, J= 6.4 Hz, 1H), 4.94 (t, J= 5.9 Hz, 1H), 4.77 (s, 2H), 4.09 (s, 2H), 4.01 (td, J= 5.7, 2.7 Hz, 2H), 3.66 (d, J= 5.9 Hz, 2H), 3.15 - 2.93 (m, 2H), 2.44 - 2.33 (m, 5H), 2.13 - 2.03 (m, 2H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 423.1. Example 94: (R)-9-(l-(l-(3-(fluoromethyl)bicyclo[l.l. 1]pentan-l-yl)-lH- 1,2,3-triazol-4-yl)ethoxy)-l, 4-dihydro-2H-pyrano[3,4-c] quinoline To a solution of (R)-(3-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-1,2,3-triazol-l-yl)bicyclo[l. 1. l]pentan-l-yl)methanol (Example 66, 20 mg, 0.051 mmol) in DCM (1.0 mL) was added Deoxo-Fluor (0.028 mL, 0.15 mmol) slowly and the reaction mixture was stirred at 20 °C for 4. After that, the mixture was cooled to 0 °C, water, DCM and saturated NaHCOs (aq) solution was added sequentially very slowly until no additional CO2 bubbles formed. The layers were separated and the organic layer was washed with brine and dried over sodium sulfate. The mixture was filtered and the solvent was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile 5-50% in 0.1% HCOOH-water) to afford (R)-9-( 1-( 1-(3-(fluoromethyl)bicyclo[ 1.1.1 ]pentan-1 -yl)- 1H-1,2,3 -triazol-4-yl)ethoxy)-1,4-dihydro-2H-pyrano[3,4-c]quinoline (8.1 mg, 40% yield) as a white solid. 'H NMR (400MHz, DMSO-dd) 5 8.44 (s, 1H), 8.40 (s, 1H), 7.88 (d, J= 9.1 Hz, 1H), 7.45 (d, J= 2.7 Hz, 1H), 7.38 (dd, J= 9.1, 2.7 Hz, 1H), 5.91 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.68 (s, 1H), 4.56 (s, 1H), 4.05 (td, J= 5.7, 3.2 Hz, 2H), 3.10 (dt, J= 17.7, 5.9 Hz, 1H), 2.99 (dt, J= 17.6, 5.6 Hz, 1H), 2.32 (s, 6H), 1.71 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 395.2. Example 95: (R)-N-(4-(4-(l-((1,4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)bicyclo[2.1.1]hexan-l-yl)me thane sulfonamide CuSO4, sodium ascorbate, t-BuOH / H2O, 25°C, 16 h Step 1: tert-butyl (R)-(4-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l ,2,3-triazol-l-yl)bicyclo [2.1. l]hexan-l-yl)carbamate: To a 10-dram vial charged with tert-butyl N-( l-amino-4-bicyclo[2.1.1 ]hexanyl)carbamate (250.0 mg, 1.18 mmol) was added sulfurazidic fluoride (2.26 mb, 624 mM in MTBE, 1.41 mmol) and potassium bicarbonate (1.96 mb, 3.0 mol / L in water, 5.89 mmol). The reaction mixture was stirred at 25 °C for 1 hours. After that, (R)-9-(but-3-yn-2-yloxy)-l,4-dihydro-2H-pyrano [3,4-c] quinoline (H-2, 250.0 mg, 0.98 mmol), sodium ascorbate (39.0 mg, 0.20 mmol), copper(II) sulfate (31.0 mg, 0.20 mmol) and tertbutyl alcohol (2.0 mb) were added. The resulting mixture was stirred at 25 °C for 16 hours under N2 atmosphere. Then the reaction mixture was concentrated in vacuo. Isopropyl acetate was then added and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with (0-10% MeOH in DCM) to afford the title compound (366.0 mg, 76% yield) as a yellow solid. XHNMR (400 MHz, CDCh) 5 8.42 (s, 1H), 7.97 (d, J= 9.0 Hz, 1H), 7.56 (s, 1H), 7.35 (dd, J= 12.2, 3.3 Hz, 2H), 5.80 (q, J= 6.6 Hz, 1H), 4.93 (s, 1H), 4.89 (s, 2H), 4.13 (td, J= 11.7, 6.0 Hz, 2H), 3.06 (d, J= 16.8 Hz, 2H), 2.58 (s, 2H), 2.24 (d, J= 7.6 Hz, 2H), 2.11 - 2.05 (m, 2H), 2.05 - 1.98 (m, 2H), 1.79 (d, J= 6.5 Hz, 4H), 1.44 (s, 9H). LCMS M / Z (M+H) 492.2. Step 2: (R)-4-(4-( 1-((1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)bicyclo[2.1.1]hexan-l-amine hydrochloride: To a solution of tert-butyl (R)-(4-(4-( 1 -((1,4-dihydro-2H-pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H-l,2,3-triazol-l-yl)bicyclo[2.1.1]hexan-l-yl)carbamate (346 mg, 0.70 mmol) in 1,4-dioxane (2.0 mb) was added hydrochloric acid (0.88 mb, 3.52 mmol, 4.0 mol / L in dioxane) at 25 °C and stir for 16 hours. Then the mixture was concentrated in vacuo to afford a crude mixture of the title compound as a white solid. LCMS M / Z (M+H) 392.0. Step 3: (R)-N-(4-(4-(l-((l, 4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)bicyclo[2.1.1]hexan-l-yl)me thane sulfonamide: To a solution of (R)-4-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)bicyclo[2.1.1]hexan-l-amine hydrochloride (30 mg, 0.077 mmol) in dichloromethane (0.5 mL) was added triethylamine (24.4 pL, 0.19 mmol). Methanesulfonyl chloride (8.1 pL, 0.11 mmol) was then added slowly to the solution at 0°C. The resulting mixture was allowed to stir at 25 °C for 2 hours. After that, the reaction mixture was quenched with saturated NaHCO? aqueous solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (25% acetonitrile in water with 0.1% ammonium hydroxide) to afford the title compound, (17.2 mg, 54% yield) as a white solid. 'H NMR (400 MHz, DMSO<L) 5 8.43 (d, J= 6.9 Hz, 2H), 7.98 (s, 1H), 7.88 (d, J= 9.0 Hz, 1H), 7.46 (d, J= 2.7 Hz, 1H), 7.39 (dd, J= 9.2, 2.6 Hz, 1H), 5.90 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.05 (td, J= 5.7, 2.5 Hz, 2H), 3.11 (dt, J= 17.9, 5.6 Hz, 1H), 2.97 (s, 4H), 2.37 (s, 2H), 2.22 - 2.10 (m, 2H), 2.06 (dd, J= 3.8, 1.8 Hz, 2H), 1.97 (t, J= 6.8 Hz, 2H), 1.72 (d, J= 6.7 Hz, 3H). LCMS M / Z (M+H) 470.2. Example 96: 4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1.1]hexane-3-carboxamide. CUSO4, sodium ascorbate, H2O / fBuOH Step 1: 4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3-triazol-l-yl)-l-methyl-2-oxabicyclo [2.1. l]hexane-3-carboxylic acid: To a 10-dram vial charged with 4-amino-l-methyl-2-oxabicyclo[2.1.1]hexane-3-carboxylic acid hydrochloride (400 mg, 1.96 mmol) was added sulfurazidic fluoride (3.77 mL, 624 mM in MTBE, 2.36 mmol) and potassium bicarbonate (3.93 mL, 3.0 mol / L in water, 11.78 mmol). The reaction mixture was stirred at 25 °C for 1 hour. After that, (R)-9-(but-3-yn-2-yloxy)-l,4-dihydro-2H-pyrano[3,4-c]quinoline (H-2, 405 mg, 1.6 mmol), sodium ascorbate (32 mg, 0.16 mmol), copper(II) sulfate (26 mg, 0.16 mmol) and tert-butyl alcohol (3 mL) were added. The resulting mixture was stirred at 25 °C for 16 hours under N2 atmosphere. Then the reaction mixture was concentrated in vacuo. Isopropyl acetate was then added and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (5-50% acetonitrile in water with 0.1% formic acid) to afford the title compound (90 mg, 13% yield) as a white solid. 'H NMR (400 MHz, DMSO-J6) 5 8.69 (s, 1H), 8.45 (d, 7=5.3 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.58 (s, 2H), 6.00 (d, J = 6.8 Hz, 1H), 4.89 (s, 2H), 4.66 (d, J = 8.7 Hz, 1H), 4.08 (s, 2H), 3.22 (s, 1H), 3.17 (s, 1H), 2.47 - 2.37 (m, 2H), 2.31 (d, J = 5.0 Hz, 2H), 1.73 (d, J = 6.5 Hz, 3H), 1.46 (s, 3H). LCMS M / Z (M+H) 437.0. Step 2: 4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1.1]hexane-3-carboxamide: To a solution of 4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1.1]hexane-3-carboxylic acid (90.3 mg, 0.21 mmol) in A.A-dimcthylformamidc (1.0 mL) and acetonitrile (2.0 mL) was added HATU (104.0 mg, 0.270 mmol), ammonium chloride (55.3 mg, 1.03 mmol) and then A. A-diisopropylcthylaminc (214.0 mg, 1.65 mmol) at 25 °C and stir for 16h. After that, the reaction mixture was quenched with saturated NH4CI aqueous solution and the layers were separated. The aqueous layer was extracted with isopropyl acetate (2x10 mL) and DCM (2x10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (5-50% acetonitrile in water with 0.1% ammonium hydroxide) and then chiral SFC (Column: Chiralpak IH, 150x21.2 mm, 5 pm, Mobile phase: A: CO2 B: Methanol. Isocratic 25% of B, Flow rate: 70 mL / min, Column temp.: 40 °C) to give the title compound (5.7 mg, 6% yield) as peak 2. 'H NMR (400 MHz, DMSO) 5 8.44 (s, IH), 8.34 (s, IH), 7.88 (d, J = 9.1 Hz, IH), 7.46 - 7.35 (m, 4H), 5.90 (q, J = 6.4 Hz, 1H), 4.84 (s, 2H), 4.50 (s, 1H), 4.04 (td, J = 5.8, 3.3 Hz, 2H), 3.06 (q, J = 6.6 Hz, 2H), 2.46 - 2.33 (m, 2H), 2.28 (d, J = 5.4 Hz, 2H), 1.71 (d, J = 6.4 Hz, 3H), 1.49 (s, 3H). LCMS M / Z (M+H) 436.2. Examples 97-122: the compounds were synthesized using methods and 5 procedures similar to those used in Example 96 using appropriate starting materials and synthetic intermediates. No. Example Compound Name 97 O-. N C / hn~o^° 0   0=( JL           / 0 N=n 4-[4-[ 1 -(2,4-dihydro-1 H-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -mcthyl-A'-(2-oxaspiro|3.3 |hcptan-6-yl)-2-oxabicyclo[2.1. l]hexane-3-carboxamide 98 / ° o           \ / z= / 4-[4-[ 1 -(2,4-dihydro-1 H-pyrano[3,4- c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -N-ethyl-1 -methyl-2-oxabicyclo[2.1. l]hexane-3-carboxamide 99 / ° 13 / it o I [4-[4-[ 1 -(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-(3-hydroxyazetidin-1 -yl)methanone No. Example Compound Name 100 \ o <5^1 ° [4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-(3-methoxyazetidin-1 -yl)methanone 101 Xu? Z-Z ° 7^3 z CT [4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone 102 TH Xj r— / N"^O n=n r 0-^ [4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-(l-oxa-6-azaspiro[3.3]heptan-6-yl)methanone 103 ? Up ° [4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-pyrrolidin-1 -yl-methanone No. Example Compound Name \ N \\ [4-[4-[ l-(2,4-dihydro-l H-pyrano[3,4- 104 N=N I c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-[3-(dimethylamino)azetidin-1 -yl] methanone O' 1 .0^ [4-[4-[ l-(2,4-dihydro-l H-pyrano[3,4- 105 r T Ci^ N—4 c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-(3- N=n ">0 hydroxypyrrolidin-1 -yl)methanone N-"\ >— OH 0^ k / N fj [4-[4-[ l-(2,4-dihydro-l H-pyrano[3,4- c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 - 106 QZ       f~ methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-(6- N=N I / 0 'N-n ^OH hydroxy-2-azaspiro[3,3]heptan-2-yl)methanone No. Example Compound Name 107 . / n=n r O^N—l 1 .