WO2019244066A2

WO2019244066A2 - Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication

Info

Publication number: WO2019244066A2
Application number: PCT/IB2019/055154
Authority: WO
Inventors: Makonen Belema; Michael S. Bowsher; Eric P. Gillis; Christiana Iwuagwu; John F. Kadow; B. Narasimhulu Naidu; Kyle E. Parcella; Kevin M. Peese
Original assignee: VIIV Healthcare UK (No.5) Limited
Priority date: 2018-06-19
Filing date: 2019-06-19
Publication date: 2019-12-26
Also published as: WO2019244066A3

Abstract

Disclosed are compounds of Formula I, including pharmaceutically acceptable salts, pharmaceutical compositions comprising the compounds, methods for making the compounds and their use in inhibiting HIV integrase and treating those infected with HIV or AIDS.

Description

PYRIDIN-3-YL ACETIC ACID DERIVATIVES AS INHIBITORS OF HUMAN

IMMUNODEFICIENCY VIRUS REPLICATION

FIELD OF THE INVENTION

The invention relates to compounds, compositions, and methods for the treatment of human immunodeficiency virus (HIV) infection. More particularly, the invention provides novel inhibitors of HIV, pharmaceutical compositions containing such compounds, and methods for using these compounds in the treatment of HIV infection. The invention also relates to methods for making the compounds hereinafter described.

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) has been identified as the etiological agent responsible for acquired immune deficiency syndrome (AIDS), a fatal disease characterized by destruction of the immune system and the inability to fight off life threatening opportunistic infections. Recent statistics indicate that an estimated 35.3 million people worldwide are infected with the virus (UNDIDS: Report on the Global HIV/AIDS Epidemic, 2013). In addition to the large number of individuals already infected, the virus continues to spread. Estimates from 2013 point to close to 3.4 million new infections in that year alone. In the same year there were approximately 1.6 million deaths associated with HIV and AIDS.

Current therapy for HIV-infected individuals consists of a combination of approved anti-retroviral agents. Over two dozen drugs are currently approved for HIV infection, either as single agents or as fixed dose combinations or single tablet regimens, the latter two containing 2-4 approved agents. These agents belong to a number of different classes, targeting either a viral enzyme or the function of a viral protein during the virus replication cycle. Thus, agents are classified as either nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (Pis), integrase inhibitors (INIs), or entry inhibitors (one, maraviroc, targets the host CCR5 protein, while the other, enfiivirtide, is a peptide that targets the gp4l region of the viral gpl60 protein). In addition, a pharmacokinetic enhancer with no antiviral activity, i.e., cobicistat, available from Gilead Sciences, Inc. under the tradename TYBOST™ (cobicistat) tablets, has recently been approved for use in combinations with certain antiretroviral agents (ARVs) that may benefit from boosting. In the US, where combination therapy is widely available, the number of HIV-related deaths has dramatically declined (Palella, F. J.; Delany, K. M.; Moorman, A. C.; Loveless,

M. O.; Furher, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. N. Engl. J. Med. 1998, 338, 853-860).

Unfortunately, not all patients are responsive and a large number fail this therapy. In fact, initial studies suggest that approximately 30-50% of patients ultimately fail at least one drug in the suppressive combination. Treatment failure in most cases is caused by the emergence of viral resistance. Viral resistance in turn is caused by the replication rate of HIV- 1 during the course of infection combined with the relatively high viral mutation rate associated with the viral polymerase and the lack of adherence of HIV -infected individuals in taking their prescribed medications. Clearly, there is a need for new antiviral agents, preferably with activity against viruses already resistant to currently approved drugs. Other important factors include improved safety and a more convenient dosing regimen than many of the currently approved drugs.

Compounds which inhibit HIV replication have been disclosed. See, for Example, the following patent applications: W02007131350, W02009062285, W02009062288,

W02009062289, W02009062308, W02010130034, W02010130842, WO2011015641, WO2011076765, WO2012033735, WO2013123148, WO2013134113, WO2014164467, WO2014159959, WO2015126726, and WO2017025915.

Allosteric Integrase Inhibitors useful for treating HIV are disclosed, for example, in

PCT/1B2018/050022 and PCT/1B2018/050021.

What is now needed in the art are additional compounds which are novel and useful in the treatment of HIV. Additionally, these compounds may desireably provide advantages for pharmaceutical uses, for Example, with regard to one or more of their mechanisms of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability. Also needed are new formulations and methods of treatment which utilize these compounds.

BRIEF DESCRIPTION OF THE INVENTION

Briefly, in one aspect, the present invention discloses compounds of Formula I,

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is hydrogen, halogen, or Ci-3alkyl;

R² is phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrazinyl, or triazinyl, and is optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, Ci-ioalkyl, Ci-iohaloalkyl, or -N(R⁶)(R⁷);

R³ is Ci-ioalkyl;

R⁴ is H, halogen, or Ci-ioalkyl;

X is O, S, or N(R⁶);

Q is a bond, Ci-ioalkyl, C3-scycloalkyl, optionally substituted with 1 to 3 subtituents independently selected from OH, halogen, C3-scycloalkyl;

R⁵ is H, pyrrolidinyl, piperidinyl, imidazolyl, morpholinyl, oxetanyl, thiomorpholinyl, pyrazolyl, pyridinyl, 2-oxopyridinyl, indenyl, dihydropyridinyl, pyrimidinyl,

tetrahydrofuranyl, tetrahydropyranyl, phenylpyrazolyl, tetrahydronaphthalenyl, tetrahydro- lH-cyclopropa[3,4]cyclopenta[ l,2-c]pyrazolyl, tetrahydro- 1H- cyclopropa[3,4]cyclopenta[l,2-c]pyrazolyl, Ci-6alkyl-0-, C3-scycloalkyl, Ar-O-, Ar-Ci-4alkyl- 0-, C2-8alkenyl, C3-scycloalkenyl, Ci-3alkyl-(0-Ci-3alkyl)i-5-0-, C3-scycloalkyl-0-,

(R⁶)(R⁷)N-, or (R⁶)(R⁷)(R⁸)Si and R⁵ is optionally substituted with 1-4 substituents independently selected from HO, halogen, Ci-salkyl, Ci-salkylO-, and CO2H;

Ar is pyridinyl, pyrimidinyl, or phenyl;

each R⁶ and R⁷ is independently hydrogen, or Ci-6alkyl; and

R⁸ is Ci-6alkyl.

The invention also provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

The invention also provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of HIV infection The invention also provides the use of a compound of Formula (I) or a

pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of HIV infection.

The invention also provides a pharmaceutical composition comprising a compound or salt of the invention.

In addition, the invention provides a method of treating HIV infection comprising administering a compound or salt of the invention to a patient.

In addition, the invention provides a method for inhibiting HIV integrase.

Also provided in accordance with the invention are methods for making the compounds and salts of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Preferably R¹ is H.

Preferably R³ is Ci-6alkyl .

Preferably R⁴ is H or Ci-3alkkyl.

Preferably R² is pyridinyl, pyrimidinyl, or phenyl and is optionally substituted with 1 or 2 substituents independently selected from halogen and NH2.

Preferably X is O, S, or NH.

Preferably Q is a bond, Ci-6alkyl, or C4-6cycloalkyl and is optionally substituted with 1 to 3 substituents independently selected from OH, halogen, and C3-6cycloalkyl.

Preferably R⁵ is H, pyrrolidinyl, piperidinyl, imidazolyl, morpholinyl, oxetanyl, thiomorpholinyl, pyrazolyl, pyridinyl, 2-oxopyridinyl, indenyl, dihydropyridinyl, pyrimidinyl, tetrahydrofiiranyl, tetrahydropyranyl, phenylpyrazolyl, tetrahydronaphthalenyl, tetrahydro- lH-cyclopropa[3,4]cyclopenta[ 1 ,2-c]pyrazolyl, tetrahydro- 1H- cyclopropa[3,4]cyclopenta[l,2-c]pyrazolyl, Ci-4alkyl-0-, C3-7Cyeloalkyl, phenyl-O-, phenyl- Ci-3alkyl-0-, C2-4alkenyl, C5-6Cyeloalkenyl, Ci-3alkyl-(0-Ci-3alkyl)i-3-0-, C4-6Cyeloalkyl-0-, (R⁶)(R⁷)N, Si(CH3)3, and is optionally substituted with 1 to 3 substituents independently selected from OH, halogen, Ci-3alkyl, Ci-3alkylO-, and CO2H.

The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention exist in stereoisomeric forms. The invention includes all stereoisomeric forms of the compounds including enantiomers and

diastereromers. Methods of making and separating stereoisomers are known in the art. The invention includes all tautomeric forms of the compounds. The invention includes atropisomers and rotational isomers.

