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

[0001] GUAB INHIBITOR COMPOUNDS AND USES THEREOF

[0002] CLAIM OF PRIORITY

[0003] 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.

[0004] TECHNICAL FIELD

[0005] 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.

[0006] BACKGROUND

[0007] 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.

[0008] SUMMARY

[0009] 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 inosine- 5 ’-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

[0010] (I): or a pharmaceutically acceptable salt thereof, wherein:

[0011] 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.

[0012] 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-moibid 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 co- administering 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).

[0013] 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.

[0014] Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims.

[0015] DESCRIPTION OF DRAWINGS

[0016] FIG. 1 A contains a schematic representation of the de novo purine biosynthesis pathway in M. tb, and GuaBi impact on de novo guanine biosynthesis.

[0017] FIG. IB contains chemical structure, whole cell activity, chemical, and pharmacokinetic properties of GuaB inhibitor (compound of Example 17).

[0018] FIG. 1C contains an image showing crystal structure of Ex.17 bound to M. tuberculosis GuaB2 protein (with IMP) bound, determined at 1.35 A resolution.

[0019] FIG. 2A contains line plot showing viability of M. tbH37Rv treated with 0.6 μM (10xMIC) Ex. 17 cmpd, and 1 μM (10xMIC) isoniazid enumerated overtime by plating for colony forming units (CPUs). Untreated was the DMSO vehicle control.

[0020] FIG. 2B contains a line plot showing viability of M. tbH37Ra treated with 0, 0.09, 0.19, and 0.39 μM Ex. 17 cmpd overtime by plating for CPUs.

[0021] FIG. 2C contains a line plot showing viability of M. tbH37Ra treated with 0, 0.78, 1.56, and 3.12 μM isoniazid overtime by plating for CPUs. FIG. 2D contains a line plot showing viability of M. t&H37Rv treated with DMSO vehicle control, 1 μM isoniazid, and 0, 0.006, 0.06, 0.6, and 6 μM Ex. 17 cmpd over time by plating for CPUs.

[0022] FIG. 3A contains a graph showing in vivo activity of Ex. 17 cmpd as a single agent against virulent M. 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 (CPUs). Isoniazid was used as a positive control.

[0023] FIG. 3B contains a graph showing in vivo activity of Ex. 17 cmpd as a single agent against virulent M.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 (CPUs). Isoniazid (10 mg / kg QD) was used as a positive control.

[0024] 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 CPUs. 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.

[0025] 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 CPUs. 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.

[0026] 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 CPUs. 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.

[0027] 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 CPUs. 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.

[0028] 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 CPU 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. tbH37Rv 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.

[0029] FIG. 6 contains a line plot showing minimal bactericidal concentration (MBC) against MtbH37Ra in vitro.

[0030] FIG. 7 contains a graph showing in vivo activity of Ex. 74 cmpd as a single agent against virulent Mtb H37Rv in acute mouse infection model.

[0031] DETAILED DESCRIPTION

[0032] 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).

[0033] 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).

[0034] 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).

[0035] 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 xintiae, 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.

[0036] 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, intra- abdominal 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.

[0037] In some embodiments, tire 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.

[0038] In some embodiments, tire 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.

[0039] Compounds

[0040] In some embodiments, the present disclosure provides a compound of Formula

[0041] (I): or a pharmaceutically acceptable salt thereof, wherein: p is an integer from 0 to 3; q is O or 1; r is an integer from 0 to 3;

[0042] X is O orNRN;

[0043] RNis 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 R4is independently selected from-CN, -OH, D, halo, C1-6 alkyl, C 1-6 haloalkyl, C1-6 alkoxy, and C 1-6 haloalkoxy; each R1is independently selected from C1-6 alkyl, C1-6 haloalkyl, Cy1, C(=O)Cy1, oxo, halo, -CN, -OR1a, -NR1aR2a, -C(O)NR1aR2a, -C(O)OR1a, -C(O)R1a, - NR1aC(O)R2a, -S(O)2R1’, and -NH-S(O)2R1a, wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, -ORlb, - NRlbR2b, -C(O)NRlbR2b, and -NRlbC(O)R2b; each Cy1is 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 RCy1; each RCy1is independently selected from C1-6 alkyl, C1-6haloalkyl, halo, -CN, - ORlb, -NRlbR2b, -C(O)NRlbR2b, and -NRlbC(O)R2b, wherein said C1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, - ORlb, -NRlbR2b, -C(O)NRlbR2b, -NRlbC(O)R2b, each R1a, R2a, Rlb, and R2bis independently selected from H, C1-6alkyl, C1-6haloalkyl, and Cy2, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy2, -CN, halo, -ORlc, and -NR1cR2c; each Cy2is 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 C1-6alkyl, C1-6haloalkyl, halo, -CN, -ORld, and - NR1dR2d; each Rlc, R2c, Rldand R2dis independently selected from H, C1-6 alkyl, and C1- 6 haloalkyl.

[0044] In some embodiments, X is O.

[0045] In some embodiments, X is NRN. In some embodiments, RNis H. In some embodiments, RNis C1-3 alkyl. In some embodiments, X is NH.

[0046] 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.

[0047] In some embodiments, R2is CN. In some embodiments, R2is OH. In some embodiments, R2is D. In some embodiments, R2is halo. In some embodiments, R2is C1-6 alkyl. In some embodiments, R2is C1-6 haloalkyl. In some embodiments, R2is C1- 6 alkoxy. In some embodiments, R2is Ci^ haloalkoxy. In some embodiments, each of R2, R3, and R4is independently selected from D, C1-6 alkyl, and halo.

[0048] In some embodiments, the compound has formula: or a pharmaceutically acceptable salt thereof.

[0049] 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.

[0050] In some embodiments, ring A is selected from:

[0051] 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.

[0052] 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.

[0053] In some embodiments, ring A is selected from:

[0054]

[0055] In some embodiments:

[0056] 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.

[0057] In some embodiments, each R1is independently selected from C1-6 alkyl, C1-6haloalkyl, Cy1, C(=O)Cy1, oxo, halo, -CN, -OR1a, -C(O)NR1aR2a, -C(O)OR1a, - C(O)R1a, -S(O)2R1’, and -NH-S(O)2R1’, wherein said C1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, -ORlb, - NRlbR2b, and -NRlbC(O)R2b.

[0058] In some embodiments, R1is Cy1. In some embodiments, R1is C(=O)Cy1. In some embodiments, Cy1is C3-10 cycloalkyl. In some embodiments, Cy1is 3-10 membered heterocycloalkyl.

[0059] In some embodiments, each RCylis independently selected from C1-6alkyl, C1- 6 haloalkyl, halo, -CN, -ORlb, and -NRlbR2b, wherein said C1-6alkyl is optionally substituted with -ORlb.

[0060] In some embodiments, each R1a, R2b, Rlb, and R2bis 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, -OR1c, and - NR1cR2c.

[0061] In some embodiments, each Cy2is independently selected from C3-10 cycloalkyl and 4-10 membered heterocycloalkyl, each of which is optionally substituted with a substituent selected from C 1-6 alkyl and C1-6 haloalkyl. In some embodiments:

[0062] X is selected from O and NH; the sum of n, p, and q is 0, 1, or 2; each R2, R3, and R4is independently selected from D, C1-6alkyl, 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 R1is independently selected from C1-6 alkyl, C1-6 haloalkyl, Cy1, C(=O)Cy1, oxo, halo, -CN, -OR1a, -C(O)NR1aR2a, -C(O)OR1a, -C(O)R1a, -S(0)2R1a, and -NH-S(O)2R1a, 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 RCy1is independently selected from C1-6 alkyl, C1-6haloalkyl, halo, -CN, - ORlb, and -NRlbR2b, wherein said C1-6alkyl is optionally substituted with -ORlb; each R1a, R2a, Rlb, and R2bis independently selected from H, C1-6alkyl, C1-6haloalkyl, and Cy2, wherein said C1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy2, -ORlc, and -NRlcR2c; each Cy2is 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 C 1-6 haloalkyl; and

[0063] In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:

[0064] or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the compound of Formula (I) is selected from any one of the following compounds: or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the compound is selected from any one of the following compounds: or a pharmaceutically acceptable salt thereof.

[0067] 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.

[0068] Compositions, formulations, and routes of administration

[0069] 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.

[0070] 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.

[0071] Depending on the intended mode of administration, the disclosed pharmaceutical compositions can be in solid, semi-solid, or liquid dosage form, such as, fbr 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 fbr intravenous administration.

[0072] 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.

[0073] 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, fbr example, sterile injectable aqueous compositions (e.g., solutions, suspensions, or emulsions), or oleaginous suspensions.

[0074] 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 fbr 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.

[0075] 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.

[0076] Definitions

[0077] As used herein, the term "about" means "approximately" (e.g., plus or minus approximately 10% of the indicated value).

[0078] 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 “C1-6alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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, n-propyl, isopropyl, n-butyl, tert- butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l -butyl, n-pentyl, 3- pentyl, n-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.

[0084] As used herein, the term “Cn-mhaloalkyl”, 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.

[0085] As used herein, the term “Cn-malkoxy”, 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., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert- butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0086] As used herein, “Cn-mhaloalkoxy” 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.

[0087] As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br.

[0088] 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 C3-10 monocyclic 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.

[0089] 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 4- 6 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.

[0090] 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.

[0091] 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 (R)-configuration. In some embodiments, any asymmetrically substituted carbon atom has the (S)-configuration.

[0092] Compounds provided herein also include tautomeric forms. Tautomeric forms result fiom 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.

[0093] 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 fiom 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.

[0094] 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.

[0095] 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 (z.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 (z.e., reversing the pathology and / or symptomatology).

[0096] 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-, ortri-alkylamines, and similar bases.

[0097] 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

[0098] Abbreviations used throughout the examples: DAST: diethylaminosulfur trifluoride; DCE: dichloroethane; DCM: dichloromethane; DEA: diethylamine; DIPEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMT: 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; NMRj nuclear magnetic resonance; PTSA: p-toluenesulfonic acid; TBAF: tetra-n-butylammonium fluoride; TBSC1: tert- butyldimethylsilyl chloride; TEA: triethylamine; TEA: trifluoroacetic acid; THE: tetrahydrofuran; TLC: thin layer chromatography; prep-TLC: preparative thin layer chromatography; SEC: supercritical fluid chromatography. Chiral SEC analytical separation methods referenced in the following synthetic examples are summarized in the table below:

[0099]

[0100]

[0101] Step 1: 4-(benzyloxy)-2-bromo-l-nitrobenzene (compound 2 in above)-. To

[0102] 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.

[0103] The filter cake was then dissolved in EtOAc, and washed with brine. The organic phase was then dried over NazSO^ filtered and concentrated under reduced pressure, to afford the title compound (580 g, 79.2% yield) as a yellow solid,1H NMR (400

[0104] MHz, DMSO-d6) δ 8.09-8.07 (d, J= 4.00 Hz, 1H), 7.56-7.55 (d, J= 2.00 Hz, 1H)

[0105] 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-l,3,2- dioxaborolane (compound 3 in above scheme): To a chemical reactor was added 1,4- dioxane (2.43 L) 4-(benzyloxy)-2-bromo-l -nitrobenzene (348 g, 1.13 mol), Bis(pinacolato)diborane (430 g, 1.69 mol), and KOAc (332 g, 3.39 mol). The mixture was degassed and purged with N2 gas, then Pd(dppf)Ch (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 filtered. 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.1H NMR (400 MHz, CDCh) b 8.17-8.15 (d, J = 4.0 Hz IH), 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).

[0106] 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 tetrahydro-4 / f-pyran-4-one (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. NaHCO3, 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, NMR (400 MHz, CDCh) b 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).

[0107] 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-2H- 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).1H NMR (400 MHz, CDCh) b = 9.30 (s, IH), 8.17- 8.15 (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.1HNMR (400 MHz, CDCI3) b 8.46 (d, 1H), 8.03-8.01 (d, J= 4.0 Hz, 1H) 7.52- 7.37 (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, J= 6.0 Hz, 2H) 3.09-3.07 (m, J= 4.0 Hz, 2H).

[0108] 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 H2atmosphere (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.

[0109] 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.

[0110] 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).1H NMR (400 MHz, DMSO-d6) b 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.

[0111] Synthesis ofHeadgroupH-2

[0112] Step 1: (S)-but-3-yn-2-yl methanesulfonate-. To a solution of (S)-(-)-3-butyn-2- ol (3.4 mL, 42.8 mmol) and Et3N (11.9 mL, 85.6 mmol) in DCM (60 mL) at 0 °C was added MsCI (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. NaHCO3aqueous 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 (S)-but-3-yn-2-yl methanesulfonate (5.2 g, 82% yield) as a pale yellow oil. r.t.1H NMR (400 MHz, CDCh) 8 = 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).

[0113] 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 (S)-but-3- yn-2-yl methanesulfonate (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 (R)-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.1H NMR (400MHz, CDCh) 8 = 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.

[0114] Synthesis ofHeadgroupH-3

[0115] 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- cjquinoline (270 mg, 1.0 mmol, 90 % yield) as a light yellow solid, which is pure enough for next step without further purification.1H NMR (400 MHz, CDCI3) 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.

[0116] Step 2: 1,1 -dideute rio-2,4-dihydropyrano[ 3, 4-c]quinolin-9-ol (HeadgroupH- 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. NaHCO3solution, 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.1HNMR (400MHz, DMSO-d6) δ = 10.03 (s, 1H), 8.37 (s, 1H), 7.83 (d, J= 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 Synthesis ofHeadgroupH-4

[0117] 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% NaHCO3aqueous solution, saturated NaHCO3solution and brine. The organic layer was 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 title compound (397.9 mg, 76% yield) as a white solid,1H 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.

[0118] 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.

[0119] Step 3: 5-fluoro-2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-ol (HeadgroupH- 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 filtered 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.1H NMR (400 MHz, CDCh) 57.83 (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 M7Z (M+H) 220.0.

[0120] Synthesis qfHeadgroupH-5

[0121] 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 NaHCO3aqueous 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 NaHCO3aqueous 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, J= 2.1 Hz, 1H), 7.88 (d, J= 8.9 Hz, 1H), 7.73 (dd, J= 8.9, 2.2 Hz, 1H), 4.84 (t, J= 1.7 Hz, 2H), 4.10 (t, J= 5.7 Hz, 2H), 3.12 (tt, J= 5.7, 1.6 Hz, 2H), 2.54 (s, 3H). LCMS M / Z (M+H) 277.9.

[0122] Step 2: 5-methyl-2,4-dihydro-lH-pyrano[3,4-c]quinolin-9-ol (HeadgroupH- 5): To a mixture of Pd(dppf)ChxDCM (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, NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.11 (d,

[0123] J= 9.1 Hz, 1H), 7.58 (d, J= 9.1 Hz, 1H), 7.37 (d, J= 2.5 Hz, 1H), 4.86 (s, 2H), 4.04 (t, J= 5.6 Hz, 2H), 3.23 (d, J= 5.9 Hz, 2H), 2.70 (s, 3H). LCMS M / Z (M+H) 215.9.

[0124] Synthesis of HeadgroupH-6

[0125] Step 1: l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl trifluoromethanesulfonate: To a solution of pyridine (0.72 mL, 9.0 mmol) and 2,4-dihydro-1H-pyrano[3,4-c] quinolin-9-ol (600 mg, 3 mmol) in DCM was added T60 (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, filtered 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 yellow oil. LCMS M / Z (M+H) 334.1.

[0126] Step 2 : tert-butyl (1, 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- 1H-pyrano[3,4-c]quinolin-9-yl trifluoromethanesulfonate (500 mg, 1.5 mmol), Pd2(dba)3 (54.9 mg 0.06 mol), CS2CO3 (1466.4 mg, 4.5 mmol) in 1,4- 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.

[0127] Step 3 : 1, 4-dihydro-2H-pyrano[3, 4-c]qutnoltn-9-amtne: A solution of tert- butyl N-(2,4-dihydro-1H-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.

[0128] Tail Group Compounds:

[0129] T-4 T-5 T-6

[0130] T-28 T-29 T-30

[0131] Synthesis of (lS,3r)-3-(4-((S)-l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)-l- methylcyclobutane-l-carbonitrile (Tail group T-1) and (lR,3s)-3-(4-((S)-l- hydroxyethyl)-lH-l , 2, 3-triazol-l-yl)-l-methylcyclobutane-l-carbonitrile (T ail group T-2)

[0132] 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 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 mLx3). The combined organic layers were washed with NaHCO3(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% ethyl acetate in petroleum ether) to afford a mixture of cis and trans amides of tert- butyl N-(3-carbamoyl-3-methyl-cyclobutyl) carbamate (270 mg, 1.18 mmol, 90.4% yield) as a white solid, NMR (400 MHz, DMSO-d6) 57.13 (s, IH, minor), 6.99 ((s, IH, major), 6.81 (s, IH, minor), 6.72 (s, IH, major), 3.97 - 3.85 (m, IH, 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).

[0133] 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.

[0134] 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 KHCOs (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.

[0135] Step 4: (S)-3-(4-(l -((tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)- 1-methylcyclobutane-l-carboxamide: To the mixture of step 3 was added tert-butyl- dimethyl-[(lS)-l-methylprop-2-ynoxy]silane (627.7 mg, 3.41 mmol), G1SO4 (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 MZZ (M+H)+= 339.1.

[0136] Step 5: (IS, 3r)-3-(4-((S)-l-((ferf-butyldimethylsilyl)oxy)ethyl)-1H-l,2,3- triazol-l-yl)-l-methylcyclobutane-l-carbonitrile and (LR, 3s)-3-(4-((S)-l-((tert- butyldimethylsilyl)oxy)ethyl)- \H- 1 ,2,3 -triazol- 1 -yl)- 1 -methylcyclobutane- 1 - carbonitrile To a solution of l-methyl-3-[4-[(lS)-l-[terfr 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 mL, 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-((S)-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 (1R,3s)-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: NMR (400 MHz, CDCl3-d) 57.40 (s, 1H), 5.20 -

[0137] 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: NMR (400 MHz, CDCl3-d) 57.49 (s, 1H), 5.21 -

[0138] 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.

[0139] Step 6: (IS, 3r)-3-(4-((S)-l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)-l- methylcyclobutane-l-carbonitrile (Tail group Tl): To a stirred solution of (lS,3r)-3- (4-((S)- 1 -((ter / -butyldimethylsilyl)oxy)ethyl)- 1H- 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-((S)-l- hydroxyethyl)-lH-l,2,3-triazol-l-yl)-l-methylcyclobutane-l-carbonitrile (22 mg, 0.106 mmol, 97.7% yield) as a yellow oil. LCMS M / Z (M+H)+= 207.2. The erode product was pure enough and used to next step directly. T-2 was prepared in a similar fashion to T-l, using (1R,3s)-3-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-Lff- 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 A -carboxylate (Tail group T-3)

[0140] Step 1: methyl l-methyl-3-((methylsulfonyl)oxy)cyclobutanecarboxylate: To a mixture of methyl 3-hydroxy-l-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. NaHCO3solution, then the resulting solution was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered 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.

[0141] 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.

[0142] 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)

[0143] 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, filtered and concentrated under reduced pressure to afford crude 3-azidocyclobutanone (2.4 g, 21.6 mmol, 94.7% yield) as a yellow oil.1HNMR (400 MHz, CDCI3) 54.37 (tt, J= 5.2, 7.6 Hz, IH), 3.49 - 3.35 (m, 2H), 3.28 - 3.12 (m, 2H).