[4-[4-[ i -(2,4-dihydro- lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexane-3-carbonyl] azetidine-3 -carbonitrile 108 f Y _ / N—^O n=n Y °^N—I L-\~F F (3,3 -difluoroazetidin-1 -y 1)-[4 - [4 - [ 1 -(2,4-dihydro- 1 / / -pyrano|3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl] methanone 109 o Yo z \= / xs__ / O           \   / z= / IZ\x\° \ / v° x 4-[4-[ 1 -(2,4-dihydro-1 H-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl -N-(3 -methyloxetan-3 -yl)-2-oxabicyclo[2.1. l]hexane-3-carboxamide 110 .0. PH N £T N=N Y 0 n--\^f H 4-[4-[ 1 -(2,4-dihydro-1 H-pyrano[3,4- c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -N-(2-fluoroethyl)-1 -methyl-2- oxabicyclo[2.1. l]hexane-3-carboxamide No. Example Compound Name Ill .0. N r T N N J 0 NH F N-(2,2-difluoroethyl)-4-[4-[ 1-(2,4-dihydro-1 H-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexane-3-carboxamide 112 / ° T"z     — / / O o Z ' \ / ' IZ  \ \ / 4-[4-[ 1 -(2,4-dihydro-1 H-pyrano[3,4-c\ quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-JV-(oxetan-2-ylmethyl)-2- oxabicyclo[2.1. l]hexane-3-carboxamide 113 .0. Lil n CT 0^N^° 1 4-[4-[ 1 -(2,4-dihydro-1 H-pyrano[3,4- c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -N, 1 -dimethyl-JV-(oxetan-3 -yl)-2- oxabicyclo[2.1. l]hexane-3-carboxamide No. Example Compound Name 114 o          ' \ / 2=7 r cpI cAy   x [4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-(3-hydroxypyrrolidin-1 -yl)methanone 115 ? j ^-cy o          ' \ / [4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-[3-(fluoromethyl)azetidin-1 -yl] methanone 116 / ° o 2   \= / vs__ / o         \ _ / / A = T] co [4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-[3-(trifluoromethyl)azetidin-1 -yl] methanone No. Example Compound Name 117 ,0. PH JT J N N J ° nl3 F [4-[4-[ l-(2,4-dihydro-l H-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-(3-fluoroazetidin-1 -yl)methanone 118 PH n rj N~N J ° OH [4-[4-[ l-(2,4-dihydro-l H-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-(3-hydroxy-3 -methyl-azetidin-1 -yl)methanone 119 .0. LH N cy n n j HO [4-[4-[ l-(2,4-dihydro-l H-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-[3-(hydroxymethyl)azetidin-1 -yl] methanone No. Example Compound Name 120 ,0. PH n it N N J °An- / 4-[4-[ 1 -(2,4-dihydro-1 H-pyrano[3,4- c] quinolin-9-yloxy)ethyl]triazol-1 -yl] - N,N,l-trimethyl-2- oxabicyclo[2.1. l]hexane-3-carboxamide 121 .0. Lil n XT N N J Xo [4-[4-[ 1 -(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]-morpholino-methanone 122 / = Z V __ / \__ o oX A azetidin-1 -yl - [4 - [4 - [ 1 -(2,4-dihydro- \H-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl] methanone Analyticla data for compounds of Examples 97-122 is provided in the table below: No. NMR m / z 97 ND 531.6 98 ND 463.5 99 'H NMR (DMS0-d6, 400 MHz) 5 8.44 (s, 1H), 8.3-8.4 (m, 1H), 7.88 (d, 1H, J =9.2 Hz), 7.4-7.5 (m, 2H), 5.91 (q, 1H, J = 6.2 Hz), 5.67 (br d, 1H, J = 1.0 Hz), 4.83 (s, 2H), 4.7-4.7 (m, 1H), 4.3-4.5 (m, 1H), 4.0-4.2 (m, 4H), 3.8-3.9 (m, 1H), 3.6-3.8 (m, 1H), 3.5-3.5 (m, 1H), 491.5 No. NMR m / z 3.0-3.1 (m, 2H), 2.3-2.4 (m, 1H), 2.31 (br s, 2H), 1.7-1.7 (m, 3H), 1.45 (d, 3H, J=3.1Hz) 100 ND 505.6 101 ND 517.6 102 ND 517.6 103 ND 489.6 104 ND 518.6 105 ND 505.6 106 ND 531.6 107 ND 500.6 108 ND 511.5 109 ND 506 110 ND 482 111 'HNMR (400 MHz, DMSO-d6) 5 8.44-8.47 (m, 1H), 8.32-8.37 (m, 1H), 8.29-8.31 (m, 1H), 7.87-7.91 (m, 1H), 7.38-7.45 (m, 2H), 5.726.11 (m, 1H), 4.79-4.90 (m, 2H), 4.57-4.66 (m, 1H), 3.98-4.11 (m, 2H), 3.40-3.46 (m, 2H), 3.04-3.13 (m, 2H), 2.32-2.39 (m, 4H), 1.691.74 (m, 3H), 1.49-1.54 (m, 3H), 0.85-0.89 (m, 1H) 500 112 ND 506 113 ND 506 114 ND 506 115 ND 508 116 ND 544 117 'HNMR (400 MHz, DMSO-d6) 5 8.42-8.47 (m, 1H), 8.35-8.40 (m, 1H), 7.84-7.91 (m, 1H), 7.35-7.47 (m, 2H), 5.86-5.98 (m, 1H), 5.035.49 (m, 1H), 4.79-4.92 (m, 2H), 4.70-4.78 (m, 1H), 3.70-4.59 (m, 6H), 2.96-3.15 (m, 2H), 2.23-2.42 (m, 4H), 1.66-1.76 (m, 3H), 1.411.51 (m, 3H) 494 118 ND 506 119 ND 506 120 ND 464 121 XH NMR (400 MHz, DMSO-d6) 5 8.43-8.45 (m, 1H), 8.34-8.38 (m, 1H), 7.85-7.90 (m, 1H), 7.35-7.45 (m, 2H), 5.88-5.96 (m, 1H), 5.095.14 (m, 1H), 4.80-4.86 (m, 2H), 4.00-4.08 (m, 2H), 3.34-3.54 (m, 6H), 3.22-3.28 (m, 1H), 2.96-3.11 (m, 2H), 2.53-2.54 (m, 1H), 2.402.47 (m, 2H), 2.26-2.34 (m, 1H), 1.68-1.76 (m, 3H), 1.43-1.46 (m, 3H) 506 122 ND 476 Example 123 & 124: N-(4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin- 9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1.1]hexan-3- yl)methyl)acetamide THF, DCM DCM, DIPEA, then chiral SFC Peak 1 Peak 2 Step 1: [4-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]-l-methyl-2-oxabicyclo[2.1.1]hexan-3-yl]methanamine: To a solution of triphenylphosphine (365.8 mg, 1.4 mmol) in THF (2.0 mL) and dichloromethane (2.0 mL) was added diisopropyl azodicarboxylate (282.0 mg, 1.4 mmol) slowly at 20 °C. The solution was allowed to stir for 10 min at 20 °C. The resulting mixture was added to a mixture of (4-(4-(( / ?)-1-((1,4-dihydro-2 / / -pyrano [3,4-c\ quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -methyl-2-oxabicyclo[2.1.1]hexan-3-yl)methanol (Racemic mixture of examples 72 / 73, 196 mg, 0.46 mmol) and phthalimide (82 mg, 0.56 mmol) in dichloromethane (1 mL) and THF (1 mL). The reaction was stirred at 20 °C for 16 hour. Then the mixture was fdtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with (0-10% MeOH in DCM) to afford the title compound (153 mg, 60% yield). 'H NMR (400 MHz, CDCh) 5 8.42 (d, J = 5.6 Hz, 1H), 7.97 (dd, J = 9.2, 5.7 Hz, 1H), 7.73 (ddd, J = 13.3, 5.5, 3.0 Hz, 2H), 7.68 - 7.61 (m, 2H), 7.58 (dd, J = 5.4, 3.1 Hz, 1H), 7.34 (dd, J = 10.1, 2.9 Hz, 1H), 5.72 (p, J = 6.4 Hz, 1H), 4.94 - 4.86 (m, 2H), 4.78 (ddd, J = 21.4, 7.5, 5.7 Hz, 1H), 4.11 (qq, J = 11.5, 5.4 Hz, 2H), 3.93 (ddd, J = 10.7, 7.3, 3.7 Hz, 1H), 3.77 (ddd, J = 14.2, 7.0, 5.8 Hz, 1H), 3.17 - 2.94 (m, 2H), 2.67 - 2.54 (m, 1H), 2.39 - 2.23 (m, 2H), 2.20 - 2.04 (m, 1H), 1.74 (t, J = 6.8 Hz, 3H), 1.49 (s, 3H). LCMS M / Z (M+H) 552.1. Step 2: [4-[4-[(1 R)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9- yloxy)ethyl]triazol-l-yl]-l-methyl-2-oxabicyclo[2.1.1]hexan-3-yl]methanamine: To a solution of 2-| |4-|4-| (I / ?)-1 -(2.4-dihydro- l / / -pyrano| j. 4-c]quinolin-9-yloxy)ethyl]triazol- 1-yl]-1 -methyl-2-oxabicyclo [2.1. l]hexan-3-yl]methyl]isoindoline-1,3-dione (153 mg, 0.28 mmol) in ethanol (2 mL, 34.0 mmol) was added hydrazine in water (10.0 equiv., 2.8 mmol, 64 mass%) at 25 °C. The reaction was stirred at 20 °C for 16 hour. Then the mixture was concentrated in vacuo to afford the crude mixture of the title compound (163.0 mg, 100% yield, 72 mass%), which was used in the next step directly. LCMS M / Z (M+H) 422.0. Step 3: N-(4-(4-((R)-l-((1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1.1]hexan-3-yl)methyl)acetcimide Peak 1                      Peak 2 To a solution of [4-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]-l-methyl-2-oxabicyclo[2.1.l]hexan-3-yl]methanamine (70 mg, 0.12 mmol, 72 mass%) in dichloromethane (10 mL, 16 mmol) was added N^V-diisopropylethylamine (3.0 equiv., 0.36 mmol) and then acetyl chloride (3.0 equiv., 0.36 mmol) slowly at 20 °C. The resulting mixture was allowed to stir at 25 °C for 5 hours. After that, the reaction mixture was quenched with saturated NaHCOs aqueous solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (5-50% acetonitrile in water with 0.1% formic acid) then chiral SFC (Column: Chiralpak IH, 250x21.2mm, 5 pm, Mobile phase: A: CO2 B: Methanol with 0.1% ammonium hydroxide. Isocratic 20% of B, Flow rate: 70 mL / min, Column temp.: 40 °C) to afford Example 123 (12.9 mg, 28% yield) as peak 1 and Example 124 (12.1 mg, 22% yield) as peak 2. Example 123: 1HNMR(400 MHz, DMSO) 5 8.44 (s, 1H), 8.40 (s, 1H), 7.87 (t, J = 8.4 Hz, 2H), 7.45 (d, J = 2.8 Hz, 1H), 7.40 (dd, J = 9.1, 2.7 Hz, 1H), 5.92 (q, J = 6.4 Hz, 1H), 4.84 (s, 2H), 4.26 (dd, J = 8.4, 4.0 Hz, 1H), 4.04 (td, J = 5.7, 2.8 Hz, 2H), 3.28 - 3.26 (m, 1H), 3.16 - 5     2.90 (m, 3H), 2.35 - 2.21 (m, 4H), 1.75 - 1.66 (m, 6H), 1.43 (s, 3H). LCMS M / Z (M+H) 464.1. Example 124: 'HNMR (400 MHz, DMSO) 5 8.44 (s, 1H), 8.40 (s, 1H), 7.87 (t, J = 8.4 Hz, 2H), 7.45 (d, J = 2.8 Hz, 1H), 7.40 (dd, J = 9.1, 2.7 Hz, 1H), 5.92 (q, J = 6.4 Hz, 1H), 4.84 (s, 2H), 4.26 (dd, J = 8.4, 4.0 Hz, 1H), 4.04 (td, J = 5.7, 2.8 Hz, 2H), 3.28 - 3.26 (m, 1H), 3.16 - 2.90 (m, 3H), 2.35 - 2.21 (m, 4H), 1.75 - 10     1.66 (m, 6H), 1.43 (s, 3H). LCMS M / Z (M+H) 464.2. Examples 125-135: the compounds were synthesized using methods and procedures similar to those used in Example 123 using appropriate starting materials and synthetic intermediates. No. Structure Stereo Compound Name 125 n=n r NH °^cf3 Peak 2 on SFC Method H SUS N-(4-(4-((R)-1 -((1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3 -triazol-1 -yl)-1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl)methyl)-2,2,2-trifluoroacetamide 126 To 'Vn-T ^NH F Peak 2 on SFC Method F SUS N-(4-(4-((R)-1 -((1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3 -triazol-1 -yl)-1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl)methyl)-2-fluoroacetamide No. Structure Stereo Compound Name 127 XL Th XNH F Peak 1 on SFC Method F SUS ^-(4-(4-((R)-1 -((1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3 -triazol-1 -yl)-1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl)methyl)-2-fluoroacetamide 128 (ll N jj N'N Y NH oY --F F MOD JV-[[4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]methyl] -3,3 -difluorocyclobutanecarboxamide 129 Th rj n=n Y NH oY^ F MOD JV-[[4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]methyl] -2-fluorocyclopropanecarboxamide No. Structure Stereo Compound Name 130 .0. N CT N'N Y 0 h V MOD JV-[[4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]methyl] cyclopropanecarboxamide 131 PH n c t n=n Y NH F MOD JV-[[4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]methyl] -2-fluorocyclopropanecarboxamide 132 "~z / / =Z    \'Z    o YY^ Y o— / MOD JV-[[4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]methyl]-2-(dimethylamino)acetamide No. Structure Stereo Compound Name 133 .0. N r t ^J'Ty N-N 1 NH oX\ F MOD A-[[4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]methyl] -3 -fluoro-propanamide 134 / X (H N LT NH MOD JV-[[4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]methyl] -2-methoxy-acetamide 135 AX Th N XT N=N Y NH F MOD JV-[[4-[4-[l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l -yl] -1 -methyl-2-oxabicyclo[2.1. l]hexan-3-yl]methyl] -2-fluorocyclopropanecarboxamide Analyticla data for compounds of Examples 125-135 is provided in the table below: No. NMR m / z 125 1H NMR (400 MHz, DMSO) 5 9.48 (t, 7=5.5 Hz, 1H), 8.43 (d, J = 10.4 Hz, 2H), 7.88 (d, J = 9.1 Hz, 1H), 7.44 (d, J = 2.7 Hz, 1H), 7.39 (dd, J = 9.0, 2.7 Hz, 1H), 5.92 (q, J = 6.4 Hz, 1H), 4.83 (s, 2H), 4.41 518 No. NMR m / z (dd, J = 8.0, 4.5 Hz, 1H), 4.04 (h, J = 5.9 Hz, 2H), 3.37 - 3.21 (m, 2H), 3.15 - 2.96 (m, 2H), 2.37 (d, J = 6.7 Hz, 1H), 2.28 (s, 3H), 1.71 (d, J =6.4 Hz, 3H), 1.43 (s, 3H). 126 'HNMR (400 MHz, DMSO) 5 8.45 (s, 1H), 8.40 (s, 1H), 8.04 (t, J = 5.9 Hz, 1H), 7.89 (d, J =9.1 Hz, 1H), 7.46 (d, J = 2.7 Hz, 1H), 7.40 (dd, J = 9.2, 2.7 Hz, 1H), 5.92 (q, J = 6.4 Hz, 1H), 4.84 (s, 2H), 4.77 - 4.65 (m, 1H), 4.65 - 4.52 (m, 1H), 4.36 (dd, J = 7.9, 4.6 Hz, 1H), 4.04 (td, J = 5.7, 3.1 Hz, 2H), 3.37 - 3.32 (m, 1H), 3.22 - 2.95 (m, 3H), 2.37 - 2.20 (m, 4H), 1.72 (d, J = 6.4 Hz, 3H), 1.42 (s, 3H). 482 127 'HNMR (400 MHz, DMSO) 5 8.44 (s, 1H), 8.40 (s, 1H), 8.03 (t, J = 5.8 Hz, 1H), 7.88 (d, J =9.1 Hz, 1H), 7.46 (d, J = 2.7 Hz, 1H), 7.40 (dd, J = 9.2, 2.7 Hz, 1H), 5.92 (q, J = 6.4 Hz, 1H), 4.84 (s, 2H), 4.76 - 4.64 (m, 1H), 4.64 - 4.52 (m, 1H), 4.36 (dd, J = 8.0, 4.7 Hz, 1H), 4.04 (hept, J = 5.8 Hz, 2H), 3.35 (d, J = 5.3 Hz, 1H), 3.24 - 2.95 (m, 3H), 2.37 - 2.26 (m, 2H), 2.25 (q, J = 5.7 Hz, 2H), 1.72 (d, J = 6.4 Hz, 3H), 1.42 (s, 3H). 482 128 'H NMR (DMSO-d6, 400 MHz) 5 8.45 (s, 1H), 8.4-8.4 (m, 1H), 8.18.1 (m, 1H), 7.8-7.9 (m, 1H), 7.45 (t, 1H, J =2.7 Hz), 7.4-7.4 (m, 1H), 5.9-6.0 (m, 1H), 4.8-4.9 (m, 2H), 4.2-4.3 (m, 1H), 4.0-4.1 (m, 2H), 3.33 (ddd, 2H, J =4.0, 6.4, 13.7 Hz), 3.0-3.1 (m, 3H), 2.7-2.8 (m, 1H), 2.6-2.6 (m, 3H), 2.2-2.3 (m, 4H), 2.1-2.1 (m, 1H), 1.72 (d, 3H, J =6.5 Hz), 1.43 (s, 3H) 539.6 129 ND 507.6 130 ND 489.6 131 ND 507.6 132 ND 506.6 133 'H NMR (DMSO-d6, 400 MHz) 5 8.45 (s, 1H), 8.4-8.4 (m, 1H), 8.08.1 (m, 1H), 7.9-7.9 (m, 1H), 7.4-7.5 (m, 1H), 7.4-7.4 (m, 1H), 5.96.0 (m, 1H), 4.8-4.9 (m, 2H), 4.6-4.6 (m, 1H), 4.4-4.5 (m, 1H), 4.34.3 (m, 1H), 4.0-4.1 (m, 2H), 3.3-3.4 (m, 2H), 2.9-3.2 (m, 3H), 2.32.4 (m, 5H), 1.6-1.8 (m, 3H), 1.4-1.5 (m, 3H) 495.6 134 ND 493.6 135 ND 507.6 Example 136 & 137: N-(4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin- 9-yl)oxy)ethyl)- 1H-1,2,3-triazol-1 -yl)-1 -methyl-2 -oxabicyclo [2.1. l]hexan-3-yl)methyl)cyclopropanamine Peak 1 Peak 2 Step 1: (4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1.1]hexan-3-yl)methyl 4-me thy lb enzene sulfonate: To a solution of (4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1. l]hexan-3-yl)methanol (Racemic mixture of examples 72 / 73, 400 mg, 1.0 mmol) in DCM (3.0 mL) was added triethylamine (192 mg, 1.9 mmol). The 4-methylbenzenesulfonyl chloride (451 mg, 2.4 mmol) was then added at 0 °C. After that, the reaction mixture was quenched with saturated NaHCOs aqueous solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, fdtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with (0-10% MeOH in DCM) to afford the title compound (491.4 mg, 90% yield) as a yellow solid. 1H NMR (400 MHz, CDCh) 5 8.43 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.67 - 7.59 (m, 3H), 7.41 - 7.33 (m, 2H), 7.28 (d, J = 2.6 Hz, 2H), 5.82 (q, J = 6.5 Hz, 1H), 4.89 (s, 2H), 4.43 (dq, J = 8.4, 4.3, 3.4 Hz, 1H), 4.13 (tq, J= 11.4, 5.9, 5.4 Hz, 4H), 3.07 (dt, J= 10.9, 5.8 Hz, 2H), 2.42 (s, 3H), 2.38 -2.29 (m, 2H), 2.22 - 2.13 (m, 2H), 1.81 (dd,7 = 6.5, 1.0 Hz, 3H), 1.48 (s, 3H). LCMS M / Z (M+H) 577.1. Step 2: N-(4-(4-((R)-l-((l, 4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1.1]hexan-3-yl)methyl)cyclopropanamine: To a solution of [l-methyl-4-[4-[rac-(lR)-l-(2,4-dihydro-1 / / -pyrano [3,4-c]quinol in-9-yl oxy )ethyl ] tri azol-1 -yl] -2-oxabicyclo[2.1. l]hexan-3-yl]methyl methane sulfonate (34.6 mg, 0.069 mmol) in acetonitrile (0.60 mL, 10.0 mmol) was added sodium bicarbonate (159.0 mg, 1.80 mmol) and cyclopropanamine (197.0 mg, 3.46 mmol) and stir at 85 °C for 72 h. After that, mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (2-30% acetonitrile in water with 0.1% ammonium hydroxide) then chiral SFC (Column: Chiralpak AD, 150x21.2mm, 5 pm, Mobile phase: A: CO2 B: Methanol with 0.1% ammonium hydroxide. Isocratic 30% of B, Flow rate: 70 mL / min, Column temp.: 40 °C) to afford Example 136 (5.9 mg, 18% yield) as peak 1 and Example 137 (6.4 mg, 20% yield) as peak 2. Example 136 1H NMR (400 MHz, DMSO) 5 8.46 - 8.42 (m, 1H), 8.40 (s, 1H), 7.91 - 7.84 (m, 1H), 7.43 (s, 1H), 7.39 (d, J = 92 Hz, 1H), 5.91 (d, J = 6.8 Hz, 1H), 4.83 (s, 2H), 4.21 (d, J = 6.8 Hz, 1H), 4.04 (d, 7 = 6.1 Hz, 2H), 3.10 (d, 7= 17.7 Hz, 1H), 2.98 (d, 7= 18.0 Hz, 1H), 2.71 - 2.58 (m, 1H), 2.50 (m, 1H), 2.24 (d, J = 5.9 Hz, 4H), 1.86 (s, 1H), 1.75 - 1.68 (m, 3H), 1.41 (s, 3H), 0.15 (d, J = 6.3 Hz, 2H), -0.01 - -0.11 (m, 2H). LCMS M / Z (M+H) 462.3. Example 137 'HNMR (400 MHz, DMSO) 5 8.44 (s, 1H), 8.40 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.43 (s, 1H), 7.38 (d, J = 9.3 Hz, 1H), 5.91 (d, J = 6.7 Hz, 1H), 4.83 (s, 2H), 4.19 (s, 1H), 4.05 (s, 2H), 3.26-3.14 (m, 1H), 3.14-2.91 (m, 2H), 2.64 (d, J = 7.6 Hz, 1H), 2.50 (m, 1H), 2.23 (t, J = 7.4 Hz, 4H), 1.85 (s, 1H), 1.79 - 1.67 (m, 3H), 1.41 (s, 3H), 0.12 (s, 2H), -0.08 (d, J = 12.1 Hz, 2H). LCMS M / Z (M+H) 462.3. Example 138: (3R)-l-((4-(4-((R)-l-((l, 4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1.1]hexan-3-yl)methyl)pyrrolidin-3-ol: Example 138 was prepared in a similar fashion to step 1 of Example 136 from a readily available intermediate. 'H NMR (400 MHz, DMSO) 5 8.44 (m, J = 2.6 Hz, 1H), 8.38 (s, 1H), 7.91 - 7.84 (m, 1H), 7.39 (m, J = 5.4 Hz, 2H), 5.91 (m, J = 6.1 Hz, 1H), 4.83 (s, 2H), 4.57 - 4.48 (m, 1H), 4.24 (s, 1H), 4.05 (s, 2H), 3.95 (s, 1H), 3.07 (s, 1H), 2.98 (s, 1H), 2.43 - 2.33 (m, 1H), 2.25 (s, 5H), 2.22 (m, J = 18.8, 11.3 Hz, 4H), 2.08 (m, J= 14.8, 11.6 Hz, 1H), 1.76- 1.69 (m, 3H), 1.40 (m, J = 2.6 Hz, 3H), 1.33 (s, 1H). LC / MS [M+H] = 429. Example 139: 2-[l-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-l-yl]-3-oxabicyclo[2.1.1]hexan-4-y I] acetonitrile A mixture of [l-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-1 -yl] -3 -oxabicyclo [2.1.1] hexan-4-yl] methyl                     4- methylbenzenesulfonate (made in a similar fashion as Example 136, step 1, starting from Example 74, 29 mg, 0.05 mmol) and potassium cyanide (7 mg, 0.1 mmol) in DMSO (0.5 mL) was stirred for 2 h. The reaction mixture was directly purified by prep HPLC eluting with 5-50% formic acid / CHsCN to yield 2-[l-[4-[(lR)-l-(2,4-dihydro-I / / -pyran o [3,4-c\ quinolin-9-yloxy)ethyl]triazol-1 -yl] -3 -oxabicyclo [2.1.1] hexan-4- yl]acetonitrile as a white solid. (3.9 mg, 18% Yield). 