In one embodiment, a method for treating or preventing an HIV infection in a patient having or at risk of having the infection is provided, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.

In one embodiment, pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided.

In one embodiment, combination pharmaceutical agents comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents are provided.

In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. For Example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp4l inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gpl20 inhibitors, G6PD and NDDH-oxidase inhibitors, compounds that target the HIV capsid ("capsid inhibitors"; e.g., capsid polymerization inhibitors or capsid disrupting compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), and WO 2013/006792 (Pharma Resources), pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other antiretroviral agents used clinically. Typically, the daily dose will be about 1-100 milligram per kilogram (“mg/kg”) body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regimen, however, will be determined by a physician using sound medical judgment.

Methods of Synthesis

The compounds of this invention can be made by various methods known in the art including those of the following schemes and in the specific embodiments section. The structure numbering and variable numbering shown in the synthetic schemes are distinct from, and should not be confused with, the structure or variable numbering in the claims or the rest of the specification. The variables in the schemes are meant only to illustrate how to make some of the compounds of this invention. The disclosure is not limited to the foregoing illustrative Examples and the Examples should be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing Examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced.

Abbreviations used in the schemes and Examples generally follow conventions used in the art. Chemical abbreviations used in the specification and Examples are defined as follows:“KHMDS” for potasium bis(trimethylsilyl)amide; "DMF" for N,N- dimethylformamide;“HATU’for 0-(t-Azabenzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate,“MeOH” for methanol;“Ar” for aryl; "TFA" for trifluoroacetic acid, “DMSO” for dimethylsulfoxide;“h” for hours;“rt” for room temperature or retention time (context will dictate);“min” for minutes; "EtOAc" for ethyl acetate; "THF" for

tetrahydrofuran;“Et₂0” for diethyl ether; "DMAP" for 4-dimethylaminopyridine;“DCE” for l,2-dichloroethane;“ACN” for acetonitrile;“DME” for l,2-dimethoxyethane;“HOBf’ for 1- hydroxybenzotriazole hydrate; and“DIEA” for diisopropylethylamine.

Certain other abbreviations as used herein, are defined as follows:“1 x” for once,“2 x” for twice,“3 x” for thrice, "°C" for degrees Celsius,“eq” for equivalent or equivalents,“g” for gram or grams,“mg” for milligram or milligrams,“L” for liter or liters,“mL” for milliliter or milliliters,“pL” for microliter or microliters,“N” for normal,“M” for molar, “mmol” for millimole or millimoles,“atm” for atmosphere,“psi” for pounds per square inch, “cone.” for concentrate,“sat” or“sat’d“ for saturated,“MW” for molecular weight,“mp” for melting point,“ee” for enantiomeric excess,“MS” or“Mass Spec” for mass spectrometry, “ESI” for electrospray ionization mass spectroscopy,“HR” for high resolution,“HRMS” for high resolution mass spectrometry ,“LCMS” for liquid chromatography mass spectrometry, “HPLC” for high pressure liquid chromatography,“RP HPLC” for reverse phase HPLC, “TLC” or“tlc” for thin layer chromatography,“NMR” for nuclear magnetic resonance spectroscopy,“1H” for proton,“d” for delta,“s” for singlet,“d” for doublet,“t” for triplet,

“q” for quartet,“m” for multiplet,“br” for broad,“Hz” for hertz, and“R”,“S”,“E”, and“Z” are stereochemical designations familiar to one skilled in the art.

Some compounds can be synthesized from an appropriately substituted heterocycle I- 1 according to Scheme I. Compounds 1-1 and 1-6 are commercially available or synthesized by reactions well known in the art. Treatment of compound 1-1 with bromine provided the dibromo intermediates 1-2 which was converted to the chloropyridine 1-3 by reacting with POCb. Intermediate 1-3 conveniently transformed to ketoester 1-5 using conditions well- known to those skilled in the art, including reacting 1-3 with Grignard reagent in the presence of catalytic copper(I) bromide dimethylsulfide complex followed by alkyl 2-chloro-2- oxoacetate. Coupling of amines 1-5 with intermediate 1-6 in the presence of an organic base such as Hunig’s base provided intermediate 1 7 Chiral Lewis acid such as 1-8 mediated reduction of ketoester 1-7 with catecholborane furnished the chiral alcohol 1 9 Tertiary butylation of alcohol 1-9 by well-known conditions, including but not limited to tertiary -butyl acetate and perchloric acid, gave intermediate 1 10 Intermediates 1-10 are conveniently transformed to intermediates 1-11 using conditions well-known in the art, including but not limited to the Suzuki coupling between intermediates 1-10 and R⁶B(OR)2. The boronate or boronic acid coupling reagents, well-known in the art, are commercially available or are prepared by reactions well-known to those skilled in the art. Hydrolysis of intermediate 1-11 by using conditions well-known to those skilled in the art furnished the carboxylic acid 1 12 Scheme I

Intermediates 1-10 are conveniently transformed to intermediates II-2 using conditions well-known in the art, including but not limited to the Suzuki coupling between intermediates 1-10 and II- 1. Cleavage of protecting group in II-2 provided phenol II-3. Alkylation of the phenol II-3 was achieved by using conditions well known to those skilled in the art, including but not limited to Mitshunobu reaction to provide the intermediate II-4. Hydrolysis of intermediate II-4 by using conditions well-known in the literature furnished carboxylic acid II-5.

Scheme II

In yet another method, some compounds of this invention can be synthesized according to Scheme III. Pyridine III-l, can be produced using methods similar to those described in the previous schemes. This intermediate can be carried on to the final products by a variety of paths. In one path, the C6 hydroxymethyl is oxidized to furnish carboxylic acid III-6 which upon heating in the presence of acid provided C6-desmethyl analog III- 7. The intermediate III-7 can be further transformed to final compounds III-9 by methods well known in the art.

Scheme III

In yet another process, some compounds of this invention can be synthesized according to Scheme IV. The intermediate III-7 transformed to boronate derivative IV-1 by methods well know to those skilled in the art. The“Pd” mediated coupling of boronate IV-1 with appropriate aryl halides or aryl triflate followed by hydrolysis furnished the target compounds. Alternatively, the target compounds could be synthesized by coupling intermediate III-7 with aryl halides under Negishi coupling conditions followed by ester hydrolysis.

Scheme IV

The compounds described herein were purified by the methods well known to those skilled in art by normal phase column chromatography on silica gel column using appropriate solvent system described. Preparative HPLC or preparative LC/MS purifications mentioned in this experimentation section, unless otherwise specified, were carried out gradient elution either on Sunfire Prep C18 ODB column (5 pm; 19 or 30 X 100 mm) or Waters Xbridge C18 column (5 pM; 19 X 200 or 30 X 100 mm) or Water Atlantis (5 pm; 19 or 30 X 100 mm) or Waters XBridge C18, (2.1 mm x 50 mm, 1.7 pm) particles using the following mobile phases. Mobile phase A: 9: 1 FLO/acctonitrilc with 10 mM NThOAc and mobile phase B: A: 9: 1 acetonitrile/HiO with 10 mM NHiOAc; or mobile phase A: 9: 1 FLO/acctonitrilc with

0.1% TFA and mobile phase B: A: 9: 1 acctonitrilc/FLO with 0.1% TFA; or mobile phase A: water/MeOH (9: 1) with 20 mM NFhOAc and mobile phase B: 95:5 McOH/FFO with 20 mM NFBOAc or mobile phase A: water/MeOH (9: 1) with 0.1% TFA and mobile phase B: 95:5 MeOFl/FhO with 0.1% TFA or mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate.

Compounds purified by preparative HPLC were diluted in methanol (1.2 mL) or DMF and purified using a Shimadzu LC-8A or LC-10A automated preparative HPLC system. Intermediate 1

(S)-Isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2,6-dimethylpyridin-3-yl)-2-(tert- butoxy)acetate was prepared according to the procedure discribed in WO2015126726.

Intermediate 2

To a stirred solution of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2,6- dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (15 g, 32.0 mmol) in DCM (150 mL) was added 77% mCPBA (10.74 g, 47.9 mmol) at rt over 5 min. After 4 h, the reaction mixture was washed with 1M NaOH (2 X 100 mL), dried (MgSOr). filtered and concentrated to give (S)- 3 -bromo-5-( 1 -(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin- 1 -yl)-2,6- dimethylpyridine 1 -oxide (15.3 g, 31.5 mmol, 99 % yield) which was used in the next step without purification. LCMS (M+l) = 485.1 and 487.1.