[0144] 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-[(l1S)-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, NMR (400 MHz, DMSO-d6) δ 8.23 (s, IH),

[0145] 5.55 - 5.33 (m, IH), 5.03 (q, J= 6.4 Hz, IH), 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.

[0146] 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 -[terfrbutyl(dimethyl)silyl]oxyethyl]triazol- 1 -yljcyclobutanone (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, NMR (400 MHz, DMSO-d6) δ 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 M7Z (M+H)+= 488.2.

[0147] Step 4: cis-l-(diJluoro(phenylsulfonyl)methyl)-3-(4-((S)-l-hydroxyethyl)-lH- l,2,3-triazol-l-yl)cyclobutanol: TBAF (5.1 mL, 5.1 mmol, 1 M in THF) was added to a solution of czs-3-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l- yl)-l -(difluoro (phenyl sulfonyl)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 l-[benzenesulfonyl(difluoro)methyl]-3-[4-[(lS)-l-hydroxyethyl]triazol-l- yljcyclobutanol (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- d6) 5 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 M7Z (M+H)+= 374.1.

[0148] Step 5: cis-l-(diJluoromethyl)-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-d6) δ 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.

[0149] Synthesis of tail group T-5

[0150] 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 czs-tert-butyl 7V-(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 NazSO4 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.

[0151] NMR (400MHz, CDC13) 55.06 (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)

[0152] Step 2: rac-(lS,2R4R & lR2S,4S)-4-amino-2- hydroxycyclopentanecarbonitrile^TFA: To a solution of rac-tert-butyl ((1R,3S,4R & 7S,3R4S)-3-cyano-4-hydroxycyclopentyl)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,2R4R & lR2S,4S)-4-azido-2- hydroxycyclopentanecarbonitrile (T-5): rac-(lS,2R,4R & 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.

[0153] Synthesis of tail group T-6

[0154] 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. NMR (400MHz, CDCI3) 5 8.16 - 7.92 (m, 2H), 7.65 - 7.53 (m, IH), 7.50 - 7.39 (m, 2H), 4.51 (t, J= 6.4 Hz, 2H), 3.79 (t, J= 6.0 Hz, 2H), 2.11 - 1.96 (m, 2H).

[0155] 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 NaHCO3(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 NazSO^ 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.1H 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).

[0156] Step 3: 2-[rac-(cis & trans)-4-bromotetrahydropyran-2-yl]etbyl 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 NtoSO4, 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:1HNMR (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:1HNMR (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^.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.

[0157] Step 4: 2-[rac-(cis)-4-azidotetrahydro-2H-pyran-2-yl]ethyl benzoate (Tail group T-6): To a solution of 2-[rac-(25, 4R)-4-bromotetrahydropyran-2-yl]ethyl benzoate (220.0 mg, 0.700 mmol) in AyV-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 erode 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

[0158] T-7)

[0159] T-7 was synthesized in a similar fashion to T-6 from 2-methylpropane-l,3- diol.

[0160] 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 NaBH* (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, filtered 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-d6) δ 4.23 - 4.13 (m, 1H), 2.68 - 2.44 (m, 3H), 2.15 - 2.06 (m, 2H), 1.46 (s, 9H).

[0161] 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 NaHCO3aqueous solution (10 mL). The mixture was extracted with dichloromethane (100 mLx3). 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. NMR (400 MHz, CDCl3-d) 54.97 - 4.85 (m, 1H), 3.00 (s, 3H), 2.72 - 2.61 (m, 3H), 2.57 - 2.46 (m, 2H), 1.45 (s, 9H).

[0162] Step 3: tert-butyl 3-azidocyclobutanecarboxylate: To a stirred solution of tert- butyl 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.1H NMR (400 MHz, CDCl3-d6) δ 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).

[0163] Step 4: tert-butyl 3-[4-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l- y 1] cyclobutane carboxy late: 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 tert- butyl 3 -[4- [( IS)- 1 -[tert-butyl (dimethyl)silyl] oxyethyl] triazol- 1 - yljcyclobutanecarboxylate (7.2 g, 18.869 mmol, 66.5% yield) as a colorless oil.1H NMR (400 MHz, CDCh-d6) δ 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.

[0164] Step 5: tert-butyl l-methylsulfanyl-3-[4-[(lS)-l-[tert- butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]cyclobutanecarboxylate: To a solution of tert-butyl 3-[4-[( IS)- 1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol- 1 - yljcyclobutanecarboxylate (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 mlx2), dried over anhydrous Na2SO4, filtered 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.

[0165] Step 6: tert-butyl l-methylsulfonyl-3-[4-[(lS)-l-[tert- butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]cyclobutanecarboxylate: To a solution of tert-butyl 1 -methylsulfanyl-3-[4-[( IS)- 1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol- 1 - yljcyclobutanecarboxylate (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 NazSO3 and aq. NaHCO3. The resulting solution was extracted with dichloromethane (3x10 mL), and the organic layers were washed with brine (5 mix 2), 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, CDCl3-d) δ 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, J= 2.4 Hz, 3H), 1.52 (d, J= 2.8 Hz, 3H), 0.91 (s, 18H), 0.11 (s, 6H), 0.06 (s, 6H). LCMS M / Z (M+H)+= 460.2.

[0166] Step 7: [l-methylsulfonyl-3-[4-[(lS)-l-[tert- butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]cyclobutyl]methanol: To a solution of tert- butyl 1 -methylsulfonyl-3-[4-[( IS)- 1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol- 1 - yljcyclobutanecarboxylate (1.4 g, 3.1 mmol) in anhydrous tetrahydrofuran (20 mL) was added LiAlHt (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 (0- 70% ethyl acetate in petroleum ether) to afford ((lS,3r)-3-(4-((S)-l-((tert- butyldimethylsilyl)oxy)ethyl)- \H- 1 ,2,3 -triazol- 1 -yl)- 1 - (methylsulfonyl)cyclobutyl)methanol methanol (550 mg, 1.4 mmol, 46.4% yield) as a colorless oil and ((1R,3s)-3-(4-((S)-l-((terbutyldimethylsilyl)oxy)ethyl)-177-l,2,3- triazol-l-yl)-l-(methylsulfonyl)cyclobutyl)methanol (450 mg, 1.2 mmol, 37.9% yield) as a colorless oil. trans-isomer:1HNMR (400 MHz, CDCl3-d) δ 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, J= 6.4 Hz, 3H), 0.91 (s, 9H), 0.11 (s, 3H), 0.05 (s, 3H). LCMS M / Z (M+H)+=390. cis-isomer:1HNMR (400 MHz, CDCl3-d) 57.82 (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.

[0167] 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 czs-[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 NaHCO3(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 cis-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.

[0168] Step 9: cis-(lS)-l-[l-[3-(fluoromethyl)-3-methylsulfonyl-cyclobutyl]triazol-4- y I] ethanol (Tail group T-8): to a solution of terfrbutyl-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, filtered and concentrated under reduced pressure to afford crude czs-(lS)-l-[l-[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.

[0169] Synthesis of trans-(S)-l-(l-(3-(difluoromethyl)-3-(methylsulfonyl)cyclobutyl)-

[0170] 15 lH-l,2,3-triazol-4-yl)ethan-l-ol (Tail group T-9)

[0171] 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 -[terf-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 NaHCO3solution at 0 °C, then saturated Na2SO3 (2 mL) and Na2S20s (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 -[tert-butyl(dimethyl)silyl]oxyethyl]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-(methylsulfonyl)cyclobutyl)-lH-l,2,3-triazole: to a mixture of trans -3 -(4-((S)- 1 -((tert-butyldimethylsilyl)oxy)ethyl)- 1H- 1 ,2,3 -triazol- 1 -yl)- 1 - (methylsulfonyl)cyclobutane-l-caibaldehyde (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 NaHCO3(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-((S)-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.

[0172] Step 3: trans-(S)-l-(l-(3-(difluoromethyl)-3-(methylsulfonyl)cyclobutyl)-lH-

[0173] 1.2.3-triazol-4-yl)ethan-l-ol (Tail group T-9): To a solution of trans-4-((S)-l-((terf- butyldimethylsilyl)oxy)ethyl)-3-(difluoromethyl)-3(methylsulfonyl)cyclobutyl)-lH-

[0174] 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 erode product trans-(S)-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.

[0175] Synthesis of (S)-l-(l-((lr,3S)-3-methyl-3-(methylsulfonyl)cyclobutyl)-lH- l,2,3-triazol-4-yl)ethan-l-ol (Tail group T-10)

[0176] Step 1 : trans-4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-3-(iodomethyl)-3- (methylsulfonyl)cyclobutyl)-lH-l, 2, 3-triazole: trans -[l-Methylsulfonyl-3-[4-[(lS)-l- [ter / -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 trans-4-((S)- l-((terfrbutyldimethylsilyl)oxy)ethyl)-3-(iodomethyl)-3- (methylsulfonyl)cyclobutyl)-lH- 1,2,3-triazole (140 mg, 0.28 mmol, 72.8% yield) as a white solid.1HNMR (400 MHz, CDCh) 57.54 (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.

[0177] 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-((tert- butyldimethylsilyl)oxy)ethyl)-3-(iodomethyl)-3-(methylsulfonyl)cyclobutyl)-lH- 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 (ImL) was stirred under Hz (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-((S)-l-((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 MZZ (M+H)+= 374.

[0178] 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 Zrans-4-((S)-l-((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 erode 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.

[0179] ( 1 S,3r)-3-(4-((S)- 1 -hydroxyethyl)- 1H- 1,2,3-triazol- 1 -yl)cyclobutane- 1 - carbonitrile T-l 1 was prepared in a similar fashion as T-l.

[0180] Synthesis of tail group T-l 2

[0181] 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-1H-imidazol-3-ium trifluoromethanesulfonate (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.

[0182] Step 2: 3-azidobicyclo[l.l.l]pentane-l-carbonitrile: To a solution of 3- aminobicyclo[l.l.l]pentane-l-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.

[0183] Step 3: (S)-3-(4-(l -hydroxyethyl)-lH-l, 2, 3-triazol-l-yl)bicyclo[ 1.1.1 Jpentane- 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 (S)-(-)-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, filtered and concentrated under reduced pressure. The erode residue was purified by flash chromatography (25% ethyl acetate in petroleum ether) to give 3-[4-[(15)-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.

[0184] Synthesis of tail group T-13

[0185] Step 1: tert-butyl (4-carbamoylbicyclo[2.1.1]hexan-l-yl)carbamate: To a solution of NHtCl (177.3 mg, 3.32 mmol), 4-(tert-butoxycarbonylamino)bicyclo [2.1.1]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-butyl7V-(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. NMR (400 MHz, DMSO- d6) 57.32 (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).

[0186] Step 2: 4-aminobicyclo [2. l.l]hexane-l -carboxamide hydrochloride: A solution of tert-butyl 7V-(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 a new spot. The reaction mixture was concentrated under reduced pressure. The resulting residue was used for next step directly.

[0187] Step 3: (S)-4-(4-(l -((tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl) bicyclo[2.1.1]hexane-l-carboxamide: 4-[4-[(lS)-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.

[0188] Step 4: (S)-4-(4-(l -((teri-butyldimethylsilyl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl) bicyclo[2.1.1]hexane-l-carbonitrile: To a solution of 4- [4- [(IS)- 1- [tert- butyl (dimethyl) silyl] oxyethy 1] triazol -1-yl] bicyclo [2.1.1]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, filtered 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-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl] triazol-l-yl]bicyclo[2.1. l]hexane-l- carbonitrile (190 mg, 0.57 mmol, 91% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 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.

[0189] 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 (S)-4-(4-(l-Hydroxyethyl)-1H-l,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, filtered and concentrated under reduced pressure. The residue was used for next step directly. LCMS M / Z (M+H) 218.9.

[0190] Synthesis of tail group T-14

[0191] 5

[0192] Step 1 : (S)-4-(4-(l -((tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)- 2-oxabicyclo [2.1.1] hexane- 1 -carboxy lie acid: To a solution of ethyl 4-[4-[(lS)-l- [tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo [2.1.1 ] hexane- 1- 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 LiOH (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(iq). Then the mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated to afford erode 4-[4- [(lS)-l-[terfrbutyl(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.

[0193] Step 2: (S)-4-(4-(l -((tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)- 2-oxabicyclo[2.1.1]hexane-l-carboxamide: To a solution of NH4CI (54.48 mg, 1.02 mmol), 4-[4-[(lS)-l- [terf-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-[( IS)- 1 -[tert- butyl (dimethyl) silyl] oxyethy 1] triazol -1-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) 354.1.1HNMR (400 MHz, DMSO-d6) δ 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).

[0194] 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-[( IS)- 1 -hydroxyethyljtriazol- 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.

[0195] Synthesis of tail group T-15

[0196] 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.

[0197] Synthesis of tail group T-16

[0198] Step 1: tert-butyl 4-(((benzyloxy)carbonyl)amino)-l-(hydroxymethyl)-2- azabicyclo[2.1.1]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.1H NMR (400 MHz, CDCh) 57.43-7.32 (m, 5H), 5.24 (hr s, 1H), 5.10 (s, 2H), 3.96 (s, 2H), 3.50 (s, 2H), 2.01 (s, 4H), 1.46 (s, 9H). LCMS [M- / Bu+H]+= 306.9. Step 2: tert-butyl 4-amino-l-(hydroxymethyl)-2-azabicyclo [2.1.1] hexanes- carboxy late: 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 (1.1 g, 87% yield) as yellow oil, which was carried on without further purification.1H NMR (400 MHz, DMSO-d6) δ 4.61 (br s, 1H), 3.80 (d, J= 5.6 Hz, 2H), 3.08 (s, 2H), 2.25 (s, 2H), 1.66 (s, 2H), 1.50- 1.42 (m, 2H), 1.39 (s, 9H).

[0199] Step 3 & 4: tert-butyl 4-azido-l-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane- 2 -carboxy late: The title compound was prepared in a similar fashion to T-12 via diazo transfer and click reactions from corresponding amine and alkyne.

[0200] 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 tert- butyl 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 BMP (1.93 g, 4.56 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h, then sat. NruSzOsfiq) (20 mL) and aq. sat. NaHCO3(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-[(lS)-l-[tert- butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-l-formyl-2-azabicyclo[2.1. l]hexane-2- carboxylate (800 mg, 1.83 mmol, 80 % yield) as a colorless oil.1H NMR (400 MHz, CDCh) 59.94 (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.

[0201] 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-azabicyclo[2.1.1 ]hexane-2-carboxylate: To a solution of tert-butyl 4-[4-[(lS)-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.1HNMR (400 MHz, CDCh) 57.48 (s, 1H), 5.44 (s, 1H), 5.13 (q, J= 6.4 Hz, 1H), 4.99-4.86 (m, 1H), 4.8M.71 (m, 1H), 4.67^.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.

[0202] 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 [2.1.1]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. l.l]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. NaHCO3and water, then extracted with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, filtrated 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-[(lS)-l-[tert- butyl(dimethyl)silyl]oxyethyl]triazol- 1 -yl] - 1 -[(E)-2 -nitrovinyl] -2- azabicyclo[2.1. l]hexane-2-carboxylate (720 mg, 1.50 mmol, 93% yield) as a colorless oil.1HNMR (400 MHz, CDCh) 57.88 (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 M7Z (M+H) 480.3.

[0203] 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-[(£)- 2-nitrovinyl]-2-azabicyclo[2.1.1]hexane-2-carboxylate (720 mg, 1.5 mmol) in ethanol (50 mL) was added NaBH* (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-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl] triazol-l-yl]-l- (2 -nitroethyl)-2 -azabicyclo [2. l.l]hexane-2 -carboxylate (640 mg, 1.3 mmol, 89% yield) as a colorless oil. NMR (400 MHz, CDCh) 57.45 (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.

[0204] Step 9: tert-butyl (S)-l-(2-amtnoethyl)-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-[(lS)-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 added NH4CI (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 dichloromethane. 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) 58.47 (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.

[0205] 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 l-(2- aminoethyl)-4-[4-[(lS)-l-[tert-butyl(dimethyl)silyl] oxyethyl]triazol-l-yl]-2- azabicyclo [2. l.l]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 NaHCC3. 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- [( IS)- 1 -[tert-butyl(dimethyl)silyl] oxyethyljtriazol- 1 -yl] -2-azabicyclo [2.1. IJhexan- 1 - yljethanamine (350 mg, 1.0 mmol, 88.2% yield) as a colorless oil.1HNMR (400 MHz, CDCh) 57.45 (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.

[0206] Step 11 : (S)-6-(4-(l -( (tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl) tetrahydro-5H-4a,6-methanopyrrolo[l,2-c]pyrimidin-l(2H)-one: To a stirred solution of 2-[4-[4-[(l1S)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl] -2- azabicyclo[2.1. l]hexan- 1-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-[(lS)-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.1H 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.

[0207] Step 12: (S)-6-(4-(l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-5H-4a,6- methanopyrrolo[l,2-c]pyrimidin-l(2H)-one T-16: To a solution of 8-[4-[( IS)- 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 erode product T-16, which was carried on to the next step without further purification. LCMS M / Z (M+H) 264.0.

[0208] Synthesis of tail group T-17 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-[( IS)- 1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol- 1 -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, filtered 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-[( IS)- 1 -[tert- butyl (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.1HNMR (400 MHz, CDCI3) 57.46 (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.

[0209] Step 2: (S)-6-(4-(l -hydroxyethyl)-lH-l, 2, 3-triazol-l-yl)-2-methyltetrahydro- 5H-4a,6-methanopyrrolo[l,2-c]pyrimtdtn-l(2H)-one T-17: To a solution of 8-[4- [( IS)- 1 -[tert-butyl(dimethyl)silyl]oxyethyl]triazol- 1 -yl]-4-methyl-4,6- diazatricyclo[6.1.1.01,6]decan-5-one (90.0 mg, 0.23 mmol) in THE (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 erode product T-17 which was carried on directly to the next step without purification. LCMS M / Z (M+H) 277.9.

[0210] Synthesis of tail group T-18

[0211] 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 (S)-4-(4-(l-((tert- butyldimethylsilyl)oxy)ethyl)- \H- 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 NaHCO3at 0°C, then the reaction was extracted with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced 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

[0212] Step 2: (S)-(4-(4-(l -((tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)- 2-(oxetan-3-yl)-2-azabicyclo[2.1.1]hexan-l-yl)metanol: A solution of (S)-(4-(4-(l- ((terr-butyldimethylsilyl)oxy)ethyl)-1H-l,2,3-triazol-l-yl)-2-azabicyclo[2.1. Ijhexan- 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

[0213] Step 3: (lS)-l-(l-(4-(hydroxymethyl)dihydro-lH, 6H-7, Sa- me thanopyrrolo[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:

[0214] To a solution of (S)-(4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-1H-l,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 BFs EtzO (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. NaHCO3. Then the mixture was extracted with ethyl acetate (50 mLx3). 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-((S)- 1 -((tert-butyldimethylsilyl)oxy)ethyl)- 1H- 1 ,2,3-triazol- 1 -yl) tetrahydro- 1H,6Zf-7,8a-methanopyrrolo[2,l-c][l,4]oxazin-4-yl)metanol (840 mg, 36.5% yield) as yellow oil. NMR (400 MHz, CDCI3) 57.45 (s, 1H), 5.12 (q, J=

[0215] 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), 2.22- 2.16 (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).