'H NMR (400 MHz, DMSO-r / e) 5 8.55 (d, J = 16.8 Hz, 2H), 7.92 (d, J = 9.1 Hz, 1H), 7.52 (d, J = 2.7 Hz, 1H), 7.50 -7.41 (m, 2H), 7.14-7.07 (m, 1H), 5.97 (q, J =6.4 Hz, 1H), 4.86 (s, 2H),4.15 (s, 2H), 4.07 (td, J = 5.8, 2.4 Hz, 2H), 3.23 (s, 2H), 3.20 - 3.10 (m, 1H), 3.05 (dt, J = 12.2, 5.6 Hz, 1H), 2.29 (s, 2H), 2.26 - 2.15 (m, 2H), 1.73 (d, J = 6.4 Hz, 3H). LC / MS [M+H] = 418. Example 140: (R)-6-(4-(l-((1,4-dihydro-2H-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)dihydro-lH, 3H, 5H-6,7a-methanopyrrolo[l, 2-c] oxazol-3-one Step 1: (R)-6-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3-triazol-l-yl)dihydro-lH, 3H, 5H-6,7a-methanopyrrolo[l, 2-c]oxazol-3-one: To a mixture of tert-butyl 1 -(hydroxymethyl)-4-|4-|( I / ?)-1-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]-2-azabicyclo[2.1. l]hexane-2-carboxylate (60.0 mg, 0.12 mmol, prepared in a similar fashion to Example 105 via diazo transfer and click reactions) in dichloromethane (3 mL) was added DAST (0.03 mL, 0.24 mmol) at -78 °C. The mixture was stirred at 25 °C for 2 h, then was quenched by adding to saturated NaHCO3(aq) (4 mL) solution slowly, then extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (acetonitrile 1-28% 0.2% formic acid in water) to afford 7-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-l-yl]-3-oxa-5-azatricyclo[5.1.1.01,5]nonan-4-one (15.5 mg, 0.035 mmol, 29.9% yield) as a white solid. 'HNMR (400 MHz, DMSO-J6) 5 8.57 (s, 1H), 8.45 (s, 1H), 7.89 (d, J= 9.2 Hz, 1H), 7.47 (d, J= 2.8 Hz, 1H), 7.40 (dd, J= 2.8, 9.2 Hz, 1H), 5.95 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.49 (s, 2H), 4.13 - 4.01 (m, 2H), 3.80 (s, 2H), 3.19 - 2.92 (m, 2H), 2.71 - 2.65 (m, 2H), 2.37 - 2.33 (m, 2H), 1.73 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 434.1. Example 141: (R)-7-(4-(l-((1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl) oxy)ethyl)-lH-l, 2,3-triazol-l-yl)dihydro-lH, 6H-7,8a-methanopyrrolo[2,l- c] [l,4]oxazin-4(3H)-one Step 1: (R)-(4-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-2-azabicyclo[2.1.1]hexan-l-yl) methanol: A solution of tertbutyl l-(hydroxymethyl)-4-[4-[ (U?)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.1 g, 2.17 mmol, prepared in a similar fashion to Example 64 via diazo transfer and click reactions) in 5% TFA in HFIP (20 mL) was stirred at 25 °C for 2 h, then the mixture was concentrated under reduced pressure to afford crude [4-[4-[(1R)-1 -(2,4-dihydro-1H-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-l-yl]-2-azabicyclo[2.1. l]hexan-l-yl]methanol as a yellow oil, which was used for next step without further purification. LCMS M / Z (M+H) 408.1. Step 2: (R)-2-chloro-l-(4-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy) ethyl)-lH-l,2,3-triazol-l-yl)-l-(hydroxymethyl)-2-azabicyclo[2.1.1]hexan-2-yl)ethan-l-one: To a solution of (J?)-(4-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-1,2,3-triazol-l-yl)-2-azabicyclo [2.1.1] hexan-l-yl) methanoll (190 mg, 0.47 mmol) and triethylamine (142 mg, 1.4 mmol) in dichloromethane (4 mL) was added chloroacetyl chloride (52.66 mg, 0.47 mmol) at 0 °C. The mixture was stirred for 1 h at 0 °C, then the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (0-2% methanol in dichloromethane) to give the title compound (120 mg, 53.2% yield) as a yellow oil. LCMS M / Z (M+H) 484.1. Step 3: (R)-7-(4-( 1-((1,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3-triazol-l-yl)dihydro-lH, 6H-7,8a-methanopyrrolo [2,1-c] [1,4] oxazin-4(3H)-one: To a solution of (R)-2-chloro-1-(4-(4-(1 -((l,4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl) oxy) ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -(hydroxymethyl)-2-azabicyclo [2.1.1] hexan-2-yl) ethan-l-one (50 mg, 0.10 mmol) in THF (3 mL) was added sodium hydride (7 mg, 60% purity, 0.15 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The resulting mixture was quenched with NH4CI (1mL). The reaction 5 mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL><3). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (0~2% methanol in dichloromethane) to afford the tittle compound (5.5 mg, 11.5% yield) as a white solid. 'HNMR (400 MHz, DMSO-de) 5 8.58 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 9.2 Hz, 10      1H), 7.48 - 7.45 (m, 1H), 7.42 - 7.37 (m, 1H), 5.97 - 5.92 (m, 1H), 4.84 (s, 2H), 4.09 - 4.01 (m, 6H), 3.92 (s, 2H), 3.16 - 2.96 (m, 2H), 2.61 - 2.57 (m, 2H), 2.28 - 2.23 (m, 2H), 1.73 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 448.2. Examples 142-144: the compounds were synthesized using methods and procedures similar to those used in Example 141 using appropriate starting materials 15 and synthetic intermediates. No. Structure Name 142 .0. [ll X T J N=N    V 0 ( / ?)-8-(4-(l-(( l,4-dihydro-22 / -pyrano[3,4-c]quinolin-9- yl)oxy) ethyl)-\H-1,2,3 -triazol- 1-yl) tetrahydro- 1 / / .5 / / . 7 / / -8.9a-mcthanopyrrolo| 2.1 -c] [ l,4]oxazepin-5- one 143 -0. fll jj o'^^ 0 Peak 1 on SFC Method U 7-(4-((J?)-l-((l,4-dihydro-22 / -pyrano[3,4-c] quinolin-9-yl) oxy) ethyl)-12 / -l,2,3-triazol-l-yl)-3-methyldihydro-1H,6 / / -7.8a-methanopyrrolo[2,l-c] [1,4] oxazin-4(3H)-one No. Structure Name 144 Til 0 Peak 2 on SFC Method U 7-(4-((R)-l-((l,4-dihydro-2 / / -pyrano[3,4-c] quinolin-9-yl)oxy) ethyl)-1 / / -1,2,3 -triazol-1 -yl)-3-mcthyldihydro-1 / / . 6 / / -7.8a-methanopyrrolo[2,l-c][l,4]oxazin-4(3H)- one Analyticla data for compounds of Examples 142-144 is provided in the table below: No. NMR m / z 142 'H NMR (400MHz, DMSO-d6) 5 8.55 (s, 1H), 8.44 (s, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.50 - 7.34 (m, 2H), 5.98 - 5.90 (m, 1H), 4.84 (s, 2H), 4.14 (s, 2H), 4.09 - 4.00 (m, 2H), 3.91 - 3.82 (m, 4H), 3.47 - 3.40 (m, 2H), 3.16 - 2.95 (m, 2H), 2.81 - 2.73 (m, 2H), 2.24 (d, J= 5.6 Hz, 2H), 1.72 (d, J =6.4 Hz, 3H). 462.1 143 'H NMR (400MHz, DMSO-J6) 5 8.57 (s, 1H), 8.45 (s, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.47 (d, J= 2.4 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.95 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.22 - 4.10 (m, 2H), 4.05 (s, 2H), 3.99 - 3.82 (m, 3H), 3.17 - 2.94 (m, 2H), 2.62 (d, J= 6.0 Hz, 1H), 2.53 (d, J =6.0 Hz, 1H), 2.31 -2.17(m, 2H), 1.73 (d,J= 6.4 Hz, 3H), 1.29 (d, J= 6.8 Hz, 3H). 462.1 144 'H NMR (400MHz, DMSO-J6) 5 8.57 (s, 1H), 8.44 (s, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.46 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.94 (q, J= 6.4 Hz, 1H), 4.83 (s, 2H), 4.23 - 4.10 (m, 2H), 4.05 (s, 2H), 3.99 - 3.83 (m, 3H), 3.17 - 2.94 (m, 2H), 2.62 (d, J= 6.4 Hz, 1H), 2.53 (s, 1H), 2.30 - 2.17 (m,2H), 1.72 (d, . / = 6.4 Hz, 3H), 1.29 (d, . / = 6.8 Hz, 3H). 462.1 Example 145: ( / ?)-7-(4-(l-((l,4-dihydro-2 / / -pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)-1 / / -1,2,3-triazol-l-yl)tetrahydro-l / / , 6 / / -7,8a-methanopyrrolo[2,l- BH3-THF THF, 70 °C , 1 h Step 1: (R)-7-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3-triazol-l-yl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2,l-c] [1,4] oxazine: To a stirred solution of (R)-7-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)dihydro-         8a-methanopyrrolo[2,1 - c][ 1,4]oxazin-4(3 / / )-onc (48.5 mg, 0.11 mmol, Example 141) in THF (1 mL) was added BH3-THF (5 mL, 5 mmol, 1 M) at 0 °C. Then the mixture was stirred at 70 °C for 1 h, then quenched with methanol (10 mL) at 0 °C. The mixture was concentrated under reduced pressure and purified by prep-TLC (10% methanol in dichloromethane) to afford the title compound (10.7 mg, 21% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 8.45 (d, J= 7.6 Hz, 2H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 7.41 - 7.36 (m, 1H), 5.95 - 5.89 (m, 1H), 4.84 (s, 2H), 4.09 - 4.01 (m, 2H), 3.76 - 3.56 (m,4H), 3.25 -2.86 (m, 4H), 2.73 (s, 2H), 2.31 - 1.97 (m,4H), 1.72 (d, J = 6.4 Hz, 3H). LCMS M / Z (M+H) 434.1. Example 146 & 147, l-(4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-(fluoromethyl)-2-azabicyclo [2.1.1]hexan-2-yl)-2-hydroxybutan-l -one Peak 1 Step 1: methyl(R)-4-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy) ethyl)-lH-l, 2,3-triazol-l-yl)-l-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate: To a solution of [4-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl] triazol-l-yl]-2-azabicyclo[2.1.1]hexan-l-yl] methanol (Example 141, step 1, 200.0 mg, 0.49 mmol) and TEA (298 mg, 3.0 mmol) in DCM (8 mL) was added methyl chloroformate (0.3 mL, 3.3 mmol) at 0 °C. Then the reaction was stirred for 16 h at 25 °C, then quenched with saturated NaHCOs aqueous solution (10 mL). The aqueous layer was extracted with DCM. The organics were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure to afford methyl 4-[4-[(lJ?)