Intermediate 3 and 4

To a stirred solution of (S)-3-bromo-5-(l-(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4- (4,4-dimethylpiperidin-l-yl)-2,6-dimethylpyridine l-oxide (5.24 g, 10.79 mmol) anhydrous DCM (50 ml) was added trifluoroacetic anhydride (3.05 ml, 21.59 mmol) at RT. After 3 h, sat NaHCCb (50 mL) was added and stirred vigorously for 10 mintues. The solution phases were separated and organic phase collected and volatiles evaporated. The residue was taken up in EtOAc and washed with 50 mL of 1 M HC1 followed by a wash with sat. sodium bicarbonate. The organic layer was then washed with brine, dried over MgSCft, filtered and volatiles evaporated to afford the crude as an orange oil. The crude product was purifed via silica gel (120 g column, 5-20% EtOAc:Hex) to give two products:

(S)-Isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-6-(hydroxymethyl)-2- methylpyridin-3-yl)-2-(tert-butoxy)acetate (intermediate 3): Clear oil that later crystallized, 4.0 g (76%). Ή NMR (500MHz, CDCb) d 6.25 (br. s., 1H), 5.06 (spt, 7=6.3 Hz, 1H), 4.75- 4.79 (m, 1H), 4.74 - 4.62 (m, 2H), 4.02-4.12 (br. s., 1H), 3.54 - 3.46 (m, 1H), 2.93 (d, .7=11.5 Hz, 1H), 2.70 - 2.63 (m, 1H), 2.61 (s, 3H), 1.65 - 1.56 (m, 2H), 1.50 - 1.43 (m, 1H), 1.35-1.40 (m, 1H), 1.23 (d, 7=6.2 Hz, 3H), (1.22 (s, 9H), 1.16 (d, 7=6.3 Hz, 3H), 1.09 (s, 3H), 1.05 (s, 3H). LCMS (M+H) = 485.35 and 487.2.

(S)-Isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2-(hydroxymethyl)-6- methylpyridin-3-yl)-2-(tert-butoxy)acetate (intermediate 4): Clear oil, 0.430 g (8.2%). Ή NMR (500MHz, CDCb) d 6.21 (br. s., 1H), 5.03 (spt, 7=6.3 Hz, 1H), 4.95 (d, 7=15.1 Hz,

1H), 4.64 (dd, 7=15.3, 5.0 Hz, 1H), 4.50 (br. s., 1H), 4.05 - 3.97 (m, 1H), 3.57 (td, .7=12.1, 2.5 Hz, 1H), 2.84 (d, .7=11.8 Hz, 1H), 2.69 (s, 3H), 2.62 (d, 7=11.8 Hz, 1H), 1.66 - 1.55 (m, 2H), 1.47 (dd, 7=13.2, 2.0 Hz, 1H), 1.40 - 1.34 (m, 1H), 1.23 (d, 7=6.3 Hz, 3H), 1.22 (s, 9H), 1.16 (d, 7=6.1 Hz, 3H), 1.09 (s, 3H), 1.05 (s, 3H). LCMS (M+H) = 485.2 and 487.05.

Intermediate 5

To a stirred solution of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-6- (hydroxymethyl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate (15.4 g, 31.7 mmol) in DCM (288 ml) and acetonitrile (28.8 ml) was added Dess-Martin Periodinane (16.15 g, 38.1 mmol) at once at rt. After 5 h, the reaction mixture was diluted with ether (250 mL), washed with 1M NaOH (2 x 100 ml), brine (200 mL), dried (MgSOr). filtered and concentrated to afford (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-6-formyl-2-methylpyridin-3-yl)-2- (tert-butoxy)acetate (15.3 g, 31.6 mmol, 99% yield) as yellow solid. 'H NMR (500 MHz, CDCb) d 10.30 (s, 1H), 6.27 (br s, 1H), 5.13 - 5.03 (m, 1H), 4.12 (br s, 1H), 3.61 - 3.52 (m, 1H), 2.96 (br d, 7=9.8 Hz, 1H), 2.76 - 2.70 (m, 1H), 2.66 (s, 3H), 1.66 - 1.54 (m, 4H), 1.23 - 1.21 (m, 12H), 1.17 (d, 7=6.1 Hz, 3H), 1.11 (s, 3H), 1.06 (s, 3H). LCMS (M+l) = 483.1 and 485.1. Intermediate 6

To a solution of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-6-formyl-2- methylpyridin-3-yl)-2-(tert-butoxy)acetate (15.3 g, 31.6 mmol) in acetonitrile (127 ml) and water (31.6 ml) was added oxone (14.79 g, 24.05 mmol) and the mixture was stirred at RT for 1 hr. The reaction was diluted with water and EtOAc. The organic layer was washed with water (2X) and brine, dried (MgSCri). filtered and concentrated to afford the product (S)-3- bromo-5 -( 1 -(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin- 1 -yl)-6- methylpicolinic acid (15.6 g, 31.2 mmol, 99 % yield) as a yellow crispy foam. Ή NMR (500 MHz, CDCb) d 6.33 - 6.17 (m, 1H), 5.09 (dt, J=l2.5, 6.3 Hz, 1H), 4.26 - 4.14 (m, 1H), 3.67 - 3.49 (m, 1H), 3.03 - 2.83 (m, 1H), 2.77 - 2.65 (m, 1H), 2.62 (s, 3H), 1.64 - 1.35 (m, 4H), 1.24 (d, .7=6.3 Hz, 3H), 1.22 (s, 9H), 1.18 (d, J=6. l Hz, 3H), 1.10 - 1.06 (m, 6H). LCMS (M+l) = 499.1 and 501.1.

Intermediate 7

Water (2.81 ml, 156 mmol) followed by acetic acid (4.65 ml, 81 mmol) was added to a stirring solution of (S)-3-bromo-5-(l-(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4- dimethylpiperidin-l-yl)-6-methylpicolinic acid (15.6 g, 31.2 mmol) in toluene (156 ml) at rt. The reaction was stirred at 90 °C for 7 hrs. The reaction volatiles were evaporated and the crude material purified via silica gel (330g column, 5-20% EtOAc:Hex) to afford the product (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-(tert- butoxy)acetate (12.8 g, 28.1 mmol, 90 % yield) as a clear oil that later crystallized. Ή NMR (500 MHz, CDCb) 5 8.46 (s, 1H), 6.35 - 6.17 (m, 1H), 5.06 (dt, J=l2.5, 6.2 Hz, 1H), 4.10 - 3.96 (m, 1H), 3.45 (br s, 1H), 2.92 (br s, 1H), 2.72 - 2.62 (m, 1H), 2.57 (s, 3H), 1.58 - 1.28 (m, 4H), 1.22 (s, 12H), 1.15 (d, J=6.3 Hz, 3H), 1.07 (br s, 6H). LCMS (M+l) = 455.3 and 457.3. Intermediate 8

To a solution of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2- methylpyridin-3-yl)-2-(tert-butoxy)acetate (2 g, 4.39 mmol) in EtOH (13.17 ml) and water (1.464 ml) was added lithium hydroxide monohydrate (0.590 g, 14.05 mmol) and heated at 75 °C for 18 hrs. The reaction was cooled to RT, netralized and made slightly acidic with the addition of HC1 (15.37 ml, 15.37 mmol). The mixture was extracted with EtOAc. The organic layer was washed with brine, collected, dried over MgSOi. filtered and the volatiles evaporated to afford the product (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2- methylpyridin-3-yl)-2-(tert-butoxy)acetic acid (1.82 g, 4.40 mmol, 100 % yield) as a white solid. LCMS (M+l) = 413.1 and 415.0.

Intermediate 9

To a stirred suspension of (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2- methylpyridin-3-yl)-2-(tert-butoxy)acetic acid (1.83 g, 4.43 mmol) and cesium carbonate (1.442 g, 4.43 mmol) in anhydrous acetonitrile (14.76 ml) and DMF (7.38 ml) was added benzy bromide (0.553 ml, 4.65 mmol). The reaction was stirred for 1 hr. After 1 hr, the LCMS indicated the reaction was complete. The reaction was diluted with water and EtOAc. The organic layer was washed with water (2X), followed by brine, collected, dried over MgS0₄, filtered and the volatiles evaporated to afford the crude product. The crude product was purified on silica gel (40 g column, 5-20% EtOAc :Hex) to afford the product (S)-benzyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate (2.19 g, 4.35 mmol, 98 % yield) as a clear oil that solidified upon sitting. ¾ NMR (500 MHz, CDCb) d 8.46 (s, 1H), 7.38 - 7.31 (m, 3H), 7.27 - 7.22 (m, 2H), 6.25 (br s, 1H), 5.24 - 5.04 (m, 2H), 4.07 - 3.90 (m, 1H), 3.34 (br d, J=2.7 Hz, 1H), 2.76 (br d, J=2.8 Hz, 1H), 2.69 - 2.57 (m, 1H), 2.52 (s, 3H), 1.60 - 1.39 (m, 4H), 1.22 (s, 9H), 1.02 (br s, 6H). LCMS (M+l) = 503.2 and 505.2.