[0216] 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. NMR (400 MHz, DMSO-d6) δ 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).

[0217] Step 4: 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]oxazine-4-carbaldehyde: To a solution of (7-(4-((S)- 1 -((tert-butyldimethylsilyl)oxy)ethyl)- 1H- 1,2,3-triazol- 1 -yl) tetrahydro- 1H,6Zf-7,8a-methanopyrrolo[2,l-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, filtered and concentrated under reduced pressure to afford the title compound (830 mg, 99% yield, crude) as a yellow oil. NMR (400 MHz, CDCh) 59.62 (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).

[0218] 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, 1-c] [l,4]oxazin-4-yl)ethan-l-ol: To a solution of 7-(4-((S)-l-((tert-butyldimethylsilyl) oxy)ethyl)-1H-l,2,3-triazol-l-yl) tetrahydro- 1H,6Zf-7,8a-methanopyrrolo[2,l-c][l,4]oxazine-4-carbaldehyde (830 mg, 2.1 mmol) in THE (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, filtered 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 M7Z (M+H) 409.2.

[0219] 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] [l,4]oxazin-4-yl)ethan-l-one: To a solution of l-(7-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-Lff-l,2,3-triazol-l- yl)tetrahydro-1H,6Zf-7,8a-methanopyrrolo[2,l-c][l,4]oxazin-4-yl)ethan-l-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 filtered, the filtrate 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.

[0220] 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] [l,4]oxazin-4-yl)propan-2-ol: To a stirring solution of l-(7-(4-((1S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-1H-l,2,3- triazol- 1 -yl)tetrahydro- 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, erode) as a yellow oil. LCMS M / Z (M+H) 423.1.

[0221] Step 8: (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, l-c][l, 4]oxazin-4- yl)methyl methanesulfonate T-18: To a solution of 2-(7-(4-((S)-l-((terfr butyldimethylsilyl)oxy)ethyl)- \H- 1 ,2,3-triazol- 1 -yl)tetrahydro- 1H,6Zf-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 -Et3N (2 mL) at 0 °C. The mixture was stirred at 50 °C for 1 h. The mixture was adjusted pH to 9 with saturated NaHCO3at 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.

[0222] Synthesis of tail group T-19

[0223] Step 1: l-(l-(4-(hydroxymethyl)dihydro-lH,6H-7,8a-methanopyrrolo[2,l- c][l,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 filtered. 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- yljethanone (299 mg, 1.074 mmol, 71% yield) as a white solid. LCMS M / Z (M+H) 278.2.

[0224] Step 2: l-(l-(4-(((tert-butyldimethylsilyl)oxy)methyl)dihydro-lH, 6H-7,8a- methanopyrrolo[2,l-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 TBSCI (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^ (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[6.1.1.0 l,6]decan-8-yl]triazol-4- yljethanone (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] [l,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 l-[l-[5-[[tert- butyl(dimethyl)silyl]oxymethyl]-3-oxa-6-azatricyclo[6.1.1.0 l,6]decan-8-yl]triazol-4- yljethanone (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 (lS)-l-[l-[5-[[ter / -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.

[0225] Synthesis of tail group T-20

[0226] 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- [( IS)- 1 -[ter / -butyl(dimethyl)silyl]oxyethyl]triazol- 1 -yl]-2-azabicyclo[2.1. IJhexan- 1 - yljmethanol (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.

[0227] 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-[( IS)- 1 -[tert-butyl(dimethyl)silyl] oxyethyl] triazol- 1 -yl] - 1 -(hydroxymethyl)-? - azabicyclo[2.1.1]hexane-2-carboxamide (330 mg, 0.86 mmol) in THF (6 mL) was added tBuOK (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, filtered 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

[0228] Step 3: (S)-6-(4-(l -hydroxyethyl)-lH-l, 2, 3-triazol-l-yl)-2-tosyltetrahydro- 3H.5H-6, 7a-methanopyrrolo[l,2-c]imidazol-3-one T-20: To a solution of 7-[4-[(lS)- 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.

[0229] Synthesis of tail group T-21 Step 1: tert-butyl (2R,4R)-4-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-

[0230] 1.2.3-triazol-l-yl)-2-(hydroxymethyl) pyrrolidine-1 -carboxylate: To a solution of (25,4R)- 1 -(tert-butoxycarbonyl)-4-(4-((S)- 1 -((tert-butyldimethylsilyl) oxy)ethyl)- 1H-

[0231] 1.2.3-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 LiAlH* (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 erode product as a colorless oil. LCMS M / Z (M+H) 427.3.

[0232] 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 / ?,4R)-4-(4-((S)-l- ((tert-butyldimethylsilyl)oxy)ethyl)- \H- 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 / ?,4R)-4-(4-((S)-l-((tert- butyldimethylsilyl)oxy)ethyl)- \H- 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.

[0233] Step 3: 1-((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 ((2R,4R)-4-(4-((5)- 1 -((tert-butyldimethylsilyl)oxy)ethyl)- 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 l-((2R,4R)-4-(4-((S)-l-((tert- 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.

[0234] 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][l,4]oxazin-4(3H)-one To a solution of 1- ((2R,4R)-4-(4-((S)- 1 -((tert-butyldimethylsilyl)oxy)ethyl)- 1H- 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 (7^,8a^)-7-(4-((S)-l-((tert- butyldimethylsilyl)oxy)ethyl)- 1H- 1 ,2,3 -triazol- 1 -yl)tetrahydro- 1H-pyrrolo [2, 1 -c] [ 1 ,4] oxazin-4(3H)-one (20 mg, 0.055 mmol, 73.3% yield) as a colorless oil. LCMS M / Z (M+H) 367.2.

[0235] Step 5: (7R,8aR)-7-(4-((S)-l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)tetrahydro- lH-pyrrolo[2,l-c] [1 ,4]oxazin-4(3H)-one T-21: To a solution of (7R,8aR)-7-(4-((S)-l- ((tert-butyldimethylsilyl)oxy)ethyl)- 1H- 1 ,2,3 -triazol- 1 -yl)tetrahydro- 1H-pyrrolo [2, 1 - c][l,4]oxazin-4(3H)-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, 8aR)-7-(4-((S)- 1 -hydroxyethyl)- YH- 1 ,2, 3-triazol- 1 -yl)tetrahydro- 1H-pyrrolo [2,1- c][l,4]oxazin-4(3H)-one (T-21, 13 mg, 0.052 mmol, 94.4% yield) as a colorless oil. LCMS M / Z (M+H) 253.2.

[0236] Synthesis of tail group T-22 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-[(lS)- 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 sulfiite, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (20% ethyl acetate in petroleum ether) to afford tert-butyl (S, £)-4-(4-(l -((tert- butyl dimethylsilyl)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.

[0237] 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 ] hexane -2-carboxylate: To a solution of tert-butyl4-[4-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-l- [(£)-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 erode tert-butyl (S)-4- (4-( 1 -((tert-butyldimethylsilyl)oxy)ethyl)- 1H- 1,2,3-triazol- 1 -yl)- 1 -(3 -ethoxy-3 - oxopropyl)-2 -azabi cyclo [2. l.l]hexane-2 -carboxylate (60 mg, 0.12 mmol, 31.5% yield) as a colorless oil. LCMS M / Z (M+H) 509.

[0238] 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-[( IS)- 1 -[tert-butyl (dimethyl)silyl]oxyethyl]triazol- 1 - yl] -2 -azabicyclo [2. l.l]hexane-2 -carboxylate (160.0 mg, 0.31 mmol) in 5% TEA in HFIP (5 ml) was stirred at 25 °C for 2 h then the reaction was quenched with NaHCO3(aq) (5 mL). The resulting solution was extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfiite, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (2% methanol in dichloromethane) to afford ethyl (S)-3-(4-(4-(l- ((tert-butyldimethylsilyl)oxy)ethyl)-12f-l,2,3-triazol-l-yl)-2-azabicyclo[2.1. IJhexan- l-yl)propanoate (40 mg, 0.1 mmol, 31.1% yield) as a colorless oil. LCMS M / Z (M+H) 409.3.

[0239] 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- [terf-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 (S)-2-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-1H- 1 ,2,3 -triazol- 1 -yl)tetrahydro- 1H, 5H-2, 7a-methanopyrrolizin-5 -one (30mg,0.0827mmol, 56.4% yield) as a yellow oil. LCMS M / Z (M+H) 363.1.

[0240] Step 6: (S)-2-(4-(l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH,5H- 2, 7a-methanopyrrolizin-5-one T-22:

[0241] To a solution of 7-[4-[(lS)-l-[terfrbutyl(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 (S)-2-(4-(l-hydroxyethyl)-1H-l, 2, 3-triazol-l-yl) tetrahydro- 1H 5H-2, 7a-methanopyrrolizin-5-one ( T-22, 7 mg, 0.03 mmol, 93.8% yield) as a yellow oil. The erode product was carried on to the next step without further purification. LCMS M / Z (M+H) 249.1

[0242] 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-[(lS)- l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-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, 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 7-[4-[(lS)-l-[tert- 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. 1H NMR (400 MHz, CDC13) 5 = 7.45 (s, 1H), 5.12 (q, J= 6.4 Hz, 1H), 3.89- 3.76 (m, 2H), 2.89-2.78 (m, 1H), 2.61 (t, J= 6.4 Hz, 1H), 2.51-2.44 (m, 2H), 2.32- 2.21 (m, 2H), 1.89 (7= 7.6, 13.6 Hz, 1H), 1.53 (d, J = 6.4 Hz, 3H), 1.32 (d, 7= 7.6 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H).

[0243] Step 2: 2-(4-((S)-l-hydroxyethyl)-lH-l, 2, 3-triazol-l-yl)-6-methyltetrahydro- 1H.5H-2, 7a-methanopyrrolizin-5-one T-23: To a solution of 3-methyl-7-[4-[(lS)-l- [tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-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- [(lS)-l-hydroxyethyl]triazol-l-yl]-5-azatricyclo[5.1.1.01,5]nonan-4-one (T-23, 30 mg, 0.1 Immol, 89.7% yield) as a yellow oil. LCMS M / Z (M+H) 263.2.

[0244] Synthesis of tail group T-24

[0245] Step 1 : 6-(4-((S)-l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)- 2-fluorohexahydro-3H-pyrrolizin-3-one To a mixture of 7-[4-[( IS)- 1 -[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 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-[( IS)- 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 oil. LCMS M / Z (M+H) 381.3.

[0246] Step 2: 6-Jluoro-2-(4-((S)-l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)tetrahydro- 1H.5H-2, 7a-methanopyrrolizin-5-one T-24: To a solution of 3-fluoro-7-[4-[(lS)-l- [tert-butyl(dimethyl)silyl]oxyethyl]triazol- l-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. 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.

[0247] Synthesis of tail group T-25

[0248] 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- [( IS)- 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. NMR (400 MHz, CDCl3-d) 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.

[0249] 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-[(lS)-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. NMR (400 MHz, CDCl3-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.

[0250] Step 3: tert-butyl (S)-4-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3- triazol-l-yl)-l-(2-oxoethyl)-2-azabicyclo[2.1.1]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 BMP (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 Na2S03(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. NMR (400 MHz, CDCl3-d) 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.

[0251] Step 4, 5, 6, 7 & 8: (S)-2-(4-(l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)tetrahydro- 1H-2, 8a-methanotndoltzin-5 (6H)-one

[0252] The title compound was prepared as a colorless oil in a similar fashion to T-22 to afford T-25.

[0253] Synthesis of tail group T-26

[0254] Step 1 : (S)-(4-(4-(l -((tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)- 2-oxabicyclo[2.1.1]hexan-l-yl)methanol: To a solution of ethyl 4-[4-[(lS)-l-[terfr butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo[2.1. l]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-[(lS)-l-[tert- butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo[2.1. l]hexan-l-yl]methanol (70 mg, 0.21 mmol, 71.5% yield) as a white solid, NMR (400 MHz, CDCh) 57.60 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.

[0255] Step 2: (S)-4-(4-(l -((tert-butyldimethylsilyl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)- 2-oxabicyclo[2.1.1]hexane-l-carbaldehyde: DMP (99.9 mg, 0.24 mmol) was added to a solution of [4- [4- [(1R)- 1- [tert- butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2- oxabicyclo[2.1. l]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 NaHCO3and sat. aq Na2S203 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 erode 4-[4-[(1R)-l-[tert- butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo[2.1. l]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,1H NMR (400 MHz, CDCh) 59.91 (s, 1H), 7.50 (s, 1H), 5.12 (q, J= 6.4 Hz, 1H), 4.38-4.33 (m, 1H), 4.32^.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.

[0256] Step 3: (S)-4-(l -((tert-butyldimethylsilyl)oxy)ethyl)-l-(l -(difluoromethyl)-2- oxabicyclo[2.1. l]hexan-4-yl)-lH-l,2,3-triazole: To a solution of 4-[4-[(lS)-l-[tert- butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2-oxabicyclo[2.1. l]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 terfrbutyl-dimethyl-[(lS)-l-[l-[l-(difhioromethyl)-2- oxabicyclo[2.1. l]hexan-4-yl]triazol-4-yl] ethoxy] silane (20 mg, 0.06 mmol, 62.6 % yield) as a colorless oil. LCMS [M+H]+360.

[0257] Step 4: (S)-l -(1-(1 -(difluoromethyl)-2-oxabicyclo[2.1.1 ]hexan-4-yl)-lH-l, 2, 3- triazol-4-yl)ethanol T26: To a mixture of tertbutyl-dimethyl-[(lS)-l-[l-[l- (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 (lS)-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.

[0258] 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-[(lS)-l- [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 fiom above step) in TEA (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, filtered 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.

[0259] 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][l,3]oxazin-l-one: To a stirred solution of 2-[4-[4-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-2- azabicyclo[2.1. IJhexan- 1-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.

[0260] Step 3: (S)-6-(4-(l-hydroxyethyl)-lH-l,2,3-triazol-l-yl)tetrahydro-lH,5H- 4a,6-methanopyrrolo[l,2-c] [l,3]oxazin-l-one T-27: To a solution of 8-[4-[(lS)-l- [tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-yl]-4-oxa-6-azatricyclo[6.1.1.01,6] decan- 5-one (40 mg, 0.1 mmol) in THE (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.

[0261] Synthesis of tail group T-28 Step 1 : (S)-l-(4-(4-(l -((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-[(lS)-l-[tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-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- 1 -[ 1 -(2-hydroxyethyl)-4-[4-[( IS)- 1 -[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.

[0262] Step2: (S)-8-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)-lH-l,2,3-triazol-l-yl) tetrahydro-lH-8,9a-methanopyrrolo[l,2-d] [l,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 (S)-8-(4-(l-((tert-butyldimethylsilyl)oxy)ethyl)- 1H- 1,2,3-triazol- 1 -yl)tetrahydro-7H-8,9a-methanopyrrolo[ 1 ,2-d] [ 1 ,4]oxazepin-5(4H)- one (17 mg, 0.043 mmol, 46.4% yield) as a white solid. LCMS M / Z (M+H) 393.3.

[0263] Step 3: (S)-8-(4-(l -hydroxyethyl)-lH-l, 2, 3-triazol-l-yl)tetrahydro-lH-8, 9a- methanopyrrolo[l,2-d][l,4]oxazepin-5(2H)-one T-28: To a solution of 9-[4-[(lS)-l- [tert-butyl(dimethyl)silyl]oxyethyl]triazol-l-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.

[0264] Synthesis of tail group T-29 l-(l-(3-(difluoromethyl)bicyclo[l.l.1 ]pentan-l-yl)-lH-l, 2, 3-triazol-4-yl)ethan-l-ol,

[0265] T-29 was prepared in a similar fashion to T-l.

[0266] Synthesis of tail group T-30

[0267] 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-l-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, filtered 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. NMR (400 MHz, CDCh) 54.79 (quin, J = 2.4 Hz, 2H), 3.08-2.74 (m, 5H), 1.46 (s, 9H).

[0268] 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. NMR (400 MHz, CDCh) 57.35-7.28 (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).

[0269] Step 3: tert-butyl 3-((benzyloxy) methyl)-! -(iodomethyl)-2- oxabicyclo[2.1.1]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 NaHCO3 (3.4 g, 40.8 mmol) and tert-butyl l-(2-benzyloxy-l-hydroxy-ethyl)-3-methylene- cyclobutanecarboxylate (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) 57.45-7.27 (m, 5H), 4.64^.52 (m, 2H), 4.36 (t, J= 5.6 Hz, 1H), 3.69- 3.56 (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).

[0270] Step 4: tert-butyl l-(acetoxymethyl)-3-((benzyloxy)methyl)-2- oxabicyclo[2.1.1]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. l.l]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) 57.39-7.27 (m, 5H), 4.67^.49 (m, 2H), 4.37^.33 (m, 1H), 4.33^.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).

[0271] Step 5: tert-butyl 3-((benzyloxy)methyl)-l-(hydroxymethyl)-2- oxabicyclo[2.1.1]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 filtered and washed with ethyl acetate. The filtrate was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude tittle compound (3500 mg, 87.6% yield) as brown oil.1H 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= 7.2, 10.4 Hz, 1H), 2.07-2.00 (m, 2H), 1.96-1.88 (m, 2H), 1.41 (s, 9H).

[0272] Step 6: tert-butyl 3-((benzyloxy)methyl)-l-(fluoromethyl)-2- oxabicyclo[2.1.1]hexane-4-carboxylate: To a solution of tert-butyl 3- (benzyloxymethyl)-l-(hydroxymethyl)-2-oxabicyclo [2.1. l]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, filtered 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)-l- (fluoromethyl)-2-oxabicyclo[2.1.1]hexane-4-carboxylate (300 mg, 0.89 mmol, 59.6% yield) as a white solid.

[0273] 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[2.1.1]hexane-4- carboxylic acid (200 mg, 0.71 mmol, 80% yield) as a colorless oil.1H 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).

[0274] 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, filtered 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 N-[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, erode [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.

[0275] Step 9: (4-azido-l-(fluoromethyl)-2-oxabicyclo[2.1.1]hexan-3-yl)methanol T- 30: To a solution of [4-amino-l-(fluoromethyl)-2-oxabicyclo[2.1.1]hexan-3- yljmethanol (40 mg, 0.24 mmol) in DMF (1 mL) was added sulfinazidic 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.

[0276] Example 1: (15,3s)-l-(difluoromethyl)-3-(4-((R)-l-((2,4-dihydro-1H- pyrano [3,4-c] quinolin-9-yl)oxy)ethyl)- 1H- 1 ,2,3 -triazol- 1 -yl)cyclobutanol To a mixture of PBu3 (173. 5 mg, 0.86 mmol), 2,4-dihydro-1H-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 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-((R)- 1 -((2,4-dihydro- 1H-pyrano [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) as a white solid, NMR (400 MHz, DMSO-d6) δ 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.

[0277] 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:

[0278]

[0279] Analyticla data for compounds of Examples 2-12 is provided in the table below:

[0280] Examples 13 and 14: Synthesis of ((1R,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 (Example 13) and ((15,3s)-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 - methylcyclobutyl)methanol (Example 14) To a mixture of (R)-methyl 3-(4-(l-((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 LiAlHt (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 1- 28% / 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 ((1R,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 ((15,3s)-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 13:1HNMR (400 MHz, DMSO-d6) δ 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, J= 6.4 Hz, 1H), 5.15 (q, J= 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: NMR (400 MHz, DMSO-d6) δ 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.