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]-l-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (90 mg, 0.193 mmol, 39% yield) as a yellow solid. 'HNMR (400 MHz, DMSO-J6) 5 8.58 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 6.04 - 5.74 (m, 1H), 4.92 - 4.78 (m, 3H), 4.08 - 4.04 (m, 2H), 4.03 (d, J= 7.2 Hz, 2H), 3.90 (s, 2H), 3.60 (s, 3H), 3.15 - 2.95 (m, 2H), 2.49 - 2.38 (m, 2H), 2.14 - 2.05 (m, 2H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 466.2. Step 2: methyl (R)-4-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy) ethyl)-lH-l, 2,3-triazol-l-yl)-l-(fluoromethyl)-2-azabicyclo[2.1.1 ]hexane-2-carboxylate: To a mixture of methyl 4-|4-|(l / ?)-l-(2.4-dihydro-l / / -pyrano|3.4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]-l-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (50 mg, 0.11 mmol) in DCM (2 mL) was added DAST (0.03 mL, 0.2 mmol) at 0 °C. The mixture was stirred at 25 °C for 1.5 h, then quenched by adding to saturated NaHCO3(aq) (5 mL) slowly. The aqueous was extracted with DCM, and the organic layer was washed with brine, dried over sodium sulfate, fdtrated and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (acetonitrile 30-60% 0.1% NH4OH in water) to afford methyl4-[4-[( 1 / / )-1 -(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl ]triazol-l-yl]-l-(fluoromethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (17.4 mg, 0.037 mmol, 34% yield) as a white solid. 'HNMR (400 MHz, CDCh) 5 8.44 (s, 1H), 8.02 (d, J= 9.2 Hz, 1H), 7.63 (s, 1H), 7.40 - 7.35 (m, 1H), 7.34 (d, J= 2.4 Hz, 1H), 5.84 (q, J= 6.8 Hz,lH), 5.22 - 4.99 (m, 2H), 4.91 (s, 2H), 4.25 - 4.07 (m, 2H), 4.00 - 3.92 (m, 2H), 3.72 (s, 3H), 3.20 - 2.95 (m, 2H), 2.64 - 2.54 (m, 2H), 2.31 - 2.20 (m, 2H), 1.81 (d, J= 6.8 Hz, 3H). LCMS M / Z (M+H) 468.2. Step 3: (R)-9-(l-(l-(l-(fluoromethyl)-2-azabicyclo[2.1.1 ]hexan-4-yl)-lH-l,2,3-triazol-4-yl)ethoxy)-l,4-dihydro-2H-pyrano[3,4-c]quinoline: To a solution of methyl 4-[4-[(lJ?)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]-l-(fluoromethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (160 mg, 0.34 mmol) in EtOH (12 mL)) was added a solution ofNaOH (205.3 mg, 5.13 mmol) in water (2 mL). The reaction mixture was stirred at 80 °C for 4 h, then the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtrated and concentrated to give crude product 9-[(lJ?)-l-[l-[l-(fluoromethyl)-2-azabicyclo[2.1.1]hexan-4-yl]triazol-4- yl]ethoxy]-2,4-dihydro-lH-pyrano[3,4-c]quinoline (120 mg, 0.293 mmol, 85.6% yield) as a yellow solid. LCMS M / Z (M+H) 410.2. Step 4: l-(4-(4-((R)-l-((l, 4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-l-(fluoromethyl)-2-azabicyclo[2.1.1]hexan-2-yl)-2-hydroxybutan-l-one: To a solution of 9-[(lR)-l-[l-[l-(fluoromethyl)-2-azabicyclo[2.1. l]hexan-4-yl]triazol-4-yl]ethoxy]-2,4-dihydro-lH-pyrano[3,4-c]quinoline (60 mg, 0.15 mmol) and 2-hydroxybutanoic acid (30.51 mg, 0.29 mmol) in DMF (3 mL) was added HATU (83.58 mg, 0.22 mmol) and DIPEA (0.07 mL, 0.44 mmol). The mixture was stirred at 25 °C for 1 h, then was diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (50% EE (25% ethanol in ethyl acetate) in petroleum ether) to afford the racemic title compound (79 mg) as a white solid. The racemate was separated by SFC (Column: Chiralpak AD-3 50x4.6mm I.D., 3 pm Mobile phase: A: CO2 B: ethanol (0.05% DEA) Isocratic: 40% B. Flow rate: 4 mL / min.) to give peak 1: (2R)-1 -[4-[4-[( 1R)-1 -(2,4-dihydro-1 H-pyrano [3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -(fluoromethyl)-2-azabicyclo[2.1.1]hexan-2-yl]-2-hydroxy-butan-l-one (21.1 mg, 0.04 mmol, 25.1% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-r / e) 5 8.63 (s, 1H), 8.45 (s, 1H), 7.89 (d, J= 9.2 Hz, 1H), 7.48 (d, J= 2.8 Hz, 1H), 7.40 (dd, J= 2.8, 9.2 Hz, 1H), 5.95 (q, 7= 6.4 Hz, 1H), 5.26 - 5.07 (m, 2H), 4.97 (d,7=6.8Hz, 1H), 4.84 (s, 2H), 4.28-4.11 (m, 2H), 4.10-3.93 (m, 3H), 3.19-2.94 (m, 2H), 2.61 (brd, J= 5.6 Hz, 2H), 2.19 (t, 7= 5.2 Hz, 2H), 1.73 (d, 7= 6.4 Hz, 3H), 1.68 - 1.40 (m, 2H), 0.89 (t, 7 = 7.6 Hz, 3H). LCMS M / Z (M+H) 496.3. And peak 2: (25)-l-[4-[4-[(lR)-l-(2,4-dihydro- lH-pyrano[3,4-c] quinolin-9-yloxy) ethyl]triazol-1 -yl] -1 -(fluoromethyl)-2-azabicyclo[2.1.1]hexan-2-yl]-2-hydroxy-butan-l-one (20.9 mg, 0.040 mmol, 25% yield) as a yellow solid. JH NMR (400 MHz, DMSO-7,) 5 8.63 (s, 1H), 8.45 (s, 1H), 7.89 (d, 7= 9.2 Hz, 1H), 7.47 (d, 7= 2.8 Hz, 1H), 7.40 (dd, 7= 2.8, 9.2 Hz, 1H), 5.95 (m, 7= 6.4 Hz, 1H), 5.27 - 5.04 (m, 2H), 4.96 (d, 7= 7.2 Hz, 1H), 4.84 (s, 2H), 4.26 -4.10 (m, 2H), 4.08 - 3.92 (m, 3H), 3.18 - 2.92 (m, 2H), 2.61 (d, 7= 4.4 Hz, 2H), 2.24 -2.12 (m, 2H), 1.73 (d,7= 6.4 Hz, 3H), 1.69-1.41 (m, 2H), 0.88 (t,7= 7.6 Hz, 3H). LCMS M / Z (M+H) 496.3. Example 148: (R)-4-(4-( 1-((1,4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-l-(fluoromethyl)-N-methyl-2-azabicyclo[2.1.1] hexane-2-carboxamide Step 1: (R)-4-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3-triazol-l-yl)-l-(fluoromethyl)-N-methyl-2-azabicyclo[2.1.1]hexane-2-carboxamide: To a solution of 9-[(l / ?)-l-[l-[l-(fluoromethyl)-2-azabicyclo[2.1.I |hcxan-4-yl |triazol-4-yl |cthoxy|-2.4-dihydro-l / / -pyrano|3.4-c]quinoline (Example 147, step 3, 40 mg, 0.10 mmol) and TEA (0.05 mL, 0.39 mmol) was added A-methyl carbamoyl chloride (18.27 mg, 0.20 mmol) dropwise at 0 °C. The reaction was stirred at room temperature for 1 h, then was quenched with saturated NaHCOs aqueous solution (10 mL) and extracted with dichloromethane. The combined oiganic was washed with brine, dried over sodium sulfate, filtrated and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (acetonitrile 30-60% 0.1% NH4OH in water) to afford 4-[4[(17?) -1 -(2,4-dihydro- IH-pyrano [3,4-c]quinolin-9-yloxy)ethyl]triazol-1 -yl] -1 -(fluoromethyl)-A-methyl-2-azabicyclo[2.1.1]hexane-2 carboxamide (23.2 mg, 0.048 mmol, 49.4% yield) as a white solid. 'H NMR (400 MHz, DMSO-r / g) 5 8.58 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 7.39 (dd, J= 2.4, 9.2 Hz, 1H), 6.60 (d, J= 4.4 Hz, 1H), 5.93 (q, J= 6.4 Hz, 1H), 5.14 - 4.97 (m, 2H), 4.84 (s, 2H), 4.05 (s, 2H), 3.81 (s, 2H), 3.16 - 2.87 (m, 2H), 2.55 (d, J= 4.4 Hz, 3H), 2.54 (s, 2H), 2.13 - 2.08 (m, 2H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 467.3. Examples 149-154: the compounds were synthesized using methods and procedures similar to those used in Example 146 using appropriate starting materials and synthetic intermediates. No. Structure Name 149 JU F\ n=n ( / / )-9-( 1-(1-(1 -(fluoromethyl)-2-(methylsulfonyl)-2-azabicyclo[2.1.1] hcxan-4-yl)-1 / / -1,2.3-triazol-4-yl) ethoxy)-1,4-dihydro-2 / / -py rano [3,4-c] quinoline 150 nA rVPo o 1 -(4-(4-(( / / )-1 -((1,4-dihydro-2 / / -pyrano [3,4-c] quinolin-9-yl) oxy) ethyl)-1 / / -1,2,3-triazol-l-yl)-l- (fluoromethyl)-2-azabicyclo[2.1.1] hexan-2-yl)-2-hydroxypropan-1 -one 151 o / = Z / z'z Q       \ / <\ ii \__ / \= / y—z o — / ( / / )-1 -(4-(4-( 1 -((1,4-dihydro-2 / / -pyrano[3,4-c] quinolin-9-yl)oxy) ethyl)-1 / / -1,2,3-triazol-1 -yl)-1 -(fluoromethyl)-2-azabicyclo[2.1.1] hexan-2-yl)-2-hydroxyethan-1 -one 152 u / =^ / —y / =\ ° \ ( / / )-1 -(4-(4-( 1 -((1,4-dihydro-2 / / -pyrano[3,4-c] quinolin-9-yl)oxy) ethyl)-1 / / -1,2,3-triazol-1 -yl)-1 -(fluoromethyl)-2-azabicyclo [2.1.1] hexan-2-yl) propan-1-one 153 / ° z'Z Uy °U / methyl ( / / )-4-(4-( 1 -((1,4-dihydro-2 / / -pyrano [3,4-c]quinolin-9-yl)oxy) ethyl)-1 / / -1,2,3-triazol-1 -yl)-1 -(fluoromethyl)-2-azabicyclo [2.1. l]hexane-2-carboxylate No. Structure Name 154 .0. Th I N-VJ n=n [4-[4-[(lR)-l-(2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]-2-azabicyclo[2.1. l]hexan-2-yl] -(1 -hydroxy cyclobutyl)methanone Analyticla data for compounds of Examples 142-144 is provided in the table below: No. NMR m / z 149 'H NMR (400 MHz, DMSO-Je) 5 8.59 (s, 1H), 8.45 (s, 1H), 7.89 (d, J= 9.2 Hz, 1H), 7.47 (d, J= 2.4 Hz, 1H), 7.39 (dd, J= 2.4, 9.2 Hz, 1H), 5.96 (q, J= 6.4 Hz, 1H), 4.96 (s, 1H), 4.84 (d, J= 2.4 Hz, 3H), 4.10 - 4.01 (m, 2H), 3.96 (s, 2H), 3.18 - 3.10 (m, 1H), 3.09 (s, 3H), 3.05 - 2.91 (m, 1H), 2.63 (br d, J= 4.4 Hz, 2H), 2.39 - 2.29 (m, 2H), 1.73 (d, J =6.4 Hz, 3H). 