Intermediate 10

To a 1L round bottom flask equipped with a large stir bar was added 6-bromopyridin- 3-ol (24.69 g, 142 mmol), benzyl alcohol (15.42 mL, 149 mmol), triphenylphosphine (39.1 g, 149 mmol) and THF (600 mL). The flask was placed in a r.t. water bath. To the stirred solution was added in six portions DIAD (29.0 mL, 149 mmol). The internal temperature increased from 20 deg to 35 deg C, and was 35 deg C at the completion of the addition. After stirring for 18 h the reaction solution was concentrated in vacuo to afford a liquid residue.

The material was diluted with hexane:Et20 (1 : 1, 850 mL). A precipitate was immediately formed. The mixture was stirred for 5 minutes, then the liquid was decanted and reserved.

The solids were treated with Et20 (200 mL), and the mixture was stirred for 5 minutes. The solution was diluted with hexanes (200 mL), and the mixture was then stirred for 5 minutes. The mixture and the reserved solution were combined and filtered through a fine-fritted vacuum funnel. The filtrate was concentrated in vacuo. The resulting residue was diluted with a small amount of acetone and then concentrated onto celite in vacuo. The resulting powder was subjected to S1O2 chromatography (330g S1O2 column, hexanes:EtOAc 100:0 -> 80:20) to afford 5-(benzyloxy)-2-bromopyridine as a colorless, crystalline solid (24.84 g, 66%). Ή NMR (400 MHz, CHLOROFORM-d) d 8.16 (d, J= 3.2 Hz, 1H), 7.45 - 7.36 (m, 6H), 7.18 (dd, J= 8.6, 3.2 Hz, 1H), 5.12 (s, 2H).

Alternative procedure : To a stirred solution of 6-bromopyridin-3-ol (100 g, 575 mmol), K2CO3 (119 g, 862 mmol) in acetone (1 L) was added benzyl bromide (0.075 L, 632 mmol). The mxiture was stirred for 3 h at 80 °C. LCMS showed completion of reaction.

Then, the mixture was cooled to 20 °C and poured into water (250 mL). The precipitate was filtered, taken up in in DCM and washed with sat. NaHCCh (50 mL), water (50 mL), brine (50 mL) and concentrated to afford 5-(benzyloxy)-2-bromopyridine (120 g, 454 mmol, 79 % yield) as a off-white solid. Intermediate 11

To a dry 250 mL round bottom flask equipped with a large stir bar and charged with 5-(benzyloxy)-2-bromopyridine (21.8527 g, 83 mmol) was added THF (150 ml) and triisopropyl borate (19.40 ml, 84 mmol). The flask was sealed with a rubber septum, then the solution was sparged with N2 for 5 min. The flask was cooled in a -78 °C bath. To the solution was added dropwise over 30 min n-butyllithium in hexanes (33.4 ml, 84 mmol). The cold bath was removed and the solution was allowed to slowly warm to r.t. with stirring. After 2 h the solution was transferred to a pressure-equalizing addition funnel. The addition funnel was fitted onto the center neck of a 3-neck 250 mL flask equipped with a large stir bar was charged with N-methyliminodiacetic acid (24.35 g, 165 mmol) and DMSO (150 ml). A side neck was fitted with a thermocouple. The other side neck was fitted with a water-cooled short-path distillation apparatus collecting into a 250 mL round bottom flask and vented to a bubbler. The addition funnel was capped with a gas adapter connected to a low-volume stream of N2 gas. The 3-neck flask was heated with an oil bath (150 °C). Once the DMSO solution had reached 115-120 °C the boronate solution was added dropwise at a rate necessary to maintain an internal temp of 115-120 °C. The blue boronate solution immediately becomes a red/amber color upon contacting the DMSO solution. The reaction mixture is a deep amber solution. Upon completion of the addition the receiver flask containing THF was exchanged for an empty 200 mL round bottom flask. The bubbler line connected to the vacuum arm of the distillation apparatus was exchanged for a controlled vacuum source. The N2 source feeding into the addition funnel was closed. The system was placed under vacuum, slowly ramping to 30 Torr. The receiver flask was emptied, then the vacuum was slowly ramped to 2 Torr. The bath temperature was set to 125 °C and the pressure was maintained at 2 Torr. When the majority of DMSO had been removed the flask was opened to ambient atmosphere. To the flask was added MeCN (100 mL). Heating was maintained until the solvent had reached reflux, then heating was stopped. To the hot mixture was added celite. The mixture was concentrated in vacuo to afford a clumpy solid which was subjected to S1O2 chromatography (EtOAc:MeCN 100:0 -> 0: 100) to afford the desired product as a colorless solid. This material was dissolved/suspended in MeCN (100 mL), then was diluted with Et20 (400 mL). The crystalline solid was collected via vacuum filtration. The solids were dried under high vacuum to afford (5-(benzyloxy)pyridin-2-yl)boronic acid MIDA ester as a colorless, fine crystalline solid (5.81 g, 21%). Ή NMR (500 MHz,

ACETONITRILE-di) d 8.50 - 8.42 (m, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.44 - 7.38 (m, 2H), 7.38 - 7.33 (m, 1H), 7.31 (dd, J=8.4, 2.9 Hz, 1H), 5.16 (s, 2H), 4.10 - 4.04 (m, 2H), 3.98 - 3.92 (m, 2H), 2.54 (s, 3H).

Simplified procedure : To a solution of 5-(benzyloxy)-2-bromopyridine (98 g, 371 mmol) and triisopropyl borate (77 g, 408 mmol) in THF (800mL) was added n-butyllithium (193 mL, 482 mmol) at -78 °C and stirred for 20 min at -78°C. Then, the reaction mixture was stirred at rt for 3 h. The reaction mixture was added to a solution of 2, 2' -(2,2'- (methylazanediyl)diacetic acid (109 g, 742 mmol) in DMSO (800 mL) at 115-120 °C (internal temperature). Then, the THF and DMSO was distilled off over 2 h to remove as much solvent as possible. The reaction flask was cooled, diluted with 3000 mL of ethyl acetate and washed with water (2000 mL x2), dried and concentrated. The residue was purifeid by silica gel chromatography to give 2-(5-(benzyloxy)pyridin-2-yl)-6-methyl- l,3,6,2-dioxazaborocane-4,8-dione (41 g, 120 mmol, 32.2 % yield) as pale solid.

Intermediate 12

To a dry 10 mL Schlenk flask equipped with a stir bar and placed under N2 was added (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-(tert- butoxy)acetate (0.114 g, 0.250 mmol), then placed under vacuum and back filled with N2 (3 times) with finally being left under positive pressure of N2. THF (3 mL) was then added followed by pyridine (0.040 mL, 0.501 mmol). The solution was cooled to -78 °C. To the solution was added butyllithium (0.100 mL, 0.250 mmol) dropwise upon which the solution turned a light brown color. The solution was stirred for 5 minutes. To the solution was added trimethyl borate (0.112 mL, 1.001 mmol). Stirring was maintained as the -78 °C for 5 minutes and then the bath was removed and slowly warmed to RT and stirred for 18 hr. The reaction mixture was transfered to a 125 mL separatory funnel and was diluted with water (25 mL), then extracted with EtOAc (50 mL). The organic phase was washed with brine, dried over MgSCri, filtered and volatiles evaporated to afford the product (S)-(5-(l-(tert-butoxy)-2- isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-l-yl)-6-methylpyridin-3-yl)boronic acid which was used in the subsequent step without purification. LCMS (M+l) = 421.1.

Intermediate 13

A mixture of isopropyl (.V)-2-(5-bromo-4-(4 4-dimcthylpipcridin- 1 -yl)-2- methylpyridin-3-yl)-2-(/ -biitoxy)acetate (0.15 g, 0.329 mmol, 1 equiv), (6-fluoropyridin-3- yl)boronic acid (0.070 g, 0.494 mmol, 1.5 equiv), SPhos (0.027 g, 0.066 mmol, 0.2 equiv), palladium(II) acetate (7.4 mg, 0.033 mmol, 0.1 equiv) and 2 M K3PO4 (0.494 ml, 0.988 mmol, 3 equiv) in dioxane (3 mL) was heated at 90 °C for 4 h. Upon cooling to ambient temperature, the reaction mixture was filtered through celite/Na2S04, diluted with ethyl acetate, concentrated in vacuo, and purified by silica gel flash chromatography (0-50% ethyl acetate in hexanes) to afford Isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-

6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (84 mg, 54%) as a colorless viscous oil. LCMS (M+l): 472.20.