[0281] Example 15: (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)cyclobutanecaibonitrile

[0282]

[0283] To a solution of 9-[(lR)-l-methylprop-2-ynoxy]-2,4-dihydro-lH-pyrano[3,4- cjquinoline (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 r-BuOH(l 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.

[0284] 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]cyclobutanecaibonitrile as a white solid. LCMS (10-80CD / 3min): RT = 1.575 min, [M+H]+376.11HNMR (400 MHz, DMSO-d6) δ: 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.

[0285] 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: Analyticla data for compounds of Examples 16-37 is provided in the table below:

[0286]

[0287] 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- cjquinoline

[0288] To a solution of 3-[4-[(1R)-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 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 NaHCO3aqueous 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 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.1H NMR (400 MHz, DMSO- d6) δ 8.44 (s, IH), 8.32 (s, IH), 7.87 (d, J= 9.1 Hz, IH), 7.44 (d, J= 2.7 Hz, IH), 7.38 (dd, J= 9.1, 2.7 Hz, IH), 5.89 (q, J= 6.4 Hz, IH), 4.89 (q, J= 8.3 Hz, IH), 4.83 (s, 2H), 4.05 (td, J= 5.7, 2.7 Hz, 2H), 3.12 (s, 3H), 3.16 - 3.04 (m, IH), 2.99 (dt, J= 17.7, 5.7 Hz, IH), 2.57 - 2.51 (m, 4H), 1.72 (d, J= 6.4 Hz, 3H), 1.34 (s, 3H). LCMS M / Z (M+H) 395.2.

[0289] Example 39: 2-((2S, 4R)-4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin- 9-yl)oxy)ethyl)- 1 H- 1 ,2,3 -triazol- 1 -yl)tetrahydro-2H-pyran-2-yl)ethan- 1 -ol

[0290] Step 1 : 2-((cis)-4-(4-((R)-l-((l, 4-dihydro-2H-pyrano[3, 4-c]qutnoltn-9- yl)oxy)ethyl)-lH-l , 2, 3-triazol-l-yl)tetrahydro-2H-pyran-2-yl)ethyl benzoate vras prepared in a similar fashion to Compound 15, using azide intermediate T-6.1H NMR (400 MHz, DMSO-d6) δ: 8.44 (s, IH), 8.35 (s, IH), 7.97 (d, J= 8.4 Hz, 2H), 7.88 (d, J= 9.2 Hz, IH), 7.70 - 7.62 (m, IH), 7.57 - 7.48 (m, 2H), 7.44 (d, J= 2.8 Hz, IH), 7.39 (dd, J= 2.8, 9.2 Hz, IH), 5.90 (q, J= 6.4 Hz, IH), 4.93 - 4.69 (m, 3H), 4.47 - 4.25 (m, 2H), 4.17 - 3.92 (m, 3H), 3.76 - 3.60 (m, IH), 3.53 (brt, J= 11.2 Hz, IH), 3.17 - 2.93 (m, 2H), 2.17 (br d, J= 12.4 Hz, IH), 2.04 - 1.99 (m, IH), 1.98 - 1.87 (m, 3H), 1.80 - 1.73 (m, IH), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H)+= 529.2.

[0291] Step 2: 2-((c is)-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-[(1R)-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-((c«)-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)ethan-l-ol (140 mg, 83% yield) as a colorless oil.

[0292] 2-((cis)-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)ethan-l-ol (140.0 mg, 0.260 mmol) was further separated by chiral SFC (Column: Chiralpak AD-3 50x4.6mm I.D., 3 μm. 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-((c»)-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. 1H NMR (400 MHz, DMSO-d6) δ 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, J= 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.

[0293] Examples 40 and 41: (S)-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 40) and (R)-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 41)

[0294]

[0295] 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 μm. Mobile phase: 40% of methanol (0.05% DEA) in CO2 Flow rate: 2.5 mL / min Column temp.: 35 °C. (S)-2-((2 R,4S)-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 , 45) -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-d6) δ = 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),

[0296] 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, J= 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 41:1HNMR (400 MHz, DMSO-d6) δ = 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),

[0297] 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 M7Z (M+H)+= 439.1.

[0298] Example 42 : (R)-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 ]hexane-l -carbonitrile

[0299] To a mixture ofPBus (148 mg, 0.73 mmol), 2,4-dihydro-1H-pyrano[3,4- c]quinolin-9-ol H-l (36.8 mg, 0.18 mmol) and 4-[4-[(lS)-l-hydroxyethyl]triazol-l- yl]bicyclo[2.1.1]hexane-l-carbonitrile T-13 (40.0 mg, 0.18 mmol) in THE (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)-l- (2,4-dihydro- 1H-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.1HNMR (400 MHz, DMSO-d6) δ 8.48 (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), 5.92 (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.

[0300] 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.

[0301] Analyticla data for compounds of Examples 43-58 is provided in the table below:

[0302] 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.

[0303] Example 59: l-(3-(4-((R)-l-((l,4-dihydro-2?7-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)-1H-l,2,3-triazol-l-yl)bicyclo[l .1. l]pentan-l-yl)ethan-l-ol

[0304] Step 1 : (R)-3-(4-(l -((1, 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-carbomtrile: The title compound was prepared in a similar fashion as Example 42 by Mitsunobu reaction between H-l and T-12.

[0305] Step 2: (R)-l-(3-(4-(l-((l,4-dthydro-2H-pyrano[3,4-c]qutnoltn-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-[(1R)-l-(2,4-dihydro-1H-pyrano[3,4-c]quinolin-9-yloxy)ethyl] triazol-1- yl]bicyclo[l.l.l]pentane-l-carbonitrile (60 mg, 0.15 mmol) in THE (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 °cfor 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-l-yl)ethan-l-ol: To a solution of l-[3-[4-[(1R)-l-(2,4-dihydro-1H-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 NaBH* (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- [( 1R)- 1 -(2,4-dihydro- 1H-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.1H NMR (400 MHz, DMSO-d6) δ 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, J= 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.

[0306] Example 60 & 61 (7-(4-((R)-l-((5-methyl-l,4-dihydro-2H-pyrano[3,4- c]qutnoltn-9-yl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)tetrahydro-lH, 6H-7, 8a- methanopyrrolo[2,l-c][l, 4] oxazin-4-y I) methanol

[0307] 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-l-yl) tetrahydro- lH,6H-7,8a-methanopyrrolo[2,l-c][l,4]oxazine: tert-Butyl-dimethyl-[[8-[4-[(1R)-l- [(5-methyl-2,4-dihydro-1H-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.

[0308] 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, 1- c] [l,4]oxazin-4-yl)methanol To a solution of tert-butyl-dimethyl-[[8-[4-[(lR)-l- [(5- methyl-2,4-dihydro-1H-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 (261 mg, 0.44 mmol) in THE (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 μm; Mobile phase: A: CO2 B: ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 2.5mL / min) to give Peak 1 (7-(4-((R)-l- ((5-methyl-l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H-l,2,3-triazol-l- yl)tetrahydro-1H,6H-7,8a-methanopyrrolo[2,l-c][l,4]oxazin-4-yl)methanol (57.3 mg, 0.12 mmol, 38% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 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.

[0309] And peak 2 (7-(4-((R)-l-((5-methyl-l,4-dihydro-2H-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)- 1H- 1,2,3 -triazol- 1 -yl)tetrahydro- 8a-methanopyrrolo [2,1- c][l,4]oxazin-4-yl)methanol (49.5 mg, 0.10 mmol, 33% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 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, IH), 2.04 (d, J= 6.8 Hz, IH), 1.92 (dd, J= 6.0, 9.6 Hz, IH), 1.71 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 478.3.

[0310] 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

[0311] Step 1 : (R)-6-(4-(l -((1, 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.

[0312] 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-[(1R)-l-(2,4-dihydro-1H-pyrano[3,4-c]quinolin-9-yloxy)ethyl] ttiazol-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) (1 M). 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 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.1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, IH), 8.45 (s, IH), 7.88 (d, J= 9.2 Hz, IH), 7.47 (d, J= 2.8 Hz, IH), 7.39 (dd, J= 2.8, 9.2 Hz, IH), 6.74 (s, IH), 5.94 (q, J= 6.4 Hz, IH), 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)~

[0313] 1H-1, 2, 3-triazol-4-yl)ethoxy)-2, 4-dihydro-lH-pyrano[3, 4-c] quinoline

[0314] 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 flora 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 Anther purification.

[0315] Step 2: (R)-9-(l -(1-(1 -(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-[(1R)-l-methylprop-2-ynoxy]-2,4-dihydro-1H-pyrano[3,4- cj]uinoline 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.1HNMR (400 MHz, DMSO-d6) δ 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), 3.162.95 (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.

[0316] 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.

[0317]

[0318] Analyticla data for compounds of Examples 64-90 is provided in the table below:

[0319] Example 91: fR)-(4-(4-(l-((2,4-dihydro-1H-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)-1H-l,2,3-triazol-l-yl)-2-oxabicyclo[2.1. l]hexan-l-yl)methanol

[0320] Step 1 : (R)-(4-(4-(l -((2, 4-dihydro-lH-pyrano[3, 4-c]quinolin-9-yl)oxy)ethyl)~ lH-l,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- 1H-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 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-d6) δ 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, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 409.1.

[0321] Example 92 : (R)-(4-(4-(l -((1, 4-dthydro-2H-pyrano[3, 4-c]qutnoltn-9-yl) oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)bicyclo[2.1.1 ]hexan-l-yl)methanol

[0322] The title compound was prepared in a similar fashion as Example 91 via diazo transfer, click reaction and reduction.1H NMR (400 MHz, DMSO-d6) δ = 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.

[0323] Example 93: [4-[4-[(lR)-l-[(5-methyl-2,4-dthydro-lH-pyrano[3,4- c]quinolin-9-yl)oxy] ethyl] triazol-l-yl]-2-oxabicyclo[2.1.1 ]hexan-l-yl]methanol

[0324] The title compound was prepared in a similar fashion as Example 91 via diazo transfer, click reaction and reduction.1H 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 -(1 -(3-(fluoromethyl)bicyclo[l.1.1 ] pentan-1 1, 2, 3-triazol-4-yl)ethoxy)-l, 4-dihydro-2H-pyrano[3, 4-c] quinoline

[0325] To a solution of (R)-(3-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)-1H-l,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 NaHCO3(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% HCOO / f-water) to afford (R)-9-(l-(l-(3-

[0326] (fluoromethyl)bicyclo[ 1.1.1 Jpentan- 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,1H NMR (400MHz, DMSO-d6) δ 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 M7Z (M+H) 395.2.

[0327] Example 95: (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)methanesulfonamide

[0328] 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[2.1.1]hexan-l-yl)carbamate: To a 10- dram vial charged with tert-butyl 7V-(l-amino-4-bicyclo[2.1.1]hexanyl)carbamate (250.0 mg, 1.18 mmol) was added sulfurazidic fluoride (2.26 mL, 624 mM in MTBE, 1.41 mmol) and potassium bicarbonate (1.96 mL, 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)-I,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 tert- butyl alcohol (2.0 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 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, NMR (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.

[0329] Step 2: (R)-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-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 mL) was added hydrochloric acid (0.88 mL, 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.

[0330] 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)methanesulfonamide: To a solution of (R)-4-(4-(l-((l,4-dihydro-2Af-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 μL, 0.19 mmol). Methanesulfonyl chloride (8.1 μL, 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 NaHCO3aqueous 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,1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J= 6.9 Hz, 2H), 7.98 (s, IH), 7.88 (d, J= 9.0 Hz, IH), 7.46 (d, J= 2.7 Hz, IH), 7.39 (dd, J= 9.2, 2.6 Hz, IH), 5.90 (q, J= 6.4 Hz, IH), 4.84 (s, 2H), 4.05 (td, J= 5.7, 2.5 Hz, 2H), 3.11 (dt, J= 17.9, 5.6 Hz, IH), 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.

[0331] 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.

[0332] Step 1 : 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: 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(n) 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, NMR (400 MHz, DMSO-d6) δ 8.69 (s, IH), 8.45 (d, J = 5.3 Hz, IH), 8.00 (d, J = 9.0 Hz, IH), 7.58 (s, 2H), 6.00 (d, J = 6.8 Hz, IH), 4.89 (s, 2H), 4.66 (d, J = 8.7 Hz, IH), 4.08 (s, 2H), 3.22 (s, IH), 3.17 (s, IH), 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.

[0333] 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)-1H- l,2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1.1]hexane-3-carboxylic acid (90.3 mg, 0.21 mmol) in N,--dimethylformamide (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 N,N-diisopropylethylamine (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 μm, 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 2.1H NMR (400 MHz, DMSO) 58.44 (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.

[0334] Examples 97-122: the compounds were synthesized using methods and procedures similar to those used in Example 96 using appropriate starting materials and synthetic intermediates.

[0335]

[0336] Analyticla data for compounds of Examples 97-122 is provided in the table below: 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

[0337] 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 -(( / ?) -l-(( 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)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 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 (153 mg, 60% yield).1H 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-[(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 2-[[4-[4-[(1R)-l-(2,4-dihydix)-1H-pyrano[5, 4-c]quinolin-9- yloxy)ethyl]triazol- 1-yl]- l-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 erode 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.

[0338] Step 3: 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

[0339] To a solution of [4-[4-[(lR)-l-(2,4-dihydro-lS-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,N- 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 NaHCO3aqueous 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 μm, 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 123:1H NMR (400 MHz, DMSO) 58.44 (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 - 1.66 (m, 6H), 1.43 (s, 3H). LCMS M / Z (M+H) 464.1. Example 124: NMR (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 - 1.66 (m, 6H), 1.43 (s, 3H). LCMS M / Z (M+H) 464.2.

[0340] 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.

[0341]

[0342] Analyticla data for compounds of Examples 125-135 is provided in the table below:

[0343] Example 136 & 137: N-(4-(4-((R)-l-((l,4-dihydro-2H-pyiano[3,4-c]quinolin-

[0344] 9-yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1. l]hexan-3- yl)methyl)cyclopropanamine 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 sulf onate: To a solution of (4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4- c]quinolin-9-yl)oxy)ethyl)-1H-l,2,3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1. IJhexan- 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 NaHCO3aqueous 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 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, CDCl3) 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, J = 6.5, 1.0 Hz, 3H), 1.48 (s, 3H). LCMS M / Z (M+H) 577.1.

[0345] 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- 1H-pyrano [3, 4-c]quinolin-9-yloxy)ethyl]triazol- 1 -yl] -2- oxabicyclo[2.1. l]hexan-3-yl]methyl methanesulfonate (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 μm, 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 1361H 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 = 9.2 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, J = 6.1 Hz, 2H), 3.10 (d, J = 17.7 Hz, 1H), 2.98 (d, J = 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 1371HNMR (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.

[0346] Example 138: (3R)-l-((4-(4-((R)-l-((l, 4-dihydro-2H-pyrano[3, 4-c]qutnoltn- 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.1H 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.

[0347] 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-yl]acetonitrile

[0348] A mixture of [l-[4-[(lR)-l-(2,4-dihydro-1H-pyrano[3,4-c]quinolin-9- yloxy)ethyl]triazol-l-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 / CH3CN to yield 2-[l-[4-[(lR)-l-(2,4-dihydro- 1H-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l-yl]-3-oxabicyclo[2.1.1]hexan-4- yljacetonitrile as a white solid. (3.9 mg, 18% Yield).1H NMR (400 MHz, DMSO-d6) δ 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.

[0349] Example 140: (R)-6-(4-(l-((l,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

[0350] Step 1 : (R)-6-(4-(l -((1, 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 l-(hydroxymethyl)-4-[4-[(1R)-l-(2,4-dihydro-1H- 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, filtered 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-[(1R)-l-(2,4-dihydro-1H-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 awhile solid, NMR (400 MHz, DMSO-d6) δ 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.

[0351] Example 141: (R)-7-(4-(l-((l,4-dthydro-2H-pyrano[3,4-c]qutnoltn-9-yl) oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)dihydro-lH, 6H-7, 8a-methanopyrrolo[2, 1- c][l.4]oxazin-4(3H)-one

[0352] Step 1 : (R)-(4-(4-(l -((1, 4-dihydro-2H-pyrano[3, 4-c]quinolin-9-yl)oxy)ethyl)~ 1H-1, 2, 3-triazol-l-yl)-2-azabicyclo [2.1.1] hexan-l-yl) methanol: A solution of tert- butyl l-(hydroxymethyl)-4-[4-[ (1R)-l-(2,4-dihydro-1H-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)-l-(2,4-dihydro-1H- pyrano[3,4-c] quinolin-9-yloxy)ethyl]triazol-l-yl]-2-azabicyclo[2.1. l]hexan-l- yljmethanol as a yellow oil, which was used for next step without further purification. LCMS M / Z (M+H) 408.1.

[0353] Step 2: (R)-2-chloro-l-(4-(4-(l -((1, 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 (R)-(4-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin- 9-yl)oxy)ethyl)-1H-l,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.

[0354] Step 3: (R)-7-(4-(l -((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, l-c][l,4]oxazin-4(3H)~ one: To a solution of (R)-2-chloro-l-(4-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c] quinolin-9-yl) oxy) ethyl)- 127-1, 2, 3-triazol-l-yl)-l-(hydroxymethyl)-2-azabicyclo [2.1.1] hexan-2-yl) ethan-l-one (50 mg, 0.10 mmol) in THE (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 (ImL). The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mLx3). 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.1HNMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 9.2 Hz, 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.

[0355] Examples 142-144: the compounds were synthesized using methods and procedures similar to those used in Example 141 using appropriate starting materials and synthetic intermediates.

[0356] Analyticla data for compounds of Examples 142-144 is provided in the table below:

[0357] Example 145: (R)-7-(4-(l-((l,4-dihydro-2ff-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)-l.H-l,2,3-triazol-l-yl)tetrahydro-1H,6Zf-7,8a-methanopyrrolo[2,l- c] [1,4] oxazine Step 1 : (R)-7-(4-(l -((1, 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'. To a stirred solution of (R)-7-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)- \H- 1 ,2,3 -triazol- 1 -yl)dihydro- 1H,6Hf-7,8a-methanopyrrolo[2, 1- c][l,4]oxazm-4(3H)-one (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,1H NMR (400 MHz, DMSO-d6) δ 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.

[0358] Example 146 & 147, l-(4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-

[0359] 15 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

[0360] Step 1 : methyl(R)-4-(4-(l -((1, 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-[(1R)-l-(2,4-dihydro-1H-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 NaHCO3aqueous solution (10 mL). The aqueous layer was extracted with DCM. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 4-[4-[(1R)-l-(2,4-dihydro-1H-pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol-l- yl]-l-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-caiboxylate (90 mg, 0.193 mmol, 39% yield) as a yellow solid.1HNMR (400 MHz, DMSO-d6) δ 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.

[0361] 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-[(1R)-l-(2,4-dihydro-1H-pyrano[3,4- c]quinolin-9-yloxy)ethyl]triazol-l-yl]-l-(hydioxymethyl)-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, 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 methyl4-[4-[(1R)-l-(2,4-dihydro-1H-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.1HNMR (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.