488.2 150 XH NMR (400MHz, DMSO-d6) 5 8.63 (s, 1H), 8.45 (s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.47 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 9.2, 2.8 Hz, 1H), 5.99 - 5.91 (m, 1H), 5.21 (s, 1H), 5.14 - 5.04 (m, 2H), 4.84 (s, 2H), 4.25-4.18 (m, 2H), 4.16 -4.11 (m, 1H), 4.10-4.00 (m, 2H), 3.15 - 2.96 (m, 2H), 2.60 (d, J = 5.6 Hz, 2H), 2.25 - 2.13 (m, 2H), 1.73 (d, J =6.0 Hz, 3H), 1.21 (d, J =6.4 Hz, 3H) 482.2 151 XH NMR (400MHz, DMSO-d6) 5 8.61 (s, 1H), 8.45 (s, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.47 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.98 - 5.91 (m, 1H), 5.25 - 5.08 (m, 2H), 4.84 (s, 2H), 4.80 -4.76 (m, 1H), 4.14 - 4.00 (m, 6H), 3.16 - 2.94 (m, 2H), 2.64 - 2.57 (m, 2H), 2.26 - 2.17 (m, 2H), 1.73 (d, J= 6.4 Hz, 3H) 486.1 152 XH NMR (400MHz, DMSO-d6) 5 8.61 (s, 1H), 8.45 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J= 9.6 Hz, 1H), 5.95 (s, 1H), 5.20 (s, 1H), 5.08 (s, 1H), 4.84 (s, 2H), 4.07 (s, 4H), 3.17 - 3.06 (m, 1H), 3.05 -2.95 (m, 1H), 2.59 (s, 2H), 2.31 -2.17 (m, 4H), 1.73 (s, 3H), 0.98 (s, 3H) 466.1 153 'H NMR (400 MHz, CDCh) 5 8.44 (s, 1H), 8.02 (d, J= 9.2 Hz, 1H), 7.63 (s, 1H), 7.40 - 7.35 (m, 1H), 7.34 (d, J= 2.4 Hz, 1H), 5.84 (q, J = 6.8 Hz, 1H), 5.22 - 4.99 (m, 2H), 4.91 (s, 2H), 4.25 - 4.07 (m, 2H), 4.00 - 3.92 (m, 2H), 3.72 (s, 3H), 3.20 - 2.95 (m, 2H), 2.64 - 2.54 (m, 2H), 2.31 -2.20 (m, 2H), 1.81 (d, 7= 6.8 Hz, 3H). 468.2 154 XH NMR (DMSO-d6, 400 MHz) 5 8.4-8.5 (m, 1H), 8.4-8.4 (m, 1H), 7.8-7.9 (m, 2H), 7.4-7.5 (m, 1H), 7.4-7.4 (m, 1H), 5.9-6.0 (m, 1H), 4.8-4.9 (m, 2H), 4.2-4.3 (m, 1H), 3.9-4.1 (m, 2H), 3.3-3.3 (m, 1H), 2.9-3.2 (m, 3H), 2.2-2.3 (m, 4H), 1.72 (d, 3H, J =6.5 Hz), 1.4-1.4 (m, 3H). LCMS M / Z (M+H) 466.6. 466.6 Example 155: (R)-1-(4-(4-( 1-((1,4-dihydro-2H-pyrano[3,4-c] quinolin-9- yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-l-(fluoromethyl)-2-azabicyclo[2.1.1]hexan-2-yl)-2-fluor oe than-1-one Step 1: (R)-1-(4-(4-(1-((1,4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl)oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-l-(fluoromethyl)-2-azabicyclo[2.1.1]hexan-2-yl)-2-fluoroethan-l-one: To a mixture of l-|4-|4-|(l / ?)-l-(2.4-dihydro-l / / -pyrano|3.4-c]quinolin-9-yloxy)ethyl] triazol-l-yl]-l-(fluoromethyl)-2-azabicyclo[2.1. l]hexan-2-yl]-2-hydroxy-ethanone (72.0 mg, 0.15 mmol, prepared in a similar fashion to Example 146) in DCM (5 mL) was added DAST (0.06 mL, 0.46 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h, then quenched by adding to saturated NaHCOs (2 mL) solution slowly, and further diluted with water. The aqueous was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (acetonitrile 30-60% 0.1% NH4OH in water) to afford l-[4-[4-[(U?)-l-(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-l-yl]-l-(fluoromethyl)-2-azabicyclo [2.1. l]hexan-2-yl]-2-fluoro-ethanone (23.1 mg, 0.047 mmol, 31% yield) as a white solid. 'H NMR (400MHz, DMSO-Jd) 5 8.62 (s, 1H), 8.45 (s, 1H), 7.89 (d, J= 9.2 Hz, 1H), 7.47 (d, J= 2.8 Hz, 1H), 7.40 (dd, J= 2.8, 9.2 Hz, 1H), 5.95 (q, J= 6.4 Hz, 1H), 5.26 - 5.10 (m, 2H), 5.08 - 4.91 (m, 2H), 4.84 (s, 2H), 4.13 - 4.00 (m, 4H), 3.17 - 2.93 (m, 2H), 2.63 (br d, J= 2.4 Hz, 2H), 2.29 - 2.20 (m, 2H), 1.73 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 470.3. Example 156 & 157, (4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1.1]hexari-3-yl)((S)-3-hydroxypyrrolidin-l-yl)methanone OH                                 OH                 OH Peak 1                     Peak 2 (4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH- 1,2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1.1]hexan-3-yl)((S)-3-hydroxy pyrrolidin-l-yl)methanone: To a stirred solution of 4-(4-1-(( 1,4-dihydro-2 / / -pyrano| 3.4- c] quinolin-9-yl)oxy)ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -methyl-2- oxabicyclo[2.1. l]hexane-3-carboxylic acid (150 mg, 0.34 mmol, prepared in a similar fashion to Example 105 via diazo transfer and click reactions), (S)-pyrrolidin-3-ol (36 mg, 0.41 mmol) and DIPEA (118.79 mg, 1.03 mmol) in DMF (3 mL) was added HATU (261 mg, 0.69 mmol) at 0 °C. The mixture was stirred for 1 h at 25 °C, then diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, fdtered and concentrated under reduced pressure. The crude was further purified by prep-HPLC (DB, Welch Xtimate C18 150x25 mmx5 pm, water (NH4HCO3)-ACN, 20% ~ 50%, 25 ml / min) to afford the racemic title compound (86 mg, 50% yield) as a white solid. The racemate was separated by SFC (CHIRALPAK IC(250 mmx30 mm, 10 pm), 30% iPrOH (0.1%NH4OH) in CO2, 70 ml / min) to afford the title compound-1 (Example 156, first peak on SFC, 35.1 mg, 40.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 8.44 (s, 1H), 8.34 (d, J= 4.4 Hz, 1H), 7.91 - 7.85 (m, 1H), 7.44 - 7.35 (m, 2H), 5.90 (q, J= 6.4 Hz, 1H), 5.02 - 4.79 (m, 4H), 4.31 - 3.99 (m, 3H), 3.67 - 3.44 (m, 1H), 3.27 - 3.00 (m, 4H), 2.68 - 2.53 (m, 1H), 2.47 - 2.23 (m, 4H), 1.88 - 1.52 (m, 5H), 1.45 (d, J = 6.8 Hz, 3H). LCMS M / Z (M+H) 528.0. And the title compound-2 (Example 157, second peak on SFC, 36.1 mg, 41.6% yield) as a white solid^H NMR (400 MHz, DMSO-d6) 5 8.44 (s, 1H), 8.37 (s, 1H), 7.87 (dd, J= 9.2, 2.0 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.41 - 7.35 (m, 1H), 5.91 (q, J= 6.4 Hz, 1H), 4.97 - 4.82 (m, 4H), 4.24 - 4.00 (m, 3H), 3.69 - 3.38 (m, 1H), 3.31 - 3.18 (m, 2H), 3.14 - 3.03 (m, 3H), 2.65 - 2.52 (m, 1H), 2.46 - 2.38 (m, 1H), 2.34 - 2.22 (m, 2H), 1.95 - 1.74 (m, 1H), 1.71 (d, J= 6.4 Hz, 3H), 1.62 - 1.49 (m, 1H), 1.45 (d, J= 2.4 Hz, 3H). LCMS M / Z (M+H) 528.0. Examples 158-165: the compounds were synthesized using methods and procedures similar to those used in Example 156 using appropriate starting materials 5 and synthetic intermediates. Chiral SFC analytical separation methods used to prepare compounds of examples 158-165 were the same as those summarized above for examples 43-58. No. Structure Name 158 u N^. hJ Peak 1 on SFC Method V (4-(4-((J?)-1 -((1,4-dihydro-2H-pyrano [3,4-c] quinolin-9-yl)oxy) ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -methyl-2-oxabicyclo [2.1.1] hexan-3-yl) ((5)-3-hydroxy-3-methylpyrrolidin-l-yl) methanone No. Structure Name 159 111 'Xf' h<5 Peak 2 on SFC Method V (4-(4-(( / ?)-1 -((1,4-dihydro-2 / / -py rano [3,4-c] quinolin-9-yl) oxy) cthy 1)-1 / / -1.2.3-tri azol-l-yl )-1-methyl-2-oxabicyclo [2.1.1] hexan-3-yl) ((5)-3-hydroxy-3-methylpyrrolidin-l-yl) methanone 160 111 0"^ Aq OH Peak 1 on SFC Method W (4-(4-(( / ?)-1 -((1,4-dihydro-2 / / -pyrano [3,4-c] quinolin- 9-yl) oxy) cthy 1)-1 / / -1.2.3-tri azol-l-yl )-1-methyl-2- oxabicyclo [2.1.1] hexan-3-yl) ((R)-3-hydroxypyrrolidin-l-yl) methanone 161 XL III zk,N 0"^ OH Peak 2 on SFC Method W (4-(4-(( / ?)-1 -((1,4-dihydro-2 / / -pyrano [3,4-c] quinolin- 9-yl) oxy) cthy 1)-1 / / -1.2.3-tri azol-l-yl )-1-methyl-2- oxabicyclo [2.1.1] hexan-3-yl) ((R)-3-hydroxypyrrolidin-l-yl) methanone No. Structure Name 162 .0. Th o"^ HO Peak 1 on SFC Method W (4-(4-((J?)-1 -((1,4-dihydro-2H-pyrano [3,4-c] quinolin-9-yl) oxy) cthy 1)-1 / / -1.2.3-tri azol-l-yl )-1-methyl-2-oxabicyclo [2.1.1] hexan-3-yl) ((R)-3-hydroxy-3-methylpyrrolidin-l-yl) methanone 163 .0. Th u HO Peak 2 on SFC Method W (4-(4-((J?)-1 -((1,4-dihydro-2 / / -pyrano [3,4-c] quinolin-9-yl) oxy) cthy 1)-1 / / -1.2.3-tri azol-l-yl )-1-methyl-2-oxabicyclo [2.1.1] hexan-3-yl) ((R)-3-hydroxy-3-methylpyrrolidin-l-yl) methanone 164 .0. Th XJ Tf T~^ OH Peak 1 on SFC Method T (4-(4-((J?)-1 -((1,4-dihydro-2 / / -pyrano [3,4-c] quinolin-9-yl)oxy) ethyl)- 1H-1,2,3 -triazol-1 -yl)-1 -methyl-2-oxabicyclo [2.1.1] hexan-3-yl) (3-hydroxy-3 -methylazetidin-l-yl) methanone No. Structure Name 165 Peak 2 on SFC (4-(4-((R)-1 -((1,4-dihydro-2H-pyrano [3,4-c] quinolin-9-yl) oxy) cthy I)-1 / / -1.2.3-tri azol-1-yl)-1-methyl-2-oxabicyclo [2.1.1] hexan-3-yl) (3-hydroxy-3 -methylazetidin-l-yl) methanone Method T Analyticla data for compounds of Examples 158-165 is provided in the table below: No. NMR m / z 158 XH NMR (400MHz, DMSO-de) 5 8.44 (s, 1H), 8.35 (d, J= 1.6 Hz, 1H), 7.90 - 7.85 (m, 1H), 7.45 - 7.36 (m, 2H), 5.96 - 5.85 (m, 1H), 4.92 (d, J= 15.2 Hz, 1H), 4.83 (s, 3H), 4.08 - 3.99 (m, 2H), 3.58 -3.34 (m, 2H), 3.26 - 2.85 (m, 4H), 2.65 - 2.57 (m, 1H), 2.43 - 2.26 (m, 3H), 1.75 - 1.48 (m, 5H), 1.45 (d, . / = 6.8 Hz, 3H), 1.28-1.12 (m, 3H) 520.1 159 'H NMR (400MHz, DMSO-de) 5 8.44 (s, 1H), 8.36 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.47 - 7.43 (m, 1H), 7.40 - 7.35 (m, 1H), 5.91 (q, J = 6.4 Hz, 1H), 4.98 - 4.68 (m, 4H), 4.12 - 3.97 (m, 2H), 3.52 - 3.42 (m, 1H), 3.26 - 2.91 (m, 5H), 2.70 - 2.59 (m, 1H), 2.46 - 2.37 (m, 1H), 2.33 -2.24 (m, 2H), 1.85 - 1.60 (m, 5H), 1.45 (d, J =2.8 Hz, 3H), 1.26- 1.10 (m, 3H). 520.1 160 'H NMR (400 MHz, DMSO-de) 5 = 8.45 (s, 1H), 8.36 (d, J = 3.6 Hz, 1H), 7.95 - 7.81 (m, 1H), 7.48 - 7.30 (m, 2H), 5.97 - 5.78 (m, 1H), 4.98 - 4.82 (m, 4H), 4.23 - 3.97 (m, 3H), 3.70 - 3.41 (m, 1H), 3.23 -3.07 (m, 4H), 2.63 (s, 1H), 2.34 - 2.25 (m, 4H), 1.71 (dd, . / = 2.4, 6.0 Hz, 5H), 1.45 (d, J= 3.2 Hz, 3H) 506.1 161 'H NMR (400 MHz, DMSO-de) 5 = 8.48 (s, 1H), 8.38 (d, J= 3.6 Hz, 1H), 7.89 (dd, J= 2.4, 9.2 Hz, 1H), 7.55 - 7.34 (m, 2H), 5.92 (d, J= 6.4 Hz, 1H), 5.08 - 4.74 (m, 4H), 4.33 - 3.97 (m, 3H), 3.59 (s, 1H), 3.21 - 3.02 (m, 4H), 2.58 (d, J= 4.8 Hz, 1H), 2.47 - 2.36 (m, 2H), 2.33 -2.22 (m, 2H), 1.87 - 1.52 (m, 5H), 1.45 (d, J =6.4 Hz, 3H). LCMS [M+H] 506.1. 