Intermediate 14

To a 100 mL Schlenk flask equipped with a stir bar was added dioxane (40 ml) and water (10.00 ml). The flask was sealed wtih a septum, then the solution was degassed viaN2 sparging for 10 min. To the solution was added (5,6-difluoropyridin-3-yl)boronic acid (2.00 g, 12.6 mmol), isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3- yl)-2-(tert-butoxy)acetate (3.82 g, 8.39 mmol), tribasic potassium phosphate (8.02 g, 37.8 mmol), and SPhos-Pd-G3 (0.327 g, 0.420 mmol). The flask was placed in a 60 °C heating bath with stirring for 4 h. The reaction mixture was cooled to r.t, then was transferred to a 500 mL separatory funnel and was diluted with water (200 mL), then was extracted with Et20 (200 mL). The organic phase was dried over MgSCri; filtered; then concentrated in vacuo.

The residue was dissolved in a min of acetone, then was concentrated onto celite in vacuo. The resulting powder was subjected to S1O2 chromatography (80g S1O2 column, hexanes:EtOAc 100:0-^60:40) to afford isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-5',6'-difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate as a solid yellow foam (3.5305 g, 86 %). ¾ NMR (500 MHz, CHLOROFORM-d) d 8.14 (s, 1H), 7.95 (t, .7=1.8 Hz, 1H), 7.54 (t, 7=8.4 Hz, 1H), 5.91 (br s, 1H), 5.12 (spt, 7=6.3 Hz, 1H), 3.43 (br s, 1H), 2.96 (br s, 1H), 2.64 (s, 3H), 2.43 - 2.22 (m, 2H), 1.26 (d, 7=6.3 Hz, 3H), 1.24 (d, 7=6.1 Hz, 3H), 1.18 (s, 9H), 1.50 - 1.12 (m, 4H), 0.94 (br s, 3H), 0.85 (br s, 3H).

Intermediate 15

To a 100 mL Schlenk flask equipped with a stir bar was added 2-(5- (benzyloxy)pyridin-2-yl)-6-methyl-l,3,6,2-dioxazaborocane-4,8-dione (3.50 g, 10.29 mmol), isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-(tert- butoxy)acetate (3.12 g, 6.86 mmol), palladium tetrakis (1.585 g, 1.372 mmol),

diacetoxycopper (0.623 g, 3.43 mmol) and anhydrous tribasic potassium phosphate, finely ground (7.28 g, 34.3 mmol). The flask was sealed with a rubber septum, then placed under N2 atm. To the flask was added a degassed (N2 sparging for 5 min) solution of diethanolamine (0.721 g, 6.86 mmol) in DMF (60 mF). The flask was placed in a 100 °C oil bath with stirring for 18 h. The reaction mixture was transfered to a 1F separatory funnel. The mixture was diluted with waterbrine and extracted with EtOAc. However, an emulsion made this process extremely problematic. The volumes of each solvent were increased incrementally to finally achieve water (175 mF) : brine (175 mF) : EtOAc (250 mF). However, the emulsion persisted. The entire mixture was filtered through celite. The filtrate was transfered back to the separatory funnel and the mixture was shaken, upon which the emulsion re-formed and persisted. The mixture was filtered through celite and the mixture was immediately partitioned in the separatory funnel without further mixing. The aq. phase was mixed with EtOAc (250 mF). The emulsion was filtered through the same celite pad as before, and the mixture was partitioned in the separatory funnel without further mixing. The combined organics were washed with waterbrine (175 mF: l75 mF) (no problematic emulsion), then brine (150 mF) (no problematic emulsion). The combined organics were dried over MgS04; were filtered; then were concentrated in vauco. The resutling amber solution/solid residue was dissolved in a min. of acetone, then was concentrated onto celite in vacuo. The resulting powder was subjected to S1O2 chromatography (220g S1O2 column, hexanes:EtOAc 100:0 -> 40:60) to afford isopropyl (S)-2-(5-(benzyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl- [2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate as a colorless solid (1.88 g, 49 %). Ή NMR (500 MHz, CHLOROFORM-d) d 8.51 (d, 7=2.4 Hz, 1H), 8.28 (s, 1H), 7.51 - 7.36 (m, 7H), 7.32 (d, .7=8.5 Hz, 1H), 6.06 (br s, 1H), 5.24 - 5.18 (m, 2H), 5.16 - 5.09 (m, 1H), 3.31 (br d, 7=11.3 Hz, 2H), 2.64 (s, 3H), 2.34 - 2.07 (m, 1H), 1.48 - 1.27 (m, 4H), 1.25 (d, 7=6.3 Hz, 3H), 1.22 (d, .7=6.1 Hz, 3H), 1.19 (s, 9H), 0.98 - 0.89 (m, 3H), 0.82 (br s, 3H).

Intermediate 16

To a 250 mL round bottom flask equipped with a stir bar and charged with isopropyl (S)-2-(5-(benzyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert- butoxy)acetate (1.8796 g, 3.36 mmol) was added palladium on carbon (Degussa type E101 NE/W, 10% dry basis Pd, 50% wt water, 0.179 g, 0.168 mmol) and MeOH (20 mL). The flask was sealed with a rubber septum, then was sparged with N2 for 5 min. The mixture was then sparged with H2 for 3 minutes, then was placed under a static balloon-pressure H2 atm. with stirring for 1 h. The mixture was sparged with N2 for 10 minutes, then the reaction mixture was directly concentrated onto celite in vacuo. The resulting powder was subjected to S1O2 chromatography (DCM:EtOH 100:0-^97.5:2.5-^90: 10) to a colorless solid. The material was co-evaporated twice with PhMe to afford isopropyl (S)-2-(tert-butoxy)-2-(4'- (4,4-dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate as a colorless solid foam (1.41 g, 80 % yield). Ή NMR (500 MHz, CHLOROFORM-d) d 8.40 (d, 7=2.7 Hz, 1H), 8.22 (s, 1H), 7.31 - 7.26 (m, 1H), 7.22 - 7.16 (m, 1H), 6.03 (br s, 1H), 5.14 (quin, 7=6.3 Hz, 1H), 3.51 - 3.09 (m, 2H), 2.71 (s, 3H), 2.44 - 2.18 (m, 2H), 1.77 - 1.42 (m, 2H),

1.41 - 1.31 (m, 4H), 1.26 (d, 7=6.1 Hz, 3H), 1.23 (d, 7=6.3 Hz, 3H), 1.20 (s, 9H), 0.90 (br s, 6H).

Intermediate 17

To a mixture of (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5- hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (500 mg, 1.065 mmol) and triethylamine (215 mg, 2.129 mmol) in dichloromethane (8 mL) was added l,l,l-trifluoro-N-(pyridin-2- yl)-N-((trifluoromethyl)-sulfonyl)methanesulfonamide (496 mg, 1.384 mmol) at 0 °C and stirred at rt for 2 h. Then, the reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL x2). The combined organic layers were dried over Na2S04, fdtered and concentrated. The residue was purified by Prep-TLC (Pet. etherEtOAc = 5: 1) to afford (S)- isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5- (((trifluoromethyl)sulfonyl)-oxy)-[2,3'-bipyridin]-5'-yl)acetate (580 mg, 0.954 mmol, 90 % yield as syrup. LCMS [M + H] = 602.

Intermediate 18

To a 40 mL vial equipped with a stir was added tribasic potassium phosphate

(anhydrous, 4.19 g, 19.76 mmol), (4-(benzyloxy)phenyl)boronic acid (0.751 g, 3.29 mmol), isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-(tert- butoxy)acetate (1.0 g, 2.196 mmol), and SPhos-Pd-G3 (0.086 g, 0.110 mmol). The vial was sealed with a screw cap rubber septum and then placed under N2 atm. To the vial was added a degassed (N2 bubbling for 5 minutes) solution of dioxane:water (15 mL : 5 mL) water (5 mL). The vial was placed in a 65 °C heating block with stirring for 2 h. The reaction mixture was transfered to 500 mL separatory funnel and was diluted with Et20 (250 mL). The mixture was washed with water (250 mL), then dried over MgSOr: filtered; then concentrated in vacuo. The resulting residue was dissovled in a min. of acetone, then was concentrated onto celite in vacuo. The resulting powder was subjected to S1O2 purification

(hexanes:EtOAc 90: 10-^40:60) to afford a colorless solid foam, isopropyl (S)-2-(5-(4- (benzyloxy)phenyl)-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-(tert- butoxy)acetate (1.0882 g, 89 % yield). Ή NMR (500 MHz, CHLOROFORM-d) d 8.18 (s, 1H), 7.49 (d, .7=7.4 Hz, 2H), 7.43 (t, 7=7.6 Hz, 2H), 7.40 - 7.35 (m, 1H), 7.23 (d, 7=8.4 Hz, 2H), 7.06 (d, 7=8.5 Hz, 2H), 6.02 (br s, 1H), 5.16 (s, 2H), 5.14 - 5.08 (m, 1H), 3.37 (br s, 1H), 3.02 (br s, 1H), 2.63 (s, 3H), 2.3 l (br s, 1H), 2.22 (br s, 1H), 1.25 (dd, 7=11.6, 6.2 Hz, 6H), 1.19 (s, 9H), 0.93 (br s, 3H), 0.77 (br s, 3H); 4 piperidine protons appear as very broad resonances between 0.7 and 1.7 ppm.