[0362] Step 3: (R)-9-(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-[(1R)-l-(2,4-dihydro-1H-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 of NaOH (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 erode product 9- [( 1R )- 1 -[ 1 -[ 1 -(fluoromethyl)-2-azabicyclo [2.1.1 ]hexan-4-yl] triazol-4- yl]ethoxy]-2,4-dihydro-1H-pyrano[3,4-c]quinoline (120 mg, 0.293 mmol, 85.6% yield) as a yellow solid. LCMS M / Z (M+H) 410.2.

[0363] 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-[(1R)-l-[l-[l-(fluoromethyl)-2- azabicyclo[2.1. l]hexan-4-yl]triazol-4-yl]ethoxy]-2,4-dihydro-1H-pyrano[3,4- cjquinoline (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 μm 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 - [ ( 12?) - 1 -(2,4-dihydro- 1H-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-d6) δ 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, J= 6.4 Hz, 1H), 5.26 - 5.07 (m, 2H), 4.97 (d, J= 6.8 Hz, 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 (br d, J= 5.6 Hz, 2H), 2.19 (t, J= 5.2 Hz, 2H), 1.73 (d, J= 6.4 Hz, 3H), 1.68 - 1.40 (m, 2H), 0.89 (t, J= 7.6 Hz, 3H). LCMS M / Z (M+H) 496.3. And peak 2: (2S)-l-[4-[4-[(LR)-l- (2,4-dihydro- 1H-pyrano[3 ,4-c] quinolin-9-yloxy) ethyljtriazol- 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, NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.45 (s, 1H),

[0364] 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 (m, J= 6.4 Hz, 1H), 5.27 - 5.04 (m, 2H), 4.96 (d, J= 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, J= 4.4 Hz, 2H), 2.24 - 2.12 (m, 2H), 1.73 (d, J= 6.4 Hz, 3H), 1.69 - 1.41 (m, 2H), 0.88 (t, J= 7.6 Hz, 3H). LCMS M / Z (M+H) 496.3. Example 148: (R)-4-(4-(l-((l,4-dthydro-2H-pyrano[3,4-c]qutnoltn-9- yl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)-l-(fluoromethyl)-N-methyl-2-azabicyclo[2.1.1 ] hexane-2-carboxamide

[0365] Step 1 : (R)-4-(4-(l -((1, 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-[(1R)-l-[l-[l-(fluoromethyl)-2- azabicyclo[2.1. l]hexan-4-yl]triazol-4-yl]ethoxy]-2,4-dihydro-1H-pyrano[3,4- cjquinoline (Example 147, step 3, 40 mg, 0.10 mmol) and TEA (0.05 mL, 0.39 mmol) was added N-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 NaHCO3aqueous solution (10 mL) and extracted with dichloromethane. The combined organic 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- [( 1R)- 1 -(2,4-dihydro- 1H-pyrano [3 ,4-c]quinolin-9-yloxy)ethyl]triazol- 1 -yl] - 1 - (fluoromethyl)-?V-methyl -2 -azabicyclo [2. l.l]hexane-2 carboxamide (23.2 mg, 0.048 mmol, 49.4% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 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.

[0366] 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.

[0367]

[0368] Analyticla data for compounds of Examples 142-144 is provided in the table below: Example 155 : (R)-l-(4-(4-(l -((1, 4-dihydro-2H-pyrano[3, 4-c]qutnoltn-9- yl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)-l-(fluoromethyl)-2-azabicyclo[2.1.1 ]hexan-2-yl)- 2-jluoroethan-l-one

[0369] Step 1: (R)-l-(4-(4-(l-((l,4-dthydro-2H-pyrano[3,4-c]qutnoltn-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-[(1R)-l-(2,4-dihydro-1H-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 NaHCO3(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, filtered 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-[(1R)-l-(2,4-dihydro-1H-pyrano[3,4-c] quinolin-9- yloxy)ethyl]triazol-l-yl]-l-(fhioromethyl)-2-azabicyclo [2.1. l]hexan-2-yl]-2-fluoro- ethanone (23.1 mg, 0.047 mmol, 31% yield) as a white solid,1H NMR (400MHz, DMSO-d6) δ 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.

[0370] Example 156 & 157, (4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)-lH- 12, 3-triazol-l-yl)-l-methyl-2-oxabicyclo[2.1.1 ]hexan-3-yl)((S)-3- hydroxypyrrolidin-l-yl)methanone

[0371] (4-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-lH-

[0372] 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-l-((l,4-dihydix)-2H-pyrano[3,4- c] quinolin-9-yl)oxy)ethyl)- \H- 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, filtered and concentrated under reduced pressure. The erode was further purified by prep-HPLC (DB, Welch Xtimate C18 150x25 mmx5 μm, 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 μm), 30% iPrOH (0.1%NH4OH) in CO2, 70 ml / min) to afford the title compound-l(Example 156, first peak on SFC, 35.1 mg, 40.4% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 58.44 (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.1H NMR (400 MHz, DMSO-d6) 58.44 (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.

[0373] Examples 158-165: the compounds were synthesized using methods and procedures similar to those used in Example 156 using appropriate starting materials 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.

[0374]

[0375]

[0376] Analyticla data for compounds of Examples 158-165 is provided in the table below:

[0377]

[0378] Example 166: 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, 1- c][l, 4]oxazine-3-carbonitrile

[0379] 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 [4-[4-[(1R)-l-(2,4-dihydix)-1H-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- 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, filtered and concentrated to afford crude product (521 mg) as a yellow oil.1H 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 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.

[0380] 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, l-c][l, 4]oxazine-3- carbonitrile: To a solution of 2-chloro-3-[l-(hydroxymethyl)-4-[4-[(1R)-l-(2,4- dihydro- 1H-pyrano [3, 4-c]quinolin-9-yloxy)ethyl]triazol- 1 -yl] -2- azabicyclo[2.1.1]hexan-2-yl] propanenitrile (491.0 mg, 0.99 mmol) in THF (10 mL) was added dropwise t-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 ‘water+NH4HCO3) in water) to give 7-(4-( (R)-l-((l,4-dihydro-27 / -pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-177-l,2,3-triazol- l-yl)tetrahydro-1H,6 / f-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. 1H 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.

[0381] Example 167: (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] [1, 4]oxazin-3-yl)methanol 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, l-c][l, 4]oxazine-3- carboxylic acid: To a solution of 8-[4-[(1R)-l-(2,4-dihydro-1H-pyrano[3,4- c]quinolin-9-yloxy)ethyl]triazol-l-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 0- 25 / 0.1% water (FA)-ACN) to afford 8-[4-[(1R)-l-(2,4-dihydro-l-pyrano[3,4- c]quinolin-9-yloxy)ethyl]triazol-l-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.

[0382] 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, l-c][l, 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, l-c][l, 4]oxazin-3- yl)methanol: Under nitrogen, to a solution of 8-[4-[(1R)-l-(2,4-dihydro-1H- 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 BH3 THF (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 0- 30 / 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 μm; Mobile phase: A: CO2 B: ethanol (0.05% DEA); Isocratic: 50% B; Flow rate: 2.8 mL / min; Column temp.: 35 °C; to afford peak! [(4R)-8-[4-[(1R)-l-(2,4-dihydro-1H- pyrano[3,4-c]quinolin-9-yloxy)ethyl]triazol- 1 -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.1HNMR (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,

[0383] 9.6 Hz, 1H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H] 464.3.

[0384] 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

[0385] 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, 1- c] [1.4] oxazine: To a stirred solution of (7-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4- c] quinolin-9-yl)oxy) ethyl)- 1H- 1 ,2, 3-triazol- 1 -yl)tetrahydro- 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, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (DB, Welch Xtimate C18 150x25 mmx5 μm, water( NH4HCO3)-ACN, 30% ~ 60%) to afford the title compound (2.2 mg, 21% yield) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ 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-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- 3 -y I) methanol

[0386] Step 1: 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]oxazine-3-carboxylic acid: To a solution of 8-[4-[(1R)-l-[(5-methyl-2,4- dihydro-1H-pyrano[3,4-c]quinolin-9-yl) oxy]ethyl]triazol-l-yl]-3-oxa-6- azatricyclo[6.1.1.01,6]decane-4-carbonitrile (290.0 mg, 0.61 mmol, prepared in a similar fashion to Example 166) in 1,4-dioxane (5 mL) was added NaOH aqueous solution (5 mL, 1 M) at 25 °C. The mixture was stirred at 100 °C for 1 h then was cooled to room temperature and partially concentrated under reduced pressure. The pH was adjusted to around 5 by progressively adding HC1 (1 M). The resulting solution was purified by reverse phase chromatography (acetonitrile 1-31 / 0.25% water (FA)-ACN) to afford 8-[4-[(1R)-l-[(5-methyl-2,4-dihydro-1H-pyrano[3,4- c]quinolin-9-yl)oxy]ethyl]triazol-l-yl]-3-oxa-6-azatricyclo [6.1.1.01,6]decane-4- carboxylic acid (190 mg, 0.39 mmol, 63% yield) as a white solid. LCMS M / Z (M+H) 492.

[0387] 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-3-yl)methanol: Under nitrogen, to a solution of 8-[4-[(LR)-l-[(5- methyl-2,4-dihydro-1H-pyrano[3,4-c] quinolin-9-yl)oxy]ethyl]triazol-l-yl]-3-oxa-6- azatricyclo[6.1.1.01,6]decane-4-carboxylic acid (190.0 mg, 0.39 mmol) in THF (2 mL) was added BH3 THF (7 mL, 7 mmol) at 25 °C. The resulting solution was stirred for 2 h at 80 °C. After cooling to 25 °C, MeOH (20 ml) was added dropwise and the solution was stirred for another 16 h at 80 °C. Then the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (4% methanol in dichloromethane) to afford the racemic title compound (125 mg) as a colorless oil. The racemate was separated by SFC: Column: Chiralpak AD-3 150*4.6 mm I.D., 3 μm; Mobile phase: 40% of iso-propanol (0.05% DEA) in CO2; Flow rate: 2.5 mL / min; Column temp.: 35 °C; to afford peak 1 [(4S)-8-[4-[(1R)-l-[(5-methyl- 2,4-dihydro- 1H-pyrano[3,4-c]quinolin-9-yl)oxy]ethyl]triazol- 1 -yl] -3-oxa-6- azatricyclo[6.1.1.01,6] decan-4-yl]methanol (25.1 mg, 0.052 mmol, 19.9% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 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), 4.76 (s, 2H), 4.71 (t, J= 5.6 Hz, 1H), 4.05 - 3.96 (m, 2H), 3.90 (d, J= 12.0 Hz, 1H), 3.62 (d, J= 12.0 Hz, 1H), 3.54 - 3.46 (m, 1H), 3.45 - 3.39 (m, 2H), 3.34 - 3.28 (m, 1H), 3.13 - 3.03 (m, 1H), 3.02 - 2.94 (m, 1H), 2.92 (dd, J= 2.0, 11.2 Hz, 1H), 2.79 (d, J= 7.6 Hz, 1H), 2.41 (s, 3H), 2.41 - 2.32 (m, 2H), 2.27 (d, J= 6.0 Hz, 1H), 2.03 (d, J = 6.8 Hz, 1H), 1.94 (dd, J= 6.4, 10.0 Hz, 1H), 1.71 (d, J= 6.4 Hz, 3H). LCMS M7Z (M+H) 478. And peak 2 [(4 / ?)-8-[4-[(l / ?)-l-[(5-methyl-2,4-dihydro-l^-pyrano[3,4- c]quinolin-9-yl) oxy]ethyl]triazol-l-yl]-3-oxa-6-azatricyclo[6.1.1 ,01,6]decan-4- yljmethanol (33.1 mg, 0.068 mmol, 26% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 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), 4.76 (s, 2H), 4.70 (t, J= 5.6 Hz, 1H), 4.06 - 3.96 (m, 2H), 3.90 (d, J= 11.6 Hz, 1H), 3.62 (d, J= 11.6 Hz, 1H), 3.53 - 3.47 (m, 1H), 3.46 - 3.40 (m, 2H), 3.33 - 3.25 (m, 1H), 3.13 - 3.03 (m, 1H), 3.02 - 2.95 (m, 1H), 2.92 (dd, J= 2.0, 10.8 Hz, 1H), 2.82 - 2.76 (m, 1H), 2.42 (s, 3H), 2.41 - 2.31 (m, 2H), 2.27 (d, J= 6.4 Hz, 1H), 2.03 (d, J= 6.8 Hz, 1H), 1.93 (dd, J= 6.0, 9.6 Hz, 1H), 1.71 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 478.

[0388] Example 171 & 172, (7-(4-((R)-l-((l,4-dthydro-2H-pyrano[3,4-c]qutnoltn-9- yl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2, 1- c][l.4] oxazin-4-y I) methanol

[0389]

[0390] 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)tetrahydro-lH, 6H-7, 8a-methanopyrrolo[2, l-c][l, 4]oxazin-4- yl)methanol & (R)-(4-(4-(l -((1, 4-dihydro-2H-pyrano[3, 4-c]qutnoltn-9-yl)oxy)ethyl)- 1H-1, 2, 3-triazol-l-yl)-2-(oxetan-3-yl)-2-azabicyclo[2.1.1 ]hexan-l-yl)methanol: To a solution of (R)-(4-(4-(l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-yl)oxy)ethyl)-1H- l,2,3-triazol-l-yl)-2-azabicyclo[2.1.1]hexan-l-yl)methanol (Example 182, step 1, 400 mg, 0.98 mmol) and oxetan-3-one (142 mg, 1.97 mmol) in DCE (4 mL) was added NaBH(OAc)3 (416 mg, 1.97 mmol) at 25 °C. The mixture was stirred at 40 °C for 16 h, and TLC (dichloromethane / methanol = 20 / 1, Rf = 0.4 & 0.5) showed two new spots. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (0-10% methanol in dichloromethane) to afford the title compound 1 (263 mg, 0.57 mmol, 57.8% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.49 - 8.42 (m, 2H), 7.88 (d, J= 8.8 Hz, IH), 7.46 (d, J= 2.4 Hz, IH), 7.39 (dd, J= 9.2, 2.8 Hz, IH), 5.92 (q, J= 6.4 Hz, IH), 4.84 (s, 2H), 4.61 (t, J= 5.2 Hz, IH), 4.11 - 3.98 (m, 2H), 3.92 - 3.84 (m, 2H), 3.53 (d, J= 11.6 Hz, IH), 3.47 - 3.38 (m, 2H), 3.25 - 2.94 (m, 5H), 2.72 - 2.63 (m, IH), 2.41 (t, J= 8.0 Hz, IH), 2.27 (d, J= 5.6 Hz, IH), 2.08 - 2.02 (m, IH), 1.95 - 1.88 (m, IH), 1.72 (d, J= 6.4 Hz, 3H). . LCMS M / Z (M+H) 464.3. Additionally, the ring opened product (compound 2, 92 mg, 0.2 mmol, 20.2% yield) was obtained as a white solid. LCMS M / Z (M+H) 464.3.

[0391] 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, l-c][l, 4]oxazin-4- yl)methanol: To a solution of (R)-(4-(4-(l-((l,4-dihydro-2Af-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)-1H-l,2,3-triazol-l-yl)-2-(oxetan-3-yl)-2-azabicyclo[2.1. l]hexan-l- yl)methanol (92 mg, 0.20 mmol) in dry DCM (2 mL) was slowly added BF3 ‘Et2O (0.24 mL) at 0 °C. The solution was slowly warmed to 25 °C and stirred for 16 h, then concentrated under reduced pressure and purified by flash chromatography (0-10% methanol in dichloromethane) to afford the title compound (62 mg, 0.57 mmol, 57.8% yield) as a white solid. LCMS M / Z (M+H) 464.3.

[0392] Step 3: (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, l-c][l, 4]oxazin-4- yl)metanol: 16 mg of (7-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)- \H- 1,2,3 -triazol- 1 -yl)tetrahydro- 8a-methanopyrrolo [2,1- c][l,4]oxazin-4-yl)methanol was separated by chiral SFC (DAICEL CHIRALPAK IG (250 mmx30 mm, 10 μm), CO2-EtOH (0.1% NH4OH), 60% 80 ml / min) to afford peak 1 (first peak on SFC, 5.6 mg, 29% yield) as white solid.1H NMR (400 MHz, DMSO-d6) δ 8.46 (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), 5.92 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.60 (t, J= 5.2 Hz, 1H), 4.09 - 4.02 (m, 2H), 3.92 - 3.84 (m, 2H), 3.53 (d, J= 11.6 Hz, 1H), 3.46 - 3.39 (m, 2H), 3.24 - 3.06 (m, 3H), 3.04 - 2.97 (m, 2H), 2.72 - 2.63 (m, 1H), 2.44 - 2.38 (m, 1H), 2.29 - 2.25 (m, 1H), 2.07 - 2.02 (m, 1H), 1.94 - 1.89 (m, 1H), 1.72 (d, J = 6.4 Hz, 3H). LCMS M / Z (M+H) 464.3. And peak 2 (second peak on SFC, 5.5 mg, 33% yield ) as white solid, NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.44 (s, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.95 - 5.88 (m, 1H), 4.84 (s, 2H), 4.61 (t, J= 5.6 Hz, 1H), 4.05 (d, J= 2.4 Hz, 2H), 3.91 - 3.84 (m, 2H), 3.53 (d, J= 12.0 Hz, 1H), 3.46 - 3.39 (m, 2H), 3.23 - 3.08 (m, 3H), 3.04 - 2.97 (m, 2H), 2.67 (br s, 1H), 2.43 - 2.38 (m, 1H), 2.29 - 2.26 (m, 1H), 2.06 - 2.02 (m, 1H), 1.95 - 1.89 (m, 1H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 464.3.

[0393] Examples 173-178: the compounds were synthesized using methods and procedures similar to those used in Example 171 & 172 using impropriate starting materials and synthetic intermediates.