506.1 162 'H NMR (400 MHz, DMSO-de) 5 = 8.46 (s, 1H), 8.38(d, J= 4.8 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.47 - 7.36 (m, 2H), 5.96 - 5.87 (m, 1H), 4.96 - 4.71 (m, 3H), 4.09 - 4.01 (m, 2H), 3.75 - 3.41 (m, 2H), 3.27 -3.00 (m, 4H), 2.93 - 2.59 (m, 1H), 2.46 - 2.35 (m, 1H), 2.34 - 2.25 (m, 2H), 2.04 - 1.62 (m, 5H), 1.45 (d, J= 3.2 Hz, 3H), 1.26 - 1.23 (m, 2H), 1.11 (s, 1H) 520.1 163 'H NMR (400 MHz, DMSO-de) 5 = 8.46 (s, 1H), 8.38 (d, J= 4.8 Hz, 1H), 7.92 - 7.84 (m, 1H), 7.48 - 7.36 (m, 2H), 5.97 (s, 1H), 4.92 - 520.1 No. NMR m / z 4.68 (m, 4H), 4.13 - 3.98 (m, 2H), 3.57 - 3.38 (m, 2H), 3.27 - 3.18 (m, 2H), 3.14-3.03 (m, 2H), 2.71 (s, 1H), 2.44 - 2.36 (m, 1H), 2.34 -2.24 (m, 2H), 1.73 - 1.43 (m, 8H), 1.27 (s, 2H), 1.09 (s, 1H). 164 'H NMR (400 MHz, DMSO-de) 5 = 8.44 (s, 1H), 8.35 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.43 (d, J= 11.2 Hz, 2H), 5.95 - 5.88 (m, 1H), 5.62 - 5.56 (m, 1H), 4.84 (s, 2H), 4.77 - 4.71 (m, 1H), 4.07 - 4.03 (m, 2H), 4.01 - 3.83 (m, 1H), 3.70 - 3.58 (m, 2H), 3.11 - 2.99 (m, 2H), 2.69 - 2.61 (m, 1H), 2.35 - 2.23 (m, 4H), 1.71 (d, J= 6.4 Hz, 3H), 1.47 - 1.44 (m, 3H), 1.35 (s, 1H), 1.15 (s, 2H). 560.1 165 'H NMR (400 MHz, DMSO-d6) 5 = 8.44 (s, 1H), 8.35 (s, 1H), 7.87 (d, J= 9.2 Hz, 1H), 7.46 - 7.35 (m, 2H), 5.99 - 5.84 (m, 1H), 5.61 -5.53 (m, 1H), 4.87 - 4.80 (m, 2H), 4.72 (d, J= 4.4 Hz, 1H), 4.07 -3.44 (m, 6H), 3.12 - 2.99 (m, 2H), 2.68 - 2.63 (m, 1H), 2.41 - 2.23 (m, 4H), 1.71 (d, 7= 6.4 Hz, 3H), 1.48 - 1.43 (m, 3H), 1.35 (s, 1H), 1.10 (s, 2H). 506.1 Example 166: 7-(4-((R)-l-((1,4-dihydro-2H-pyrano[3,4-c] quinolin-9- yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH,6H-7,8a-methanopyrrolo[2,l-c] [1,4] oxazine-3-carbonitrile t-BuOK THF,-30 °C - rt, 2h 5            Step 1: 2-chloro-3-(4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9- yl)oxy) ethyl)-lH-l,2,3-triazol-l-yl)-l-(hydroxymethyl)-2-azabicyclo[2.1.1]hexan-2-yl) propanenitrile: To a mixture of 14-[ 4-[ (1 / ?)-1 -(2.4-dihydro-1 / / -pyrano[ 3.4-c]quinolin-9-yloxy)ethyl] triazol-l-yl]-2-azabicyclo[2.1. l]hexan-l-yl]methanol (Example 141 step 1, 400.0 mg, 0.98 mmol) in DMF (8 mL) was added 2 10 chloroacrylonitrile (0.17 mL, 2.16 mmol). The mixture was stirred at 25 °C for 16 h, then diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, fdtered and concentrated to afford crude product (521 mg) as a yellow oil. 'H NMR (400 MHz, CHLOROFORM-d) 5 = 8.44 (s, 1H), 8.29 - 8.18 (m, 1H), 8.02 (s, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 5.84 (q, J= 6.8 15 Hz, 1H), 4.93 (s, 2H), 3.96 (s, 2H), 3.31 (d, J= 6.4 Hz, 2H), 2.97 (s, 4H), 2.89 (s, 4H), 2.32 - 2.18 (m, 4H), 1.82 (d, J= 6.4 Hz, 3H). LCMS [M+H] 495.1. Step 2: 7-(4-((R)-l-((l, 4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3-triazol-l-yl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2,1-c] [1,4]oxazine-3- carbonitrile: To a solution of 2-chloro-3-[l-(hydroxymethyl)-4-[4-[(lR)-l-(2,4-dihydro-1 H-pyrano [3,4-c]quinol in-9-yl oxy )ethyl ] tri azol-1 -yl] -2-azabicyclo[2.1.1]hexan-2-yl] propanenitrile (491.0 mg, 0.99 mmol) in THF (10 mL) was added dropwise / -BuOK (1.98 mL, 1 M in THF) at -30 °C. The mixture was stirred at 25 °C for 2 h, then concentrated under reduced pressure and purified by flash chromatography (5% methanol in dichloromethane) to afford the title product (34 mg) as a yellow solid. Then the product was further purified by reverse phase chromatography (acetonitrile 28-58% 0.2% (NH3 • watcr+NH^CCh) in water) to give 7-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH,6H-7,8a-methanopyrrolo[2,l-c][l,4]oxazine-3-carbonitrile as a mixture of diastereomers (11.6 mg, 0.02 mmol, 12% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 = 8.51- 8.42 (m, 2H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.4, 9.2 Hz, 1H), 5.93 (q, J= 6.4 Hz, 1H), 5.04 (s, 1H), 4.84 (s, 2H), 4.09 - 4.00 (m, 2H), 3.94 (s, 2H), 3.22 - 3.06 (m, 2H), 3.06 - 2.84 (m, 4H), 2.30 (s, 2H), 2.15 (s, 2H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 459.2. Example 167: (7-(4-((R)-l-((l, 4-dihydro-2H-pyrano[3,4-c] quinolin-9- yl)oxy)ethyl)-lH-l,2,3-triazol- 1-yI) tetrahydro- 1H, 6H-7,8a-methanopyrrolo[2,l-c] [1,4] oxazin-3-yl)methanol ,O. NaOH(1M) m dioxane, 100 °C, 1 h I N—n N=N .0. ill Il T                 SFC o^^               r    ?' .0. / V           BHs-THF JI J          0 II       THF, 80 °C , 2 h V N-\4 o N=N .0. ill Peak 2 Step 1: 7-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3-triazol-lyl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2,1-c] [1,4]oxazine-3-carhoxylic acid: To a solution of 8-[4-[(l / ?)-l-(2,4-dihydro-lH-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -3 -oxa-6-azatricyclo [6.1.1.01,6]decane-4-carbonitrile (211.0 mg, 0.46 mmol, Example 166 in 1,4-dioxane (2 mL) was added NaOH aqueous solution (5 mL, 1 M) dropwise at 25 °C. The mixture was stirred at 100 °C for 1 h.. The resulting solution was adjusted to around pH 5 by progressively adding 1 M HC1, then was purified by reverse phase chromatography (acetonitrile 025 / 0.1% water (FA)-ACN) to afford 8-[4-[(l / ?)-l-(2,4-dihydro-l-pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-1 -yl] -3 -oxa-6-azatricyclo [6.1.1.01,6]decane-4-carboxylic acid (123 mg, 0.26 mmol, 56% yield) as a white solid. LCMS M / Z (M+H) 478.2. Step 2: (7-(4-((R)-l-((l, 4-dihydro-2H-pyrano[3,4-c]quinolin-9-y I) oxy) ethyl)-1H-1,2,3-triazol-l-yl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2,1-c] [1,4]oxazin-3-yl)methanol & (7-(4-((R)-l-((l, 4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3-triazol-l-yl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2,1-c] [1,4]oxazin-3-yl)methanol: Under nitrogen, to a solution of 8-|4-|( I / / )-1-(2.4-dihydro-1 / / -pyrano[3,4-c]quinoline -9-yloxy)ethyl]triazol-l-yl]-3-oxa-6-azatricyclo[6.1.1.01,6]decane-4-carboxylic acid (103.0 mg, 0.22 mmol) in THF (3 mL) was added BH3THF (5 mL, 5 mmol) at 25 °C. The resulting solution was stirred for 2 h at 80 °C. After cooling to 25 °C, MeOH (10 ml) was added dropwise and the solution was stirred for 3 h at 80 °C, then the mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile 030 / 0.25% water (FA)-ACN) to afford the racemic title compound 78 mg as a white solid. The racemate was separated by SFC: Column: Cellulose-2 100*4.6 mm I.D., 3 pm; Mobile phase: A: CO2 B: ethanol (0.05% DEA); Isocratic: 50% B; Flow rate: 2.8 mL / min; Column temp.: 35 °C; to afford peak2 [(4J / )-8-[4-[(U / )-l-(2,4-dihydro-127-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]-3-oxa-6-azatricyclo[6.1.1.01,6]decan-4-yl]methanol (5.58 mg, 0.0116mmol, 26.8% yield) as a white solid. 'HNMR (400 MHz, DMSO-d6) 5 = 8.45 (d, J= 6.8 Hz, 2H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 7.39 (J = 2.8, 9.2 Hz, 1H), 5.92 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.71 (t, J= 5.6 Hz, 1H), 4.09 - 3.99 (m, 2H), 3.90 (d, J= 11.6 Hz, 1H), 3.62 (d, J= 11.6 Hz, 1H), 3.53 - 3.46 (m, 1H), 3.45 -3.38 (m, 2H), 3.31 (s, 1H), 3.15 - 3.05 (m, 1H), 3.04 - 2.96 (m, 1H), 2.95 - 2.89 (m, 1H), 2.80 (d, J= 8.0 Hz, 1H), 2.43 - 2.31 (m, 2H), 2.28 (d, J= 6.0 Hz, 1H), 2.03 (d, J= 6.8 Hz, 1H), 1.94 (J = 6.0, 9.6 Hz, 1H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H] 464.3. Example 168: 7-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl) oxy)ethyl)-lH-l, 2,3-triazol-l-yl)-3-(fluoromethyl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2,l-c] [1,4] oxazine Step 1: 7-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-1,2,3-triazol-l-yl)-3-(fluoromethyl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2,l-c][1,4]oxazine: To a stirred solution of (7-(4-(( / / )-1-((1.4-dihydro-2 / / -pyrano| 3.4-c] quinolin-9-yl)oxy) ethyl)-I / / -1,2,3-triazol-1 -yl)tetrahydro-1 / / .6 / / -7.8a-methanopyrrolo[2,l-c][l,4]oxazin-3-yl)methanol (Example 167, 10 mg, 0.02 mmol) in DCM (1 mL) was slowly added BAST (10 mg, 0.04 mmol) at -78 °C. The resulting mixture was stirred at -78 °C for 1 h, then quenched by saturated NaHCO3(aq) solution and extracted with DCM. The combined organic phases were dried over sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (DB, Welch Xtimate C18 150x25 mmx5 pm, water( NH4HCO3)-ACN, 30% ~ 60%) to afford the title compound (2.2 mg, 21% yield) as yellow solid. T1 NMR (400 MHz, DMSO-de) 5 8.46 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 7.39 (dd, J= 2.4, 9.2 Hz, 1H), 5.92 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.53 - 4.45 (m, 1H), 4.41 - 4.33 (m, 1H), 4.11 - 4.02 (m, 2H), 3.95 (d, J= 11.8 Hz, 1H), 3.82 -3.70 (m, 1H), 3.67 (d,J= 12.0 Hz, 1H), 3.47 - 3.40 (m, 1H), 3.16 - 3.06 (m, 1H), 3.04 - 2.95 (m, 1H), 2.93 - 2.87 (m, 1H), 2.86 - 2.81 (m, 1H), 2.47 -2.37 (m, 2H), 2.32 - 2.27 (m, 1H), 2.09 - 2.05 (m, 1H), 1.98 - 1.92 (m, 1H), 1.72 (d, J = 6.4 Hz, 3H). LCMS M / Z (M+H) 466.1. Example 169 & 170, (7-(4-((R)-l-((5-methyl-l,4-dihy...