Intermediate 19

To a 100 mL round bottom flask equipped with a stir bar and charged with isopropyl (S)-2-(5-(4-(benzyloxy)phenyl)-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-(tert- butoxy)acetate (1.0882 g, 1.948 mmol) was added 10% Pd-C (0.104 g, 0.097 mmol) and MeOH (20 mL). The flask was sealed with a rubber septum, then the mixture was sparged via N2 bubbling through the solvent for 5 min. The mixture was then sparged with Th for 3 minutes. The mixture was placed under a static balloon-pressure Th atm. with stirring for 30 min. The atmosphere was exchanged to N2 (5 min bubbling). The reaction mixture was filtered through a pad of celite and the filtrate was concentrated onto celite in vacuo. The resulting powder was subjected to S1O2 purification (hexanes :EtOAc 100:0-^0: 100) to afford a colorless solid, isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5-(4- hydroxyphenyl)-2-methylpyridin-3-yl)acetate (784 mg, 85 % yield). Ή NMR (500 MHz, CHLOROFORM-d) d 8.15 (s, 1H), 7.15 - 7.11 (m, 2H), 6.96 - 6.91 (m, 2H), 6.00 (br s, 1H), 5.11 (spt, J=6.3 Hz, 1H), 3.36 (br s, 1H), 3.01 (br s, 1H), 2.64 (s, 3H), 2.39 (br s, 1H), 2.23 (br s, 1H), 1.62 (br s, 4H), 1.24 (dd, J=\ 1.1, 6.2 Hz, 6H), 1.18 (s, 9H), 0.96 - 0.74 (m, 6H).

One-pot procedure : (S)-Isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2- methylpyridin-3-yl)-2-(tert-butoxy)acetate (100 mg, 0.220 mmol), (4-hydroxyphenyl)boronic acid (36 mg, 0.26 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-l,l'-biphenyl)[2- (2'-amino-l,r-biphenyl)]palladium(II) (16 mg, 0.022 mmol), potassium phosphate tribasic (140 mg, 0.659 mmol) were combined under N2 (g). l,4-dioxane (3.7 ml) and water (0.7 ml) was added under N2 (g). The reaction was stirred at 80 °C. for 1 hr. The reaction was concentrated, adsorbed onto celite and was purified on silica gel (Biotage, EtO Ac/hexanes gradient, 0-100% over 10 CVs) to give the expected product (S)-isopropyl 2-(tert-butoxy)-2- (4-(4,4-dimethylpiperidin-l-yl)-5-(4-hydroxyphenyl)-2-methylpyridin-3-yl)acetate (75 mg, 0.160 mmol, 72.9 % yield). LCMS (M+H) = 469.25. Intermediate 20

To a stirred solution of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2- (hydroxymethyl)pyridin-3-yl)-2-(tert-butoxy)acetate (.443 g, 0.940 mmol) in DCM (8.54 ml) and Acetonitrile (0.854 ml) was added Dess-MartinPeriodinane (0.598 g, 1.410 mmol) at once at rt. After 6 h, the reaction mixture was diluted with ether (25 mL), washed with 1M NaOH (2 x 25 ml), brine (25 mL), dried (MgSCri). filtered and concentrated to afford the product (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2-formylpyridin-3-yl)-2- (tert-butoxy)acetate (425 mg, 0.905 mmol, 96 % yield) as a yellow oil. ESI-MS(+) m/z = 469.1 (M+l).

Intermediate 21

To a suspension of methyltriphenylphosphonium bromide (753 mg, 2.109 mmol) in THF (8 ml) at 0 °C was added sodium hydride (84 mg, 2.109 mmol) and the resulting mixture was stirred at rt for 45 min. (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)- 2-formylpyridin-3-yl)-2-(tert-butoxy)acetate (330 mg, 0.703 mmol) dissolved in THF (0.5 mF) THF (8 ml) was added dropwise and the mixture was stirred at 0°C for 1 h then warmed to rt and stirred 18 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried (MgSCri). filtered and concentrated. The residue was purlified by silica gel chromatography (40 g column; 5-20% EtO Ac/hexane) to afford (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2- vinylpyridin-3-yl)-2-(tert-butoxy)acetate (184 mg, 0.394 mmol, 56.0 % yield). ESI-MS(+) m/z = 467.3 (M+l). Intermediate 22

To a dry 10 mL Schlenk flask equipped with a stir bar was added 2-(5- (benzyloxy)pyridin-2-yl)-6-methyl-l,3,6,2-dioxazaborocane-4,8-dione (1.091 g, 3.21 mmol), isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin- l-yl)-2-vinylpyridin-3-yl)-2-(tert- butoxy)acetate (1 g, 2.139 mmol), palladium tetrakis (0.494 g, 0.428 mmol), diacetoxycopper (0.194 g, 1.070 mmol) and anhydrous tribasic potassium phosphate, finely ground (2.270 g, 10.70 mmol). The flask was sealed with a rubber septum, then placed under N2 atm (vac/fill x 3). To the flask was added a degassed (N2 sparging for 5 min) solution of DMF + diethanolamine (0.225 g, 2.139 mmol). The flask was placed in a 100 °C oil bath with stirring for t=l 8h. The reaction mixture was transferred to a 125 mL separatory funnel and was diluted with water: brine (1 : 1, 50 mL). The mixture was extracted with EtOAc (3 x 50 mL). The combined organics were washed with waterbrine (1 : 1, 50 mL), then brine (50 mL). The organics were dried over MgS04; filtered; then concentrated in vacuo to afford an amber oil. This material was dissolved in a min of acetone, then was concentrated onto celite in vacuo. The resulting powder was subjected to Si02 purification to afford the product isopropyl (S)- 2-(5-(benzyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-vinyl-[2,3'-bipyridin]-5'-yl)-2-(tert- butoxy)acetate (670 mg, 1.172 mmol, 54.8 % yield). ¹H NMR (400 MHz, chloroform-d) d 8.52 (d, .7=2.7 Hz, 1H), 8.37 (s, 1H), 7.53 - 7.48 (m, 2H), 7.45 (t, 7=7.5 Hz, 2H), 7.42 - 7.32 (m, 4H), 6.33 (dd, 7=16.8, 2.1 Hz, 1H), 6.10 (br s, 1H), 5.43 (dd, 7=10.6, 2.1 Hz, 1H), 5.21

(s, 2H), 5.10 (dt, 7=12.6, 6.2 Hz, 1H), 3.44 - 3.22 (m, 2H), 1.23 (d, 7=6.1 Hz, 3H), 1.19 (s, 9H), 1.17 (d, 7=6.4 Hz, 3H), 0.98 - 0.80 (m, 6H). 6 protons of the methylenes on the piperidine were not observed in the HNMR spectrum. ESI-MS(+) m/z = 572.6 (M+l).

Intermediate 23

To an N₂ sparged solution of isopropyl (S)-2-(5-(benzyloxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-vinyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (670 mg, 1.172 mmol) inMeOH (15 mL) was added Pd-C (125 mg, 0.117 mmol) and capped with a rubber septum. Th was then bubbled through the solution for 10 minutes. The reaction was left under postiive pressure of Th for 1 hr. The LCMS indicated the reaction was complete. The reaction was filtered through a 0.45 m nylon frit filter and volatiles evaporated to afford the product isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-ethyl-5-hydroxy-[2,3'- bipyridin]-5'-yl)acetate (447 mg, 0.924 mmol, 79 % yield). Ή NMR (400 MHz, chloroform- d) d 8.39 (d, .7=2.4 Hz, 1H), 8.26 (s, 1H), 7.31 (br d, 7=2.7 Hz, 1H), 7.24 - 7.19 (m, 1H), 6.05 (br s, 1H), 5.17 - 5.08 (m, 1H), 3.05 (dq, 7=13.9, 7.1 Hz, 1H), 2.97 - 2.88 (m, 1H), 1.38 - 1.35 (m, 3H), 1.25 (d, 7=6.4 Hz, 3H), 1.23 - 1.19 (m, 12H), 0.89 (br s, 6H). 8 protons on the methylenes on the piperidine ring were not observed in the HNMR spectrum. ESI-MS(+) m/z = 484.5 (M+l).