[0394]

[0395] Analyticla data for compounds of Examples 173-178 is provided in the table below:

[0396] Example 179 & 180, 7-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)-4-(fluoromethyl)tetrahydro-lH, 6H-7, 8a- methanopyrrolo[2,l-c] [1, 4] oxazine

[0397] 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)-4-(fluoromethyl)tetrahydro-lH, 6H-7, 8a-methanopyrrolo [2, 1- c] [l,4]oxazine: A solution of (7-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)- \H- 1,2,3 -triazol- 1 -yl)tetrahydro- 8a-methanopynolo [2,1- c][l,4]oxazin-4-yl)methanol (Racemic mixture of Examples 171 / 172, 150 mg, 0.32 mmol), pyridine-2-sulfbnyl fluoride (208 mg, 1.29 mmol) and DBU (197 mg, 1.29 mmol) in 1,4-dioxane (5 mL) was stirred at 60 °C for 1 h. Then KF (20 mg) was added, and the mixture was stirred at 90 °C for another 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography (DB, Welch Xtimate C18 150x25 mmx5 μm, water (NH4HCO3)- ACN, 25% ~ 55%) to afford the racemic title compound (16 mg, 11% yield) as a white solid. The racemate was separated by SFC: (DAICEL CHIRALPAK IF (250 mmx30 mm, 10 μm), A: CO2 B: 60% EtOH (0.1%NH4OH) to afford peak 1 (first peak on SFC, 5 mg, 31% yield) as a white solid,1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J= 3.6 Hz, 2H), 7.88 (d, J= 8.8 Hz, 1H), 7.46 (d, J= 2.8 Hz, 1H), 7.39 (dd, J = 9.2, 2.8 Hz, 1H), 5.92 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.49 - 4.24 (m, 2H), 4.10 - 3.98 (m, 2H), 3.93 - 3.82 (m, 2H), 3.56 (d, J= 12.0 Hz, 1H), 3.44 (d, J= 8.0 Hz, 1H), 3.29 - 3.23 (m, 1H), 3.15 - 2.88 (m, 4H), 2.44 (dd, J= 10.0, 6.8 Hz, 1H), 2.30 (d, J= 6.4 Hz, 1H), 2.08 (d, J= 6.8 Hz, 1H), 1.95 (dd, J= 10.0, 6.4 Hz, 1H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 466.1. And peak 2 (second peak on SFC, 3.8 mg, 23% yield) as a white solid, NMR (400 MHz, DMSO-d6) 5 8.45 (d, J= 4.4 Hz, 2H), 7.88 (d, J= 8.8 Hz, 1H), 7.46 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 9.2, 2.8 Hz, 1H), 5.92 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.49 - 4.25 (m, 2H), 4.11 - 4.00 (m, 2H), 3.94 - 3.83 (m, 2H), 3.56 (d, J= 11.6 Hz, 1H), 3.45 (d, J= 8.4 Hz, 1H), 3.29 - 3.23 (m, 1H), 3.14 - 2.89 (m, 4H), 2.44 (dd, J= 9.6, 6.8 Hz, 1H), 2.30 (d, J= 6.0 Hz, 1H), 2.08 (d, J= 6.8 Hz, 1H), 1.95 (dd, J= 9.6, 6.0 Hz, 1H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 466.1.

[0398] Example 181 & 182, 2-(7-(4-((R)-l-((l,4-dthydro-2H-pyrano[3,4-c]qutnoltn- 9-yl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)tetrahydro-lH, 6H-7, 8a-methanopyrrolo[2, 1- c][l, 4]oxazin-4-yl)acetonttrile

[0399] Step 1: 2-(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, 1- c][l, 4]oxazin-4-yl)acetonitrile:

[0400] To a solution of DIAD (122.15 mg, 0.60 mmol), acetone cyanohydrin (0.01 mL, 0.12 mmol) and [8-[4-[(1R)-l-(2,4-dihydro-1H-pyrano[3,4-c]quinolin-9- yloxy)ethyl] triazol-l-yl]-3-oxa-6-azatricyclo[6.1.1.01,6]decan-5-yl]methanol (Racemic mixture of Examples 171 / 172, 70.0 mg, 0.15 mmol) in THF (2 mL) was added PPha (158.44 mg, 0.60 mmol) at 0 °C. The reaction was stirred at 25 °C for 16 h, then diluted with water and extracted with ethyl acetate. The combined organic layer was washed brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (Welch Xtimate C18 150x30 mmx5 μm; mobile phase: [water (FA)-ACN); B%: 46%-76%, 7 min) to afford the racemic title compound 70 mg as a white solid. The racemate was further separated by SFC: Chiralcel OJ-3 150x4.6 mm I.D., 3 μm; 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 0.2 min, then hold 5% for 1.8 min; Flow rate: 2.5 mL / min to afford peak 1 (7.5 mg, 0.016 mmol, 25% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J= 4.4 Hz, 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), 5.90-5.95 (m, 1H), 4.84 (s, 2H), 4.10 - 4.00 (m, 2H), 3.90 (d, J= 11.4 Hz, 1H), 3.83 (dd, J= 3.2, 11.2 Hz, 1H), 3.58 (d, J= 11.6 Hz, 1H), 3.42-3.44 (m, 1H), 3.21-3.28 (m, 1H), 3.15 - 2.94 (m, 3H), 2.92 - 2.85 (m, 1H), 2.68 - 2.62 (m, 2H), 2.41-2.45 (m, 1H), 2.30 (d, J= 5.6 Hz, 1H), 2.10 (d, J= 6.8 Hz, 1H), 1.95-1.99 (m, 1H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 473.2. And peak 2 (7.2 mg, 0.015 mmol, 24% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J= 5.2 Hz, 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), 5.90-5.95 (m 1H), 4.84 (s, 2H), 4.10 - 4.00 (m, 2H), 3.90 (d, J= 11.8 Hz, 1H), 3.83 (dd, J= 3.2, 11.2 Hz, 1H), 3.58 (d, J= 11.8 Hz, 1H), 3.42-3.44 (m, 1H), 3.21-3.27 (m, 1H), 3.15 - 2.94 (m, 3H), 2.86-2.89 (m, 1H), 2.68 - 2.61 (m, 2H), 2.42 (dd, J= 6.8, 9.6 Hz, 1H), 2.31 (d, J= 6.4 Hz, 1H), 2.09 (d, J= 6.2 Hz, 1H), 1.98 (dd, J= 6.4, 10.0 Hz, 1H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 473.2.

[0401] Example 183 & 184, 2-7-(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, 1- c][l, 4]oxcain-4-yl)ethan-l-ol

[0402]

[0403] Step 1: 2-(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, 1- c][l,4]oxazin-4-yl) acetaldehyde: To a solution of 2-[8-[4-[(1R)-l-(2,4-dihydro-1H- pyrano[3,4-c]quinolin-9-yloxy) ethyl] triazol-l-yl]-3-oxa-6- azatricyclo[6.1.1.01,6]decan-5-yl]acetonitrile (Racemic mixture of Examples 171 / 172, 300.0 mg, 0.63 mmol, intermediate prepared from above step) in DCM (6 mL) was added DIBAL-H (2.22 mL, 2.22 mmol) at -78 °C. Then the mixture was stirred at 0 °C for 30 min, then quenched by NaSO4xH2O (600 mg). After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (10% methanol in dichloromethane) to afford 2-[8- [4- [ ( 1R)- 1 -(2,4-dihydro- 1H-pyrano [3 ,4-c]quinolin-9-yloxy)ethyl] triazol- 1 -yl] -3 -oxa- 6-azatricyclo[6.1.1.01,6]decan-5-yl] acetaldehyde (190 mg, 0.40 mmol, 62.9% yield) as a yellow oil. LCMS M / Z (M+H) 476.

[0404] Step 2: 2-(7-(4-((R)-l-((l,4-dthydro-2H-pyrano[3,4-c]qutnoltn-9- yl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)tetrahydro-lH, 6H-7,8a-methanopyrrolo[2, 1- c] [l,4]oxazin-4-yl)ethan-l-ol: To a solution of 2-[8-[4-[(1R)-l -(2,4-dihydro- 1H- pyrano[3,4-c]quinolin-9-yloxy)ethyl] triazol-l-yl]-3-oxa-6- azatricyclo[6.1.1.01,6]decan-5-yl]acetaldehyde (190.0 mg, 0.40 mmol) in MeOH (4 mL) was added NaBHt (30.23 mg, 0.80 mmol) at 0 °C. The reaction was stirred at 0 °C for 1 h, then quenched with saturated NH4Cl(aq) (1 mL), 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 resulting residue was purified by flash chromatography (3.5% methanol in dichloromethane) to afford the racemic title compound 80 mg as a yellow solid. LCMS M / Z (M+H) 478. The racemate was further separated by SFC: Column: Chiralpak AD-3 50x4.6 mm I.D., 3 μm; Mobile phase: A: CO2 B: ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 4 mL / min; Column temp: 35 °C; to afford peak 1 (19.9 mg, 0.041 mmol, 24.6% yield) as a white solid, NMR (400 MHz, DMSO-d6) 5 = 8.45 (d, J= 7.2 Hz, 2H), 7.88

[0405] (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 2.8, 9.2 Hz, 1H), 5.92 (q, J = 6.4 Hz, 1H), 4.83 (s, 2H), 4.49 (t, J= 5.2 Hz, 1H), 4.11 - 3.99 (m, 2H), 3.88 - 3.81 (m, 2H), 3.53 (d, J= 11.6 Hz, 1H), 3.48 - 3.42 (m, 2H), 3.40 (d, J= 8.0 Hz, 1H), 3.16 - 3.11 (m, 1H), 3.11 - 3.05 (m, 1H), 3.04 - 2.96 (m, 1H), 2.93 (d, J= 7.2 Hz, 1H), 2.75 - 2.67 (m, 1H), 2.41 (dd, J= 6.8, 9.6 Hz, 1H), 2.27 (d, J= 6.0 Hz, 1H), 2.04 (d, J= 6.8 Hz, 1H), 1.93 (dd, J= 6.0, 9.6 Hz, 1H), 1.72 (d, J= 6.4 Hz, 3H), 1.59 - 1.50 (m, 1H), 1.39 - 1.28 (m, 1H). LCMS M / Z (M+H) 478. And peak 2 (26.72 mg, 0.055 mmol, 32.7% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 5 = 8.45 (d, J = 6.4 Hz, 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), 5.92 (q, J= 6.4 Hz, 1H), 4.84 (s, 2H), 4.47 (t, J= 5.2 Hz, 1H), 4.08 - 4.01 (m, 2H), 3.88 - 3.81 (m, 2H), 3.54 (d, J= 11.6 Hz, 1H), 3.47 - 3.42 (m, 2H), 3.40 (d, J = 8.4 Hz, 1H), 3.16 - 3.11 (m, 1H), 3.11 - 3.05 (m, 1H), 3.03 - 2.96 (m, 1H), 2.93 (d, J= 8.0 Hz, 1H), 2.74 - 2.66 (m, 1H), 2.41 (dd, J= 6.8, 9.6 Hz, 1H), 2.27 (d, J= 6.0 Hz, 1H), 2.04 (d, J= 6.4 Hz, 1H), 1.94 (dd, J= 6.0, 9.6 Hz, 1H), 1.72 (d, J= 6.4 Hz, 3H), 1.59 - 1.50 (m, 1H), 1.38 - 1.29 (m, 1H). LCMS M / Z (M+H) 478.

[0406] Example 185 & 186, 7-(4-((R)-l-((l,4-dthydro-2H-pyrano[3,4-c]qutnoltn-9- yl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)-4-((2-methoxyethoxy)methyl)tetrahydro-lH, 6H- 7, 8a-methanopyrrolo[2, l-c][l,4]oxazine

[0407] 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)-4-((2-methoxyethoxy)methyl)tetrahydro-lH, 6H-7, 8a- methanopyrrolo[2,l-c] [l,4]oxazine: To a stirred solution of [8-[4-[(lR)-l-(2,4- dihydro-1H-pyrano[3,4-c]quinolin-9-yloxy) ethyl]triazol-l-yl]-3-oxa-6- azatricyclo[6.1.1.01,6]decan-5-yl]methanol (racemic mixture of Examples 171 / 172, 100.0 mg, 0.22 mmol, intermediate prepared from above step) in DMF (2 mL) was added NaH (12.94 mg, 0.32 mmol) 0 °C. After 30 minutes, 2-bromoethyl methyl ether (0.03 mL, 0.32 mmol) was added, and the reaction mixture was slowly warmed to room temperature and stirred for 2 h. 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 (25% ethyl acetate in petroleum ether) to afford the racemic title compound 100 mg as a white solid. The racemate was separated by SFC: Chiralcel OJ-3 150*4.6 mm 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% for 1.8 min; Flow rate: 2.5 mL / min; to afford peak 1 (30.4 mg, 0.055 mmol, 22.3% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J = 3.6 Hz, 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), 5.90 - 5.95 (m, 1H), 4.83 (s, 2H), 4.05 - 3.96 (m, 2H), 3.86 - 3.80 (m, 2H), 3.55 - 3.50 (m, 3H), 3.42 - 3.31 (m, 4H), 3.30 - 3.21 (m, 1H), 3.19 (s, 3H), 3.1 - 2.90 (m, 4H), 2.85 - 2.75 (m, 1H), 2.49 - 2.40 (m, 1H), 2.26 (d, J= 6.4 Hz, 1H), 2.05 (d, J = 6.4 Hz, 1H), 1.95 - 1.85 (m, 1H), 1.72 (d, J= 6.4, Hz, 3H). LCMS M7Z (M+H) 522.2. And peak 2 (33.3 mg, 0.058 mmol, 23.3% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J= 3.6 Hz, 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), 5.90 - 5.95 (m, 1H), 4.83 (s, 2H), 4.05 - 3.96 (m, 2H), 3.86 - 3.80 (m, 2H), 3.55 - 3.50 (m, 3H), 3.42-3.31 (m, 4H), 3.30 - 3.21 (m, 1H), 3.19 (s, 3H), 3.1 - 2.90 (m, 4H), 2.85 - 2.75 (m, 1H), 2.49 - 2.40 (m, 1H), 2.26 (d, J= 6.4 Hz, 1H), 2.05 (d, J= 6.4 Hz, 1H), 1.95 - 1.85 (m, 1H), 1.72 (d, J = 6.4, Hz, 3H). LCMS M7Z (M+H) 522.2.

[0408] Example 187 & 188, 7-(4-((R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)-lH-l,2,3-triazol-l-yl)-4-(methoxymethyl)tetrahydro-lH,6H-7,8a- methanopyrrolo[2,l-c] [1, 4] oxazine

[0409]

[0410] 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)tetrahydro-lH, 6H-7, 8a-methanopyrrolo[2, l-c][l, 4]oxazin-4- yl)methyl methanesulfonate: To a solution of (7-(4-((R)-l-((l,4-dihydro-2H- pyrano[3,4-c]quinolin-9-yl) oxy) ethyl)- 1H- 1,2, 3 -triazol- 1-yl) tetrahydro- 8a- methanopyrrolo[2,l-c][l,4]oxazin-4-yl) methanol (racemic mixture of Examples 171 / 172, 260 mg, 0.56 mmol) and EtsN (170 mg, 1.68 mmol) in DCM (5 mL) was added MsCl (71 mg, 0.62 mmol) at 0 °C. The resulting solution was stirred for 1 h at 0 °C. The reaction was diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (265 mg, 87% yield, crude) as a white solid.

[0411] Step 2: 7-(4-l-((l, 4-dihydro-2H-pyrano[3, 4-c]quinolin-9-yl)oxy)ethyl)-lH- 1, 2, 3-triazol-l-yl)-4-(methoxymethyl)tetrahydro-lH, 6H-7, 8a-methanopyrrolo[2,l- c] [l,4]oxazine: A solution of (7-(4-( (R)-l-((l,4-dihydro-2H-pyrano[3,4-c]quinolin-9- yl)oxy)ethyl)- 1H-l,2,3-triazol-l-yl) tetrahydro- 1H,6H-7,8a-methanopyrrolo[2, 1- c][l,4] oxazin-4-yl) methyl methanesulfonate (70 mg, 0.13 mmol) andNaOMe (35 mg, 0.65 mmol) in MeOH (2 mL) was stirred at 80 °C for 16 h, then concentrated under reduced pressure. The residue was purified by reverse phase chromatography (DB, Welch Xtimate C18 150x25 mmx5 μm, water (NH4HCO3)-ACN, 25%~55%) to afford the racemic title compound (32 mg, 52% yield) as a white solid. The racemate was separated by SFC: (DAICEL CHIRALPAK IG (250 mmx30 mm, 10 μm), CO2- EtOH (0.1% NH3H2O), 35%, 80 ml / min) to afford peak 1 (first peak on SFC, 11.6 mg, 28% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 8.45 (d, J= 6.0 Hz, 2H), 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), 4.10 - 4.00 (m, 2H), 3.90 - 3.80 (m, 2H), 3.54 (d, J= 11.6 Hz, 1H), 3.40 (d, J= 8.4 Hz, 1H), 3.31 - 3.29 (m, 1H), 3.24 (s, 3H), 3.20 - 3.14 (m, 2H), 3.13 - 3.06 (m, 1H), 3.05 - 2.94 (m, 2H), 2.87 - 2.79 (m, 1H), 2.46 - 2.41 (m, 1H), 2.30 - 2.25 (m, 1H), 2.07 - 2.03 (m, 1H), 1.95 - 1.89 (m, 1H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 478.1. And peak 2 (second peak on SFC, 10.6 mg, 26% yield) as a white solid, NMR (400MHz, DMSO-d6) 5 8.45 (d, J= 6.4 Hz, 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), 5.92 (q, J= 6.0 Hz, 1H), 4.84 (s, 2H), 4.11 - 4.00 (m, 2H), 3.90 - 3.79 (m, 2H), 3.54 (d, J= 11.6 Hz, 1H), 3.40 (d, J= 8.0 Hz, lH), 3.31 (s, 1H), 3.24 (s, 3H), 3.20 - 3.14 (m, 2H), 3.13 - 3.06 (m, 1H), 3.05 - 2.94 (m, 2H), 2.86 - 2.78 (m, 1H), 2.46 - 2.40 (m, 1H), 2.30 - 2.26 (m, 1H), 2.07 - 2.02 (m, 1H), 1.95 - 1.90 (m, 1H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 478.1.

[0412] Example 189 & 190, l-(7-(4-((R)-l-((l,4-dthydro-2H-pyrano[3,4-c]qutnoltn- 9-yl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)tetrahydro-lH, 6H-7, 8a-methanopyrrolo[2, 1- c][l,4]oxazin-4-yl)-N,N-(timethylmet>ianamine

[0413] Step 1 : l-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, l-c][l, 4]oxazin-4- yl)-N,N-dimethylmethanamine: A solution of [8-[4-[(1R)-l-(2,4-dihydix)-1H- pyrano[3,4-c]quinolin-9-yloxy)ethyl] triazol-l-yl]-3-oxa-6- azatricyclo[6.1.1.01,6]decan-5-yl]methyhnethanesulfonate (racemic mixture of Examples 187 / 188, step 1, 50.0 mg, 0.09 mmol, intermediate prepared from above step), K2CO3 (12.76 mg, 0.09 mmol) and Me2NH’HCl (104.04 mg, 0.92 mmol) in DMF (1 mL) was stirred at 80 °C for 8 hs. The TLC (10% methanol in dichloromethane, Rf = 0.3) showed the starting material was consumed and a new spot appeared. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (acetonitrile 28-58% 0.2% (NH3water+NH4HCO3) in water) to afford the racemic title compound 30 mg as a white solid. The racemate was separated by SFC ( Phenomenex-Cellulose-2 (250 mmx50 mm, 10 μm, 0.1% NH3H2OxEtOH, 25%, 200 ml / min) to afford peak 1 (2.68 mg, 0.0055 mmol, 5.4% yield) as a yellow solid,1H NMR (400 MHz, DMSO-d6) δ = 8.46 (d, J= 12.4 Hz, 2H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.8 Hz, 1H), 7.37-7.40 (m, 1H), 5.89-5.94 (m, 1H), 4.84 (s, 2H), 4.10 - 4.01 (m, 2H), 3.91 - 3.79 (m, 2H), 3.53 (d, J= 11.2 Hz, 1H), 3.40 - 3.42 (m, 1H), 3.16 - 3.06 (m, 2H), 3.03 - 2.93 (m, 2H), 2.81 - 2.68 (m, 1H), 2.48 - 2.44 (m, 1H), 2.27 (d, J= 5.6 Hz, 1H), 2.04 (d, J= 6.8 Hz, 1H), 1.89-1.93 (m, 1H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 419.2. And peak 2 (4 mg, 0.0082 mmol, 8% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.46 (d, J= 11.6 Hz, 2H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 7.37-7.40 (m, 1H), 5.89-5.94 (m, 1H), 4.84 (s, 2H), 4.11 - 4.00 (m, 2H), 3.85- 3.88 (m, 2H), 3.53 (d, J= 11.6 Hz, 1H), 3.40 - 3.42 (m, 1H), 3.16 - 3.05 (m, 2H), 3.04 - 2.94 (m, 2H), 2.81 - 2.72 (m, 1H), 2.48 - 2.44 (m, 1H), 2.27 (d, J= 5.6Hz, 1H), 2.04 (d, J= 6.4 Hz, 1H), 1.89-1.93 (m, 1H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 419.2.