Claims

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:p is an integer from 0 to 3;q is 0 or 1;r is an integer from 0 to 3;XisOorNRN;RN is selected from H, C1-3 alkyl, and C1-3 haloalkyl;ring A is selected from C3-10 cycloalkyl and 3-10 membered heterocycloalkyl;m is an integer from 0 to 8;each R2, R3, and R4 is independently selected from-CN, -OH, D, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy;each R1 is independently selected from C1-6 alkyl, C1-6 haloalkyl, Cy1, C(=O)Cy1, oxo, halo, -CN, -ORla, -NRlaR2a, -C(O)NRlaR2a, -C(O)ORla, -C(O)Rla, -NRlaC(O)R2a, -S(O)2Rla, and -NH-S(O)2Rla, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, -ORlb, -NRlbR2b, -C(O)NRlbR2b, and -NRlbC(O)R2b;each Cy1 is independently selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from RCyl;each RCyl is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, -CN, -ORlb, -NRlbR2b, -C(O)NRlbR2b, and -NRlbC(O)R2b, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, -ORlb, -NRlbR2b, -C(O)NRlbR2b, -NRlbC(O)R2b,each Rla, R2a, Rlb, and R2b is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, and Cy2, wherein said Ci-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, -CN, halo, -0Rlc, and -NRlcR2c;each Cy2 is independently selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, -CN, -ORld, and -NRldR2d; andeach Rlc, R2c, Rld and R2d is independently selected from H, Cm alkyl, and Ci-6 haloalkyl.

2. The compound of claim 1, wherein X is O.

3. The compound of claim 1, wherein X is NH.

4. The compound of any one of claims 1-3, wherein the sum of n, p, and q is 0, 1, or 2.

5. The compound of any one of claims 1-4, wherein each R2, R3, and R4 is independently selected from D, C1-6 alkyl, and halo.

6. The compound of claim 1, having formula:or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-6, wherein ring A is a monocyclic C3-10 cycloalkyl.

8. The compound of any one of claims 1-6, wherein ring A is a monocyclic 3-10 membered heterocycloalkyl.

9. The compound of any one of claims 1-6, wherein ring A is selected from:

10. The compound of any one of claims 1-6, wherein ring A is a polycyclic C3-10 cycloalkyl.

11. The compound of claim 10, wherein ring A is a bridged C3-10 cycloalkyl or a spirocyclic C3-10 cycloalkyl.

12. The compound of any one of claims 1-6, wherein ring A is a polycyclic 3-10 membered heterocycloalkyl.

13. The compound of claim 12, wherein ring A is a bridged 3-10 membered heterocycloalkyl or a spirocyclic 3-10 membered heterocycloalkyl.

14. The compound of any one of claims 1-6, wherein ring A is selected from:

15. The compound of any one of claims 1-14, wherein :

16. The compound of any one of claims 1-15, wherein m is an integer from 0 to 3.

17. The compound of any one of claims 1-16, each R1 is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, Cy1, C(=O)Cy1, oxo, halo, -CN, -ORla, -C(0)NRlaR2a, -C(O)ORla, -C(O)Rla, -S(0)2Rla, and -NH-S(O)2Rla, wherein said Ci-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, -ORlb, -NRlbR2b, and -NRlbC(0)R2b.

18. The compound of any one of claims 1-17, wherein each RCyl is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, halo, -CN, -ORlb, and -NRlbR2b, wherein said Ci-6 alkyl is optionally substituted with -ORlb.

19. The compound of any one of claims 1-18, wherein each Rla, R2a, Rlb, and R2b is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, and Cy2, wherein said Ci-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy2, -ORlc, and -NRlcR2c.

20. The compound of any one of claims 1-19, wherein each Cy2 is independently selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with a substituent selected from C1-6 alkyl and C1-6 haloalkyl.

21. The compound of claim 1, wherein:X is selected from O and NH;the sum of n, p, and q is 0, 1, or 2;each R2, R3, and R4 is independently selected from D, C1-6 alkyl, and halo;ring A is selected from a monocyclic C3-10 cycloalkyl, a monocyclic 3-10 membered heterocycloalkyl, a bridged C3-10 cycloalkyl, a spirocyclic C3-10 cycloalkyl, a bridged 3-10 membered heterocycloalkyl, and a spirocyclic 3-10 membered heterocycloalkyl.m is an integer from 0 to 3;each R1 is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, Cy1, C(=O)Cy1, oxo, halo, -CN, -0Rla, -C(0)NRlaR2a, -C(O)ORla, -C(O)Rla, -S(0)2Rla, and -NH-S(0)2Rla, wherein said Ci-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, -0Rlb, -NRlbR2b, and -NRlbC(0)R2b;each RCyl is independently selected from Ci-6 alkyl, Ci-6 haloalkyl, halo, -CN, -0Rlb, and -NRlbR2b, wherein said Ci-6 alkyl is optionally substituted with -0Rlb;each Rla, R2a, Rlb, and R2b is independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, and Cy2, wherein said Ci-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy2, -0Rlc, and -NRlcR2c;each Cy2 is independently selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with a substituent selected from C1-6 alkyl and C1-6 haloalkyl; and22. The compound of claim 1, selected from any one of the following compounds:or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

24. A method of treating a bacterial infection caused by a species of the genus mycobacterium, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof.

25. The method of claim 24, wherein the bacterial infection is caused by Mycobacterium tuberculosis, Mycobacterium leprae, or one or more nontuberculous mycobacterium species, or a combination thereof.

26. The method of claim 25, wherein the bacterial infection is tuberculosis or leprosy.

27. The method of claim 25, wherein the bacterial infection is caused by nontuberculous mycobacterium species selected from Mycobacterium fortuitum complex (MAC) (Mycobacterium fortuitum, Mycobacterium peregrinum, Mycobacterium porcinum), Mycobacterium chelonae, Mycobacterium abscessus complex (Mycobacterium abscessus subspecies abscessus, Mycobacterium abscessus subspecies bolletii, Mycobacterium abscessus subspecies massiliense), Mycobacterium smegmatis, Mycobacterium mycogenicum, Mycobacterium kansasii, Mycobacterium marinum, Mycobacterium gordonae, Mycobacterium scrofulaceum, Mycobacterium avium complex (Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium chimaera), Mycobacterium terrae complex, Mycobacterium ulcerans, Mycobacterium xenopi, Mycobacterium ximiae, Mycobacterium malmoense, Mycobacterium szulgai, Mycobacterium asiaticum, Mycobacterium haemophilum, or a combination thereof.

28. The method of claim 27, wherein the infection is pulmonary infection, a respiratory tract infection (RTI), an upper respiratory tract infection, a lower respiratory tract infection, a nasopharyngeal infection, pneumonia, nosocomial pneumonia, community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator associated pneumonia (VAP), Mycobacterium avium complex (MAC) lung disease, disseminated Mycobacterium avium complex (DMAC) infection, disseminated Mycobacterium avium intracellulare complex (DMAIC) infection, MAC mastitis, MAC pyomyositis, genitourinary infection, a bloodstream infection (BSI), central line associated bloodstream infection, intraabdominal infection (IAI), complicated intra-abdominal infection (cIAI), skin and soft tissue infection (SSTI), complicated skin and soft tissue infection (cSSTI), surgical site infection (SSI), complicated surgical site infection (cSSI), skin and skin structure infection (SSSI), complicated skin and skin structure infection (cSSSI), osteomyelitis, prosthetic joint infection, or a post-operative infection.

29. The method of any one of claims 24-28, wherein the subject has a co-morbid condition selected from cystic fibrosis, chronic obstructive pulmonary disease, chronic pulmonary disorder, bronchiectasis, non-CF bronchiectasis, emphysema, and acquired immune deficiency syndrome.

30. The method of any one of claims 24-29, comprising administering to the subject one or more additional antibacterial therapeutic agents.

31. The method of claim 30, wherein the additional antibacterial therapeutic agent is rifampicin, rifapentine, ethambutol, pyrazinamide, isoniazid, levofloxacin, moxifloxacin, gatifloxacin, ofloxacin, kanamycin, amikacin, aztreonam, azithromycin, capreomycin, streptomycin, ethionamide, prothionamide, cycloserine, terididone, para-aminosalicylic acid, clofazimine, clarithromycin, amoxicillin-clavulanate, pretomanid, prothionamide, isoxyl, thiacetazone, a diarylquinoline such as bedaquiline or TBAJ-587, nitroimidazo-oxazine PA-824 (pretomanid), delaminid (OPC-67683), an oxazolidinone such as linezolid, tedizolid, radezolid, sutezolid, posizolid, or TBI-223, EMB analog SQ109, OPC-16732, GSK 3036656, GSK3036656A (also known as GSK070), GSK2556286, GSK3211830, a benzothiazinone such as BTZ043 or PBTZ169, an azaindole such as TBA-7371, a dinitrobenzamide, and a beta-lactam such as sanfetrinem,meropenem, faropenem, ertapenem, tebipenem, gepotidacin, thiacetazone, or meropenem-clavulanate, or a pharmaceutically acceptable salt thereof.

32. The method of claim 30, comprising administering to the subject bedaquiline, pretomanid, sutezolid, moxifloxacin, and / or pyrazinamide, or a pharmaceutically acceptable salt thereof.

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