Intermediate 24

To a 100 mL r.b. flask equipped with a stir bar was added isopropyl (S)-2-(5-bromo- 4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate (3.00 g, 6.59 mmol) and trifhioroacetic acid (TFA) (15 mL). The resulting yellow solution was stirred at r.t. for 3 h. The orange solution was diluted with dichloroethane (DCE) (30 mL) and then concentrated in vacuo. The residue was dissolved in DCE (10 mL) and concentrated in vacuo to afford an orange oil. The oil residue was dissolved in acetone (25 mL), then diluted with water (0.5 mL). To the solution was added NaHC03 in portions until effervescence was no longer observed. The solution was further diluted with acetone (25 mL) and then dried over NaiSOu filtered; then concentrated in vacuo. The resulting residue was dissolved in a min. of acetone and then was concentrated onto celite in vacuo. The resulting powder was subjected to S1O2 chromatography (80g silica gel column, gradient of hexanes:EtOAc 100:0 -> 0: 100 over 13 column volumes, product detected by UV at 254 nm) to afford a colorless solid foam. This material is the desired product, isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-l- yl)-2-methylpyridin-3-yl)-2-hydroxyacetate, 2.3915 g (91%). Ή NMR (CHLOROFORM-d) d: 8.49 (s, 1H), 5.87 (br d, J=8.2 Hz, 1H), 5.55 (d, J=7.6 Hz, 1H), 5.06 (dt, J=l2.4, 6.3 Hz, 1H), 3.84 (br s, 1H), 3.77 (br s, lH), 2.7l (br s, lH), 2.58 (s, 4H), 1.70 (br s, 1H), 1.59 (br s, 1H), 1.38 (br s, 2H), 1.25 (d, J=6. l Hz, 3H), 1.14 (d, J=6. l Hz, 3H), 1.04 (br d, J=l3.4 Hz, 6H). LCMS (M+H) = 399 and 401.

Intermediate 25

To a 3-neck 1L flask equipped with a stir bar was added isopropyl (S)-2-(5-bromo-4- (4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-hydroxyacetate (14.16 g, 35.5 mmol) as a solution in DMF (500 mL). One neck of the flask was connected via a gas adapter to the Schlenk line; the other two necks were stoppered. The flask was placed under argon atm. The flask was placed in a 60 deg bath. To the stirred solution was added sodium hydride as a 60% dispersion in oil (2.84 g, 70.9 mmol), then 2-iodopropane (7.09 mL, 70.9 mmol). Following the addition, the flask was left open under an active purge of argon for 5 min. Then the flask was vented through a bubbler with a slow active purge of Ar. Significant effervescence was observed for up to 15 minutes. After stirring for 45 minutes, to the reaction mixture was added sodium hydride (60% dispersion in oil, 2.84 g, 70.9 mmol), then 2-iodopropane (7.09 mL, 70.9 mmol). The vessel was purged with argon as described for the previous addition. The mixture was stirred for 1.5 h. To the solution was added sodium hydride (60% dispersion in oil, 2.84 g, 70.9 mmol), then 2-iodopropane (7.09 mL, 70.9 mmol). The mixture was stirred for 15 minutes under active argon purge through the bubbler. After stirring for 15 minutes, to the solution was added sodium hydride (60% dispersion in oil, 2.84 g, 70.9 mmol), then 2-iodopropane (7.09 mL, 70.9 mmol). After stirring for 30 minutes the reaction mixture was analyzed by LCMS to find 61% conversion to the desired product. While under an active purge of argon the reaction was carefully quenched via the addition of water (3 x 1 mL, 5 min of stirring following each addition). Additional water (50 mL) was added and the mixture was stirred for 1 h. The reaction solution was concentrated in vacuo (bath = 40 deg C, pressure = 3 mbar) to afford an amber oil which solidified upon standing. The residue was transferred to a 1L separatory funnel using EtOAc (300 mL) and water (250 mL). The mixture was shaken; the phases were separated. The aq. phase was extracted with EtOAc (300 mL). The combined organics were washed with brine (200 mL); dried over MgS04; filtered; then concentrated in vacuo to afford an amber liquid. This liquid was diluted with acetone and then concentrated onto celite in vacuo. The resulting powder was subjected to SiCh chromatography (330g silica gel column, gradient of hexanes:EtOAc 100:0 -> 50:50 over 11 column volumes, detected by UV at 254 nm and by ESI) to afford a colorless solid foam, the desired product, isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2- methylpyridin-3-yl)-2-isopropoxyacetate, 5.93 g (38%). Ή NMR (CHLOROFORM-d) d: 8.46 (s, 1H), 6.13 (s, 1H), 5.06 (dt, J=l2.3, 6.2 Hz, 1H), 3.94 (br t, J=l l.4 Hz, 1H), 3.64 (dt, J=l2.2, 6.1 Hz, 1H), 3.51 (br t, J=l 1.4 Hz, lH), 2.8l (br d, J=l l .0 Hz, 1H), 2.56-2.62 (m, 1H), 2.53 (s, 3H), 1.48-1.62 (m, 2H), 1.42 (br d, J=l 1.9 Hz, 1H), 1.34 (br d, J=l l .9 Hz, 1H), 1.27 (br d, J=5.8 Hz, 3H), 1.19 (d, J=6. l Hz, 3H), 1.11 (br d, J=4.9 Hz, 6H), 1.06 (br s, 3H), 1.01 (br s, 3H). ESI-MS(+) m/z = 441.3 and 443.3

Intermediate 26

To a 250 mL RB flak equipped with a stir bar was added: K3P04 (23.30 g, 110 mmol),diacetoxycopper (1.994 g, 10.98 mmol), 2-(5-(benzyloxy)pyridin-2-yl)-6-methyl- l,3,6,2-dioxazaborocane-4,8-dione (11.20 g, 32.9 mmol), isopropyl (S)-2-(5-bromo-4-(4,4- dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate (10.0 g, 21.96 mmol), Pd(PPh3)4 (5.07 g, 4.39 mmol). The flask was equipped with an internal thermometer and was sealed and degassed with argon (vacuum and back fill with argon x 3). Then to the flask was added2,2'-azanediylbis(ethan-l-ol) (2.308 g, 21.96 mmol) in anhydrous DML (200 mL). The flask was degassed with argon (vacuum and back fill with argon x 3). The flask was placed in a 100 °C heating block and stirred for 16 hr overnight. The internal temperature reached 93 °C. The reaction mixture was transfered to a 2 L Erylnmyer. The mixture was diluted with water (250 mL), brine (250 mL), and EtOAc (400 mL). The mixture was vigorously mixed, then was filtered through a pad of celite (in order to clear a significant and persistent emulsion). The filtrate was transfered back to the separatory funnel and, without further mixing, the phases were partitioned. The aq. phase was vigoursly mixed with EtOAc (400 mL), then was through the same celite pad as before, and the mixture was partitioned in the separatory funnel without further mixing. The combined organics were washed with waterbrine (250 mL:250 mL), then brine (250 mL). The combined organics were dried over NaiSOi: were filtered; then were concentrated in vauco. The resutling residue was dissolved in a minimum of acetone and then was concentrated onto celite in vacuo. The resulting powder was subjected to SiCh purification as described. The pure product fractions and mixed fractions containing a significant amount of the desired product were pooled and concentrated in vacuo to afford the expected product isopropyl (S)-2-(5-(benzyloxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-isopropoxyacetate (3.65 g, 6.69 mmol, 50.2 % yield) consistent by LCMS. LCMS: Wavelengthl : 220 nm, Wavelength2: 254 nm, Injection Vol.: 5.00 mΐ, Stop Time: 4.00, Grad. Time: 3.0, Start %B: 0, End %B: 100, Total Elow: 0.80 ml/min, Solvent A: 95:5 WaterMeCN 0.1% TFA, Solvent B: 5:95 WaterMeCN 0.1% TFA, Col. Name: 1 - Acquity UPLC BEH C18 l .7um, rt: 1.459 min, M+H: 546.40.