[0414] Example 191 & 192, 7-(4-((R)-l-((l,4-dthydro-2H-pyrano[3,4-c]qutnoltn-9- yl)oxy)ethyl)-lH-l, 2, 3-triazol-l-yl)-4-((oxetan-3-yloxy)methyl) tetrahydro-lH, 6H- 7, 8a-methanopyrrolo[2, l-c][l,4]oxazine

[0415] 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)-4-((oxetan-3-yloxy)methyl)tetrahydro-lH, 6H-7,8a- methanopyrrolo[2,l-c] [l,4]oxazine: To a solution of oxetan-3-ol (90.0 mg, 1.21 mmol) in DMF (2 mL) was added NaH (75.0 mg, 1.87 mmol) at 0 °C. The mixture was stirred for 30 min, then [8-[4-[(1R)-l-(2,4-dihydro-1H-pyrano[3,4-c]quinolin-9- yloxy)ethyl]triazol- l-yl]-3-oxa-6-azatricyclo[6.1.1.0 l,6]decan-5-yl]methyl methanesulfonate (Racemic mixture of Examples 187 / 188 step 1, 70.0 mg, 0.13 mmol) was added. The mixture was stirred for 3 h at 80 °C, then quenched with water, and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (5% ethyl acetate in petroleum ether) to afford the racemic title compound 70 mg as a white solid. The racemate was separated by SFC: DAICEL CHIRALPAK IG column, 10 μm, 250x30 mm; 60% (v / v) EtOH (containing 0.1% of 25% aq. NH3) / CO2) to afford peak 1 (17.9 mg, 0.032 mmol, 17.7% yield) as a yellow solid.'HNMR. (400 MHz, DMSO-d6) δ = 8.45 (d, J= 3.6 Hz, 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), 5.90 - 5.95 (m 1H), 4.65 - 4.63 (m, 2H), 4.64 - 4.51 (m, 1H), 4.39 - 4.38 (m, 2H), 4.04-4.03 (m, 2H), 3.88 - 3.85 (m, 2H), 3.53 (d, J= 11.6 Hz, 1H),3.41 - 3.39 (m, 2H), 3.38 - 3.21 (m, 2H), 3.2 - 2.90 (m, 3H), 2.85 - 2.75 (m, 1H), 2.49 - 2.40 (m, 1H), 2.26 (d, J= 6.4 Hz, 1H), 2.05 (d, J= 6.4 Hz, 1H), 1.95 - 1.85 (m, 1H), 1.72 (d, J= 6.4, Hz, 3H). LCMS M7Z (M+H) 520.2. And peak 2 as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.45 (d, J= 3.6 Hz, 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), 5.90 - 5.95 (m, 1H), 4.65 - 4.63 (m, 2H), 4.64 - 4.51 (m, 1H), 4.39 - 4.38 (m, 2H), 4.04 - 4.03 (m, 2H), 3.88 - 3.85 (m, 2H), 3.53 (d, J= 11.6 Hz, 1H),3.41 - 3.39 (m, 2H), 3.38 - 3.21 (m, 2H), 3.2 - 2.90 (m, 3H), 2.85 - 2.75 (m, 1H), 2.49 - 2.40 (m, 1H), 2.26 (d, J= 6.4 Hz, 1H), 2.05 (d, J= 6.4 Hz, 1H), 1.95 - 1.85 (m, 1H), 1.72 (d, J= 6.4, Hz, 3H). LCMS M / Z (M+H) 520.2.

[0416] Examples 193 & 194: N-( 1-(1 -(3-(difluoromethyl)bicyclo[ 1.1.1 ]pentan-l-yl)- 1H-1, 2, 3-triazol-4-yl)ethyl)- 7, 8, 9, 10-tetrahydrophenanthridin-2-amine

[0417] Step 1 : 4-(l -chloroethyl)-l-(3-(difluoromethyl)bicyclo[l.1.1 ]pentan-l-yl)-lH- 1,2,3-triazole: To a solution of l-[6-(difluoromethyl)-4-[3-(difluoromethyl)pyrazol-l- yl]-2-pyridyl] ethanol (100 mg, 0.4 mmol) in DCM (4 mL) was added SOCh (0.32 mL, 4.4 mmol). The mixture was stirred at 50 °C for 3 h, then the reaction was concentrated to afford the crude title compound as a white solid, which was carried forward to the next step without further purification.

[0418] Step 2 : N-(l -(1 -(3-(difluoromethyl)bicyclo[l.1.1 ]pentan-l-yl)-lH-l,2, 3- triazol-4-yl)ethyl)-l,4-dihydro-2H-pyrano[3,4-c]quinolin-9-amine: A mixture of 2- chloro-5-[4-(l-chloroethyl)triazol-l-yl]pyridine (100 mg, 0.4 mmol), CS2CO3 (402 mg, 1.2 mmol), KI (34.1 mg, 0.2 mmol) and l,4-dihydro-2H-pyrano[3,4-c]quinolin-9- amine (133 mg, 0.6 mmol, H-6) in acetonitrile (4 mL) was stirred at 100 °C for 16 h, then concentrated under reduced pressure. The residue was purified by flash chromatography (20% EE [25% ethyl alcohol in ethyl acetate] in petroleum ether) to afford the title compound (80 mg, 47.3% yield) as a colorless oil. LCMS M / Z (M+H) 412.3. N-[l-[l-[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]triazol-4-yl]ethyl]-2,4- dihydro-1H-pyrano[3,4-c]quinolin-9-amine (80 mg, 0.2 mmol) was separated by chiral SFC (Phenomenex-Cellulose-2 (250 mm*50 mm, 10 μm, 0.1%NH3water EtOH, 25%~25%, 200 ml / min) to afford Peak 1 (29 mg) as a pink solid,1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.15 (s, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.18 (d, J= 2.0, 9.2 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 6.58 (d, J= 7.6 Hz, 1H), 6.49 6.11 (m, 1H), 4.90 4.82 (m, 1H), 4.77 (s, 2H), 4.05 3.98 (m, 2H), 3.00 2.89 (m, 1H), 2.85 2.74 (m, 1H), 2.41 (s, 6H), 1.56 (d, J= 6.8 Hz, 3H). LCMS M / Z (M+H) 412.2. And Peak 2 (26.5 mg) as a pink solid.1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.15 (s, 1H), 7.66 (d, J= 9.2 Hz, 1H), 7.18 (d, J= 2.0, 9.2 Hz, 1H), 6.72 (d, J= 2.0 Hz, 1H), 6.58 (d, J= 7.6 Hz, 1H), 6.49 6.11 (m, 1H), 4.904.82 (m, 1H), 4.77 (s, 2H), 4.05 3.98 (m, 2H), 3.00 2.89 (m, 1H), 2.85 2.74 (m, 1H), 2.41 (s, 6H), 1.56 (d, J= 6.8 Hz, 3H). LCMS M / Z (M+H) 412.2.

[0419] Example 195 & 196, 9-((R)-l-(l-(l-(fluoromethyl)-2- oxabicyclo[2.2.1 ]heptan-4-yl)-lH-l, 2, 3-triazol-4-yl)ethoxy)-l, 4-dihydro-2H- pyrano[3, 4-c] quinolone

[0420]

[0421] Step 1 : 9-((R)-l-(l -(1 -(fluoromethyl)-2-oxabicyclo[2.2.1 ]heptan-4-yl)-lH- 1, 2, 3-triazol-4-yl)ethoxy)-l, 4-dihydro-2H-pyrano[ 3, 4-c] quinolone : 9-(( 1R)- 1 -( 1 -( 1 - (fluoromethyl)-2-oxabicyclo[2.2. l]heptan-4-yl)- 1H- 1 ,2,3-triazol-4-yl)ethoxy)- 1 ,4- dihydro-2H-pyrano[3,4-c]quinoline (27 mg, 0.06 mmol, made in a similar fashion as Example 168 from Example 67) was separated by chiral SFC (Column: Chiral pak IG-3 100x4.6 mm I.D., 3um; Mobile phase: 40% of ethanol (0.05% DEA) in CO2 Flow rate: 2.8mL / min; Column temp. 35 °C) to give peak 1: (13.5 mg, 0.03 mmol, 49.5% yield) as a white solid, NMR (400 MHz, DMSO-d6) δ 8.47 (d, J= 18.0 Hz, 2H), 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), 4.77 - 4.57 (m, 2H), 4.08 (d, J= 6.4 Hz, 1H), 4.05 (t, J= 5.6 Hz, 2H), 3.97 (dd, J= 3.6, 6.4 Hz, 1H), 3.15 - 2.94 (m, 2H), 2.37 - 2.32 (m, 2H), 2.31 - 2.16 (m, 2H), 2.01 - 1.93 (m, 1H), 1.88 - 1.77 (m, 1H), 1.72 (d, J = 6.4 Hz, 3H). LCMS M / Z (M+H) 425.3. And peak 2: (13.4 mg, 0.03 mmol, 49% yield) as a white solid, NMR (400 MHz, DMSO-d6) δ 8.47 (d, J= 18.0 Hz, 2H), 7.88 (d, J= 9.2 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 7.39 (dd, J = 2.8, 9.2 Hz, 1H), 5.92 (q, J = 6.4 Hz, 1H), 4.84 (s, 2H), 4.76 - 4.52 (m, 2H), 4.09 (d, J= 6.4 Hz, 1H), 4.05 (t, J= 6.0 Hz, 2H), 3.97 (dd, J= 3.6, 6.4 Hz, 1H), 3.17 - 2.92 (m, 2H), 2.36 - 2.32 (m, 2H), 2.30 - 2.18 (m, 2H), 1.97 (m, J= 4.4, 12.4 Hz, 1H), 1.88 - 1.79 (m, 1H), 1.72 (d, J= 6.4 Hz, 3H). LCMS M / Z (M+H) 425.3.

[0422] Example 197 - antibacterial activity of tested compounds

[0423] Protocols for determining Minimum Inhibitory Concentrations (MICs) of test compounds against bacterial species.

[0424] This protocol describes steps for determining the minimal inhibitory concentration (MIC) for compounds of interest against strains of Mycobacterium tuberculosis (ATCC 25177, 27294), Mycobacterium avium (ATCC 700898), Mycobacterium bovis (ATCC 35737), Mycobacterium intracellulare (ATCC 35761), Mycobacterium abscessus (ATCC 23045), M. peregrinum (ATCC 700686), M. smegmatis (ATCC 19420), M. kansasii (ATCC 12478), M. marinum (ATCC 927), M. fortuitum (ATCC 35931).

[0425] Scope: This protocol describes the preparation of bacterial suspensions and execution of antibiotic susceptibility testing using the broth dilution method following the basic principles of the clinical laboratory and standards institute (CLSI). Modification of standard CLSI protocol included using the fluorometric detection microplate Alamar blue assay protocol for slow-growing Mycobacterium, and the use of defined broth media for several species (Table below).

[0426] Safety considerations: Bacterial strains described here require work within a BSL2 lab with a biosafety cabinet, lab coat, safety glasses, and disposable gloves. Virulent Mycobacterium tuberculosis H37Rv (ATCC 27294) requires work within the BSL3 lab with disposable bonnet, N95 mask, two sets of gloves, and disposable booties. M. tuberculosis H37Rv MICs were performed at the Trudeau Institute (Saranac Lake, New York).

[0427] Reagents: Mycobacterium, Acinetobacter, Staphylococcus, Enterococcus, and Streptococcus strains (ATCC & NGS); Antibiotics and compounds to be tested (10 mM stocks in DMSO); Middlebrook 7H9 broth base (Sigma M0178); Middlebrook 7H10 agar base (Sigma M0303); OADC growth supplement (Sigma M0678); ADC growth supplement (Sigma M0553); Cation-adjusted Mueller-Hinton II broth (BD BBL 212322); Granulated agar (BD DIFCO 214530); Laked horse blood (Thermo Fisher R54072); RPMI1640 (Gibco 31800); Sodium bicarbonate (ThermoFisher 25080094); M9 minimal salts (Gibco A1374401); Alamar blue (ThermoFisher DAL 1025); Tryptic soy agar with 5% sheep blood (BD BBL 221261); Casamino acids (casein hydrolysate)(Sigma 22090); Thiamine (Sigma T4625); Glucose (Sigma D9434); Tween80 (Sigma P1754); Rifampicin (Sigma R3501); Isoniazid (Sigma 13377); Levofloxacin (Sigma 28266); Amikacin (Sigma A1774).

[0428] Materials: Personal Protective Equiμment (PPE); 96-Well, round-bottom, microtiter plates (Coming #3788); Deep Well (10mL) 96 well plate blocks with sterile lids for serial dilution of compounds; 37 °C incubators, both shaking and stationary; Spectrophotometer Cuvettes; Spectrophotometer for OD600 readings; Vortex mixer, Plastic bags; Sterile Conical tubes 15 mL and 50 mL; Pipettes 1, 5, 10, 25 mL; Pipette tips P20, P200, and P1000; Single channel pipettors 20 pl, 200 pl, and 1000 pl.; Multichannel pipettors (8-channel and 12-channel) 200-1000 μL; Autoclave Bags and Tape; Sterile multichannel troughs for dispensing / diluting compounds, 7H9, and bacterial strains into 96 well plates with multichannel pipettors.

[0429] MIC overview

[0430] 1. MIC experiments were performed in a round-bottom polystyrene 96- well plates (coming # 3788).

[0431] 2. Depending on how many compounds or strains were tested, each 96- well plate contained either a single strain and multiple compounds, or multiple strains and a single compound.

[0432] 3. Dilutions were made in the assay media, and these dilutions are made across columns 1-11 (column 12 contained only media without compound).

[0433] 4. Plates were incubated without shaking at 37 °C, with plastic lids on but no adhesive seals. The incubator was humidified to prevent evaporation from the MIC plate. Simply placing a large dish with water at the bottom of the incubator was sufficient.

[0434] 5. Variables that were standardized are: (a) Plate type: polystyrene non- treated surface round-bottom; (b) Media: (i) Slow-growing Mycobacterium: 7H9 + 10%ADC + 1.6%glycerol; (ii) Fast-growing Mycobacterium: cation-adjusted Mueller-Hinton II broth; (iii) Acinetobacter baumannii: M9; (iv) Staphylococcus & Enterococcus: RPMI1640; (v) Streptococcus pneumoniae: cation-adjusted Mueller- Hinton II broth with 5% laked horse blood; (c) Inoculum: 5 x 105CFU / mL from a log phase broth culture, or a scrape from a growing streak on solid media. Saturated cultures are not acceptable by CLSI guidelines; (d) Incubation method: static, 37 °C, humidified, 5% CO2 is optional but recommended for RPMI-based MICs.

[0435] Detailed Protocol:

[0436] Serial dilutions of test compounds and controls were prepared in assay plates

[0437] 1. Aliquoted 1 mL of media into wells of a deep 96-well plate in columns

[0438] 2 to 12.

[0439] 2. Added 2 mL of compound dissolved in media at two-fold the highest starting concentration into column 1 of the deep-well plate.

[0440] 3. Using an electronic multichannel Pl 000 pipette, performed 2-fold dilutions from column 1 to column 11, mixing the contents of each well 3 times per dilution. It is not necessary to change tips during the dilution process. Any compound carryover is small relative to the 2-fold dilution scheme. 4. Disposed of the extra 1 mL left in column 11 such that all wells contain

[0441] 1 mL.

[0442] 5. Dispensed 100 pl of the dilutions from the deep-well plate to each row of a round-bottom 96-well plate; as described each row of a deep-well plate prepares enough media with compound for all eight rows of a round-bottom 96-well plate.

[0443] 6. Included antibiotic controls in each experiment to verify reproducibility across experiments. Rifampicin and isoniazid, levofloxacin, and amikacin were preferred controls for the species tested in this protocol.

[0444] Obtained growing cultures of bacteria and inoculated assay plates

[0445] 7. Obtained a log-phase culture or scrape several colonies from a plate that was streaked onto solid media; if scraping colonies from a plate, re-suspended colonies into 1.0 mL of media in a 1.5 mL Eppendorf tube.

[0446] 8. Determined the OD of the culture or bacterial suspension by adding 200 μL of either bacterial solution to 800 μL 7H9 broth in a cuvette, and measure vs. blank on a spectrophotometer.

[0447] 9. From the OD reading, determined the dilution required in broth to achieve a final MIC starting OD600= 0.01 (~1 x 106CFU / mL) in a sterile 50 mL conical tube. Note: Every 96 well plate requires 10 mL of bacterial inoculum. Each strain has a unique OD600run to CFU / ml correlation, but typically OD600nm = 1 = ~108- 109CFU / ml.

[0448] 10. Using an electronic multichannel P-1000, aspirated 600 μL of each suspension and dispensed 100 μL of the diluted cells into 100 μL of the MIC plate beginning at column 12 and moving through to column 7. Changed tips and repeated the inoculation by aspirating 600 μL of each suspension and dispensed 100 μL of the diluted cells into 100 μL of the MIC plate beginning at column 6 and moving through to column 1. In the last row of the plate, dispensed 100 μL of media without cells to serve as a sterility control for the plate. Since there is there no compound in column 12, that column will serve as a control for bacterial growth. Note: each well of the round-bottom plate contained 200 μL of volume.

[0449] 11. Placed the plates into a humidified incubator set to 37 °C for 1 day for

[0450] Gram-positive bacteria, 3-7 days for fast-growing Mycobacterium, and 11 days for slow-growing Mycobacterium. Confirmation of bacterial inoculum

[0451] 12. Confirmed the bacterial inoculum by removing 10 μL from the growth control well A12 and performed 10-fold serial dilutions and spot-plate 5 μL of each dilution onto appropriate solid media (see MIC specifications table).

[0452] 13. Placed the agar plates into a humidified incubator set to 37 °C for appropriate time (1, 3, or 14-21 days).

[0453] 14. After the incubation period, enumerated CPUs to determine the bacterial inoculum.

[0454] Measurement of bacterial growth (Visual MIC for fast-growing Mycobacterium, Acinetobacter, Staphylococcus, Enterococcus, and Streptococcus)

[0455] 15. After the appropriate incubation period (1-3 days), removed the MIC plates from the incubator.

[0456] 16. Visually examined tire wells and recorded the growth patterns on a paper template (no growth, reduced growth, strong growth). Also noted any suspicious growth that could indicate contamination. The MIC is the lowest drag concentration inhibiting growth.

[0457] 17. Transferred the data of the MIC results to an MS Excel template

[0458] 18. Adjusted the template as necessary to reflect any changes in the starting compound concentrations

[0459] 19. The final output of the MIC was a table with the MIC of each strain for each compound.

[0460] Fluorometric MIC for slow -growing Mycobacterium

[0461] The fluorometric MIC assay followed the microtiter Alamar blue assay protocol that measured reduction of resazurin dye that produces a colorimetric readout of bacterial growth & metabolism. This method of detection enabled visual MIC determination, but may also be quantified using a fluorimeter. The steps described below started after the 11 day incubation period of slow-growing Mycobacterium MIC assay plates.

[0462] 1. After the appropriate incubation period (11 days), removed assay plates from incubator.

[0463] 2. Made a mixture of Alamar blue solution + 20% Tween80, and add 20 μl per well of this solution to every well of the assay plates.

[0464] 3. Incubated assay plates at 37 °C for 24 h. 4. Fluorescence (FL) was measured with a fluorimeter using excitation at

[0465] 530 nm and emission at 590 nm. Percent inhibition is defined as: “1 - (test well FL - blank FL) / (mean FL of growth control wells- blank FU)x100%”. The lowest drag concentration generating an inhibition of >=90% is defined as the fluorometric MIC.

[0466] Minimum inhibitory concentration (MIC) specifications:

[0467] Supplements are given in % (vol. / vol.) CAMHIIB = cation-adjusted Mueller-

[0468] Hinton II broth (BBL; BD 212322); Laked horse blood (Thermo Fisher R54072;

[0469] RemelTM); 7H9 = Middlebrook 7H9 broth base (Sigma M0178); 7H10 =

[0470] Middlebrook 7H10 agar base (Sigma M0303); ADC = Middlebrook ADC supplement

[0471] (albumin, dextrose, catalase) (Sigma M0553); OADC = Middlebrook OADC supplement (oleic add, albumin, dextrose, catalase) (Sigma M0678); RPMI1640 = lx RPMI1640 (Gibco 31800) + 2g / L sodium bicarbonate (ThermoFisher 25080094), pH 7.0; M9 = lx M9 minimal salts (Gibco A1374401) + O.lmM CaC12 + O.lmM MgSO4 + 0.5% casamino acids (Sigma 22090) + 0.0001%Thiamine (Sigma T4625) + 0.2%glucose (Sigma D9434); Alamar blue (Thermo Fisher Scientific DAL 1025); Tryptic soy agar with 5% sheep blood (BD BBL 221261).

[0472] Summary of results evaluating test compounds:

[0473] B2: M.avium ATCC 700898 MIC [μM]

[0474] C3: M.tuberculosis ATCC 25177 MIC [μM]

[0475] D4: M.tuberculosis H37Rv ATCC27294 MIC [μM]

[0476] E5: M.abscessus ATCC23045 MIC [μM]

[0477] F6: M.bovis ATCC35737 MIC [μM]

[0478] G7: M.fortuitum ATCC35931 MIC [μM]

[0479] H8: M.kansasii ATCC12478 MIC [μM]

[0480] I9: M.marinum ATCC927 MIC [μM]

[0481] J10: M.peregrinum ATCC700686 MIC [μM]

[0482] K11: M.intracellulare ATCC35761 MIC [μM]

[0483] Example 198 - GuaB inhibitory activity of tested compounds

[0484] NADH-Glo protocol for determining GuaB (M.tb and WMPDH2) inhibitory concentrations (IC50) of selected test compounds. The NAD / NADH-Glo assay was performed according to the manufacturers instructions (Promega, G9061 / G9062). For M. tuberculosis GuaB and H. sapiens IMPDH2 (hIMPDH2) enzymes, GuaB inhibitors or DMSO were dispensed as serial dilutions on a Labcyte Echo555 acoustic dispenser (Beckman Coulter) to a 384-well solid white plate (Proxiplate, Revvity, 6008280) immediately prior to use. Total volume of DMSO was 100 nl per well, with a final DMSO concentration of 1%. Recombinant GuaB or IMPDH2 (0.25 and 5 nM for GuaBMtband hIMPDH2, respectively), substrate IMP (40 and 30 μM for GuaBMtband hIMPDH2, respectively) and NAD+ cofactor (700 and 40 μM for GuaBMtband hIMPDH2, respectively) were diluted in Assay Buffer, and subsequently added to the assay plate. GuaB- or hIMPDH2 -mediated NADH production is detected with the addition of NAD(P)H-Glo detection system (Promega, G9062). In the presence of NADH, a Reductase / Luciferase enzyme cascade produced luminescence proportional to the amount of NADH. Luminescence values were normalized to no inhibition and

[0485] 100% inhibition controls, and the normalized data were fit to a 4-parameter sigmoidal equation to determine IC50 values for each inhibitor. Summary of the test results is provided in the table below. Example 199 - In Vitro and In Vivo activity of GuaB inhibitors

[0486] As described herein, Mtb is a human pathogen that is very difficult to treat due to the complex pathology of disease and adaptation to survive in different host environments. Especially pernicious is an ability of Mtb to replicate within lung macrophages that are the frontline defense of the host innate immune system against bacteria. Mtb is able to persist for decades as a chronic latent infection encased within granulomas that are in a stalemate with the host. Over time, cellular granulomas harboring intracellular bacteria develop into necrotic caseating lesions that are hypoxic and contain large numbers of extracellular bacteria. The ability of Mtb to thrive in unique host environments (intracellular, extracellular, normoxic, hypoxic, lipid-rich caseum, blood), and in various states (replicating, dormant non-replicating) make it difficult to cure. Bacteria also exist in unique environments that present challenges to achieving pharmacodynamic concentration of antibiotics across different sites of infection. Taken together, the complex pathophysiology of disease helps explain why multiple antibiotics, each with a distinct mechanism of action, are required for cure. Treatment of drug-susceptible Mtb infection is a 6 month regimen that includes rifampicin, isoniazid, ethambutol, and pyrazinamide, whereas treatment for drug-resistant Mtb may be much longer and carry greater safety risks. Each antibiotic in a given regimen must contribute activity against Mtb in one or more of the many host environments.

[0487] The Mtb genome encodes three separate genes that have been denoted as GuaBl, GuaB2, and GuaB3, but only GuaB2 exhibits catalytic activity of a functional inosine 5’-monophosphate dehydrogenase (IMPDH), and only GuaB2 is essential for bacterial viability of Mtb both in vitro, and in vivo mouse lung infection. GuaBl is a guanosine 5 ’-monophosphate reductase, whereas GuaB3 has an unknown function and lacks catalytic activity in Mtb. See Figure 1A. GuaB2 catalyzes the rate limiting and first committed step in de novo guanine biosynthesis. The GuaB2 enzyme converts IMP to xanthosine-5 ’-monophosphate (XMP) through an oxidation reaction that requires the cofactor NAD. The consequence of inhibiting Mtb GuaB2 is that the pool of available guanosine 5'-triphosphate (GTP) plummets, resulting in prevention of RNA and DNA synthesis, translation elongation, and cell division. A reduction in available GTP may also lead to incorporation of alternative nucleobases like hypoxanthine into the replicating DNA, and corruption of the genome. Without being bound by any particular theory or speculation, it is believed that purine salvage by bacteria (including Mtb) is not sufficient to rescue inhibition of de novo purine biosynthesis, and GuaB2 function is essential in patients with active Mtb infection.

[0488] The present disclosure provides, e.g., extremely potent, orally bioavailable, small molecule inhibitors of inosine 5'- monophosphate dehydrogenase (GuaB) that catalyzes the rate limiting step in bacterial de novo guanine biosynthesis. For example, Ex. 17 cmpd (See Example 17 and Figure IB) had excellent biochemical potency (MtbGuaB IC50 = 0.94 nM), bacterial selectivity (hIMPDH2 IC50 > 50 μM), whole cell activity against virulent MtbH37Rv (minimal inhibitory concentration (MIC) = 0.058 μM), pharmacokinetic profile, low P-gp efflux, no observed drug-drug interaction risk, and a predicted human half-life amenable to oral QD dosing. See Fig. IB. The co-crystal structure of Ex. 17 cmpd bound to MtbGuaB2 (with the IMP substrate) is shown in Figure 1C. The binding site is located at an interface between two GuaB protomers of the tetramer, packing against the IMP enzymatic substrate and occupying a cavity that is otherwise observed to accommodate the NADH co- factor. In the Fig. 1C, the labels show the IMP molecule (lighter ball and stick at upper left), the Ex.17 inhibitor (“LIG” in darker ball and stick at center and right) with several of the salient protein pocket amino acids labeled via the 3-letter codes and residue position numbers, and shown in sticks on the cartoon thread of the protein backbone. The two different GuaB protomers of the cartoon are in different shading, and residues in the neighboring partner display the added tick (') mark on the residue numbering. Some water molecules that were sufficiently ordered to be included in the built structural model are shown as small grey detached spheres to mark then- dominant positions.

[0489] Overall, Ex. 17 cmpd exhibited bactericidal activity against Mtb in extracellular, intracellular, and hypoxic environments that are features of advanced disease pathology. The data provided herein shows, e.g., in vivo efficacy of GuaB2 inhibitors in three different mouse models of Mtb lung infection including the C57BL / 6 super acute, C57BL / 6 chronic, and Kramnik (C3HeB / FeJ). The Kramnik model recapitulates advanced pathophysiology and heterogeneous disease that includes caseous necrotic granulomas, intracellular and extracellular reservoirs of Mtb, and lethal progressive infection. In this model, treatment regimens that included GuaBi (e.g. , Ex. 17 cmpd) led to a more rapid sterilization of infection in some mice. Hence, the present disclosue provides, inter alia, GuaB inhibitor-containing therapeutic regimens that help reduce time to non-relapsing cure compared to the current standard of care therapies. For example, as the data provided in the present disclosure shows, combination of Ex. 17 cmpd with other antibiotics bedaquiline (B), pretomanid (P), and moxifloxacin (M), and B+P+ sutezolid (S), shortened time to sterilization in the mouse models.

[0490] Characterization ofMtb GuaB2 inhibitor activity;

[0491] Extracellular activity of GuaB inhibitor against MtbH37Rv was tested using a time-kill study of Ex. 17 cmpd at 0.1 x, 1x, 10x, and 100x the MIC, or isoniazid as a control, and viable bacteria were enumerated over a time course of 1, 2, 4, 7, 14, and 21 days of growth in shaking (200 rpm) aerobic culture at 37 °C (Fig. 2A & 2D). Ex. 17 cmpd showed clear bactericidal activity at 10x and 100x the MIC, bacteriostatic activity at 1 x MIC, and no effect at 0.1 x MIC (FIG. 2D). Culture sterilization was observed after treatment ofMtb with either 10x or 100x MIC Ex. 17 cmpd after 21 days. In contrast, treatment ofMtb with isoniazid led to a rapid loss of viable bacteria over the first 7 days, followed by a rapid rebound of bacterial growth by 14 days (Fig.2A). Similar dose proportional bactericidal activity was observed in M.tbH37Ra treated with Ex.17 at 0.09 μM, 0.19 μM, and 0.39 μM, whereas treatment with isoniazid at 0.78 μM, 1.56 μM, and 3.12 μM failed to achieve durable sterilization of the culture (Fig. 2B & Fig.2C). These results show selection for isoniazid (INH)- resistant mutants and outgrowth in the culture during the time-course of the experiment, because the frequency of spontaneous resistance ofMtb to isoniazid is very high (-3.5E-06), and occurs primarily through mutation of catalase G (katG) required to activate the INH prodrag. In contrast, spontaneous resistance to GuaBi is uncommon (-1E-09) in MtbH37Rv and may be linked to elevated expression of M. tbGuaB2. The minimum bactericidal concentration (MBC) of Ex.17 against M.tbH37Ra was determined to be four times the MIC at 0.39 μM after 21 days of treatment as determined by CFU plating (Fig. 6). The in vivo pharmacokinetic dosing of Ex.17 was designed to achieve complete 24 hour coverage of the MBC in vivo (Fig. 5).

[0492] Activity of GuaBi as a single agent against acute and chronic Mtb infection in vivo; The excellent in vitro activity and improved pharmacokinetic profile and ADME properties of Ex. 17 cmpd allowed to test whether pharmacologic inhibition of MtbGuaB2 was efficacious in vivo. Initially, efficacy of Ex. 17 cmpd was tested in a super-acute C57B1 / 6 mouse infection model. In this model, MtbH37Rv are delivered in an intratracheal high-dose infection (1E5 CFU / mouse), and treatments (vehicle control, isoniazid, Ex. 17 cmpd at 5, 10, 25, 50, and 100 mg / kg) were dosed orally beginning 1 day post infection (pre-treatment) for 8 consecutive days. Viable Mtb from mouse lung at the end of the study were enumerated by CFU plating, and showed a clear dose-proportional reduction in the viable Mtb compared to the vehicle control (FIG. 3A). A modest reduction of bacterial burden below the pre-treatment level was observed in this acute model characterized by rapidly replicating intracellular bacteria, whereas the positive control isoniazid significantly reduced bacterial load. As compared to the vehicle control, all treatments with Ex.17 yielded statistically significant reductions in lung CFU (P=0.0007***, Mann-Whitney test). Similar efficacy of another GuaBi (Ex.74) as a single agent in the acute lung infection model was observed with Ex.74 dosed at 5, 10, and 30 mg / kg b.i.d. (Fig.7).

[0493] Next, Ex. 17 cmpd was tested in a more challenging chronic infection model in C57BL / 6 mice. Chronic infection in C57B1 / 6 mice was established using a low- dose aerosol intranasal infection (100 CFU / mouse) of MtbH37Rv, followed by 21 days of bacterial outgrowth in the lungs that generated a stable burden of 5E6 CFU / mouse. Mice were then treated orally with either vehicle control, isoniazid (10 mg / kg QD), Ex. 17 cmpd (100 mg / kg BID), or Ex. 17 cmpd (200 mg / kg QD) for 28 or 56 days, after which the Mtb bacterial load in mice were enumerated. After 1 month of dosing, only the positive control isoniazid was effective at reducing bacterial load (PO.OOOl). After two months of treatment, the high dose Ex. 17 cmpd (200 mg / kg QD) group showed a significant reduction of Mtb bacterial load as a single agent (P=0.0035**, day 77), and the low dose Ex. 17 cmpd group was dose-proportionally less effective (Fig.3B). The positive control isoniazid significantly reduced bacterial load after two (PO.OOOl) months of treatment (Fig.3B).

[0494] Next, Ex. 17 cmpd was tested in combination with other antibiotics in a more aggressive lethal Mtb infection in the high-bar Kramnik model. In this model, Kramnik (C3Heb / FeJ) mice were infected with Mtb (Erdman strain) using low dose aerosol intranasal infection, and allowed to establish advanced pathology over 56 days at which time lungs harbored over 10E8 CFU / mouse and harbored heterogenous necrotic granulomas. Then, Ex. 17 cmpd as a single agent, or combinations of approved antibiotics with and without Ex. 17 cmpd, were dosed orally in different combinations for one and two months and bacterial burden in the lungs of mice were enumerated. The first set of treatment groups showed that Ex. 17 cmpd improved depth of kill and bacterial clearance when combined with bedaquiline (B), pretomanid (P), and moxifloxacin (M). All treatment combinations (B+P, B+P+M, and B+P+M+Ex.17) led to significant reduction in viable Mtb in the lungs of mice as compared to the pre-treatment, and each group exhibited significant reduction after two months of treatment compared to one month. Importantly, the 2 month dosing group that included Ex. 17 cmpd (B+P+M+Ex.17) led to a significant improvement over 2 month dosing without Ex. 17 cmpd, and Vi the mice had no viable Mtb detected in their lungs, showing that these mice were cured of Mtb infection after only 2 months of combination treatment (FIG. 4A). When Ex. 17 cmpd was dosed alone as a single agent there was a significant reduction in Mtb in the lungs of mice after one month when compared to pretreatment (Fig. 4C). All Erdman-infected Kramnik mice treated with Ex. 17 cmpd survived the 2 month study, whereas all untreated mice failed to survive progressive infection in this model.

[0495] Synergy with bedaquiline: bedaquiline’s mechanism of action as an ATP- synthase inhibitor causes a reduction of the intracellular energy required for active transport that may include the transport of exogenous guanine via the salvage pathway. Therefore, combination of GuaBi with bedaquiline may increase the bactericidal efficacy of GuaB inhibition in vivo, and help explain the observed combinatorial efficacy of B + P + M + Ex.17, and B + P + S + Ex.17.

[0496] OTHER EMBODIMENTS

[0497] It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

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;X is O orNRN;RNis 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 R4is independently selected from-CN, -OH, D, halo, C1-6alkyl, C 1-6 haloalkyl, C1-6alkoxy, and C1-6haloalkoxy; each R1is independently selected from C1-6 alkyl, C1-6 haloalkyl, Cy1, C(=O)Cy1, oxo, halo, -CN, -OR1a, -NR1aR2a, -C(O)NR1aR2a, -C(O)OR1a, -C(O)R1a, -NR1aC(O)R2a, -S(O)2R1a, and -NH-SCO^R1’, wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, -ORlb, - NRlbR2b, -C(O)NRlbR2b, and -NRlbC(O)R2b; each Cy1is 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 RCylis independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, -CN, - ORlb, -NRlbR2b, -C(O)NRlbR2b, and -NRlbC(O)R2b, wherein said C1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from - CN, -ORlb, -NRlbR2b, -C(O)NRlbR2b, -NRlbC(O)R2b,each R1a, R2*, Rlb, and R2bis 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 -NR1cR2c; each Cy2is 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 C1-6alkyl, C1-6haloalkyl, halo, -CN, - ORld, and -NR“R2d; and each Rlc, R2c, Rldand R2dis independently selected from H, C1-6 alkyl, and C1- 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 R4is 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 spirocychc 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 spirocychc 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 R1is independently selected from C1-6alkyl, C1-6haloalkyl, Cy1, C(=O)Cy1, oxo, halo, -CN, -OR1a, -C(O)NR1aR2a, - C(O)OR1a, -C(O)R1a, -S(O)2R1a, and -NH-S(O)2R1a, wherein said C1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from - CN, -ORlb, -NRlbR2b, and -NRlbC(O)R2b.

18. The compound of any one of claims 1-17, wherein each RCylis independently selected from C1-6alkyl, C 1-6 haloalkyl, halo, -CN, -ORlb, and -NRlbR2b, wherein said C1-6 alkyl is optionally substituted with -ORlb.

19. The compound of any one of claims 1-18, wherein each R1a, R2*, Rlb, and R2bis 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 -NR1cR2c.

20. The compound of any one of claims 1-19, wherein each Cy2is 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 R4is independently selected from D, C1-6alkyl, 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 R1is independently selected from C1-6alkyl, C1-6haloalkyl, Cy1, C(=O)Cy1, oxo, halo, -CN, -OR1a, -C(O)NR1aR2a, -C(O) OR1a, -C(O)R1a, - S(O)2R1a, and -NH-SCO^R1a, wherein said C1-6alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from -CN, -0Rlb, -NRlbR2b, and - NRlbC(0)R2b; each RCylis independently selected from C1-6 alkyl, C1-6haloalkyl, halo, -CN, - 0Rlb, and -NRlbR2b, wherein said C1-6 alkyl is optionally substituted with -0Rlb; each R1a, R2*, Rlb, and R2bis independently selected from H, C1-6alkyl, C1-6haloalkyl, and Cy2, wherein said C1-6alkyl is optionally substituted with 1 or 2 substituents independently selected from Cy2, -0Rlc, and -NR1cR2c; each Cy2is 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 C 1-6 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 scrojulaceum, 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, intra- abdominal 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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