Intermediate 27

To a 250 mL r.b. flask equipped with a stir bar and charged with isopropyl (S)-2-(5- (benzyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2- isopropoxyacetate (3.65 g, 6.69 mmol) and methanol (39.8 ml) under argon. Then palladium on carbon (Degussa type E101 NE/W, 10% dry basis Pd, 50% wt water, Pd/C (0.712 g, 0.669 mmol)) was added. The flask was sealed with a rubber septum, and the atmosphere was replaced with argon (vaccuum and back fill with argon 3x). Then the atmosphere was replaced with H2 (g) by vacuum and back fill with a H2 (g) ballon. The reaction was stirred under a static balloon-pressure Eh atm until reaction was complete as monitored by LCMS (4 hrs). The mixture was sparged with argon for 5 minutes, and then the reaction mixture was filtered through a pad of celite washing with MeOH. The filtrate was concentrated and adsorbed onto celite. The resulting powder was subjected to Si02 purification (330 g column) running EtOAc 100% over 3CVs and then 10% EtOH/DCM over 5 CVs. The pure fractions were combined and concentrated. The residue was co-evaporated twice with PhMe (2X, 50 mL ea) to ensure that no EtOH remains (EtOH would be a problem in the downstream step). The material was further concentrated under high vacuum to afford a colorless solid foam, isopropyl (S)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)- 2-isopropoxyacetate (2.42 g, 5.05 mmol, 75 % yield) consistent by LCMS. LCMS:

Wavelengthl: 220 nm, Wavelength2: 254 nm, Injection Vol.: 5.00 mΐ, Stop Time: 4.00, Grad. Time: 3.0, Start %B: 0, End %B: 100, Total Flow: 0.80 ml/min, Solvent A: 95:5

WaterMeCN 0.1% TFA, Solvent B: 5:95 WaterMeCN 0.1% TFA, Col. Name: 1 - Acquity UPLC BEH C18 l.7um, rt: 1.247 min, M+H: 456.30.

Intermediate 28

To a 100 mL Schlenk flask equipped with a stir bar was added isopropyl (S)-2-(5- bromo-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-hydroxyacetate (2.0232 g,

5.07 mmol) as a solution in DMF (35 mL). The flask was placed under argon atm. The flask was placed in a 60 °C oil bath. To the solution was added sodium hydride (60% dispersion in oil, 0.405 g, 10.13 mmol), then l-iodopropane (0.988 mL, 10.13 mmol). The solution was stirred for 15 minutes upon which LCMS analysis indicated clean and complete conversion. To the solution was added iPrOH (5 mL) in order to quench the reaction. The solution was stirred for 10 minutes, then was transferred to a 500 mL separatory funnel. The solution was diluted with water (50 mL), then extracted with EtOAc (150 mL). The organic solution was dried over MgSOr filtered; then concentrated in vacuo. The residue was adsorbed onto celite in vacuo. The resulting powder was subjected to S1O2 chromatography (80 g silica gel column, gradient of hexanes: EtOAc 100:0

65:35 over 11 column volumes, detected by UV at 254 nm and by ESI) to afford isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2- methylpyridin-3-yl)-2-propoxyacetate, 1.9706 g (88%). Ή NMR (CHLOROFORM-d) d:

8.47 (s, 1H), 6.01 (s, 1H), 5.08 (dt, J=l2.0, 6.1 Hz, 1H), 3.87 (br t, J= 11.1 Hz, 1H), 3.49-3.60 (m, 2H), 3.22-3.28 (m, 1H), 2.78 (br d, J=8.9 Hz, 1H), 2.56-2.64 (m, 1H), 2.51 (s, 3H), 1.47- 1.65 (m, 4H), 1.42 (br d, J=l l .3 Hz, 1H), 1.34 (br d, J=l2.2 Hz, 1H), 1.19 (d, J=5.8 Hz, 3H), 1.12 (d, J=6. l Hz, 3H), 1.05 (br s, 3H), 1.00 (br s, 3H), 0.90 (t, J=7.2 Hz, 3H).

Intermediate 29

To a 100 mL RB flak equipped with a stir bar was added: tripotassium phosphate (4.81 g, 22.65 mmol),diacetoxycopper (0.411 g, 2.265 mmol), 2-(5-(benzyloxy)pyridin-2-yl)- 6-methyl-l,3,6,2-dioxazaborocane-4,8-dione (2.312 g, 6.80 mmol), isopropyl (S)-2-(5- bromo-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-propoxyacetate (2 g, 4.53 mmol), Pd(Ph3p)4 (1.047 g, 0.906 mmol). The flask was equipped with an internal thermometer and was sealed and degassed with argon (vacuum and back fill with argon x 3). Then to the flask was added 2,2'-azanediylbis(ethan-l-ol) (0.476 g, 4.53 mmol) in anhydrous DMF (34.9 ml). The flask was degassed with argon (vacuum and back fill with argon x 3). The flask was placed in a 100 °C heating block and stirred for 16 hr overnight. The reaction mixture was transfered to a 1 L Erylnmyer. The mixture was diluted with water (125 mL), brine (125 mL), and EtOAc (200 mL). The mixture was vigorously mixed, then was filtered through a pad of celite (in order to clear a significant and persistent emulsion). The filtrate was transfered back to the separatory funnel and, without further mixing, the phases were partitioned. The aqueous phase was vigoursly mixed with EtOAc (200 mL), then was through the same celite pad as before, and the mixture was partitioned in the separatory funnel without further mixing. The combined organics were washed with waterbrine (125 mL: 125 mL), then brine (125 mL). The combined organics were dried over Na2S04; were filtered; then were concentrated in vauco. The resutling residue was dissolved in a minimum of acetone and then was concentrated onto celite in vacuo. The resulting powder was subjected to S1O2 purification as described. The pure product fractions and mixed fractions containing a significant amount of the desired product were pooled and concentrated in vacuo to afford residue with ppt (likely PPh3 oxide). The material was taken up in 30 mL of MeOH and allowed to sit for 30 min. The slurry was filtered through a pad of celite washing with MeOH to remove the PPh3oxide. The resulting filtrate was concentrated to afford the expected product isopropyl (S)-2-(5-(benzyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)-2-propoxyacetate (2.2 g, 4.03 mmol, 89 % yield) consistent by LCMS. LCMS: Wavelengthl : 220 nm, Wavelength2: 254 nm, Injection Vol.: 5.00 mΐ, Stop Time: 4.00, Grad. Time: 3.0, Start %B: 0, End %B: 100, Total Flow: 0.80 ml/min, Solvent A: 95:5 WaterMeCN 0.1% TFA, Solvent B: 5:95 WaterMeCN 0.1% TFA, Col. Name: 1 - Acquity UPFC BEH C18 l .7um, rt: 1.525 min, M+H: 546.40.

Intermediate 30

To a 250 mF r.b. flask equipped with a stir bar and charged with isopropyl (S)-2-(5- (benzyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2- propoxyacetate (2.2 g, 4.03 mmol) and Methanol (24.00 ml) under argon. Then palladium on carbon (Degussa type E101 NE/W, 10% dry basis Pd, 50% wt water, Pd/C (0.429 g, 0.403 mmol)) was added. The flask was sealed with a rubber septum, and the atmosphere was replaced with argon (vaccuum and back fill with argon 3x). Then the atmosphere was replaced with H2 (g) by vacuum and back fill with a H2 (g) ballon. The reaction was stirred under a static balloon-pressure Eh atm until reaction was complete as monitored by LCMS (4 hrs). The mixture was sparged with argon for 5 minutes, and then the reaction mixture was filtered through a pad of celite washing with MeOH. The filtrate was concentrated and adsorbed onto celite. The resulting powder was subjected to Si02 purification (330 g column) running EtOAc 100% over 3CVs and then 10% EtOH/DCM over 5 CVs (see attached ISCO Purification). The pure fractions were combined and concentrated. The residue was co evaporated twice with PhMe (2X, 50 mL ea) to ensure that no EtOH remains (EtOH would be a problem in the downstream step). The material was further concentrated under high vacuum to afford a colorless solid foam, isopropyl (S)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5- hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-propoxyacetate (608 mg, 1.201 mmol, 29.8 % yield) consistent by LCMS and NMR. LCMS: Wavelengthl : 220 nm, Wavelength2: 254 nm, Injection Vol.: 5.00 mΐ, Stop Time: 4.00, Grad. Time: 3.0, Start %B: 0, End %B: 100, Total Flow: 0.80 ml/min, Solvent A: 95 :5 WaterMeCN 0.1% TFA, Solvent B: 5:95 WaterMeCN 0.1% TFA, Col. Name: 1 - Acquity UPLC BEH C18 l .7um, rt: 1.504 min, M+H: 456.30. ¾ NMR (CHLOROFORM-d, 500 MHz) d 8.4-8 4 (m, 1H), 8.3-8 3 (m, 1H), 8.3-8 3 (m, 2H), 8.2-8.2 (m, 1H), 8.1-8.2 (m, 1H), 7.47 (br s, 1H), 5.83 (s, 1H), 5.0-5.2 (m, 1H), 3.58 (td, 1H, J=6.5, 8.9 Hz), 3.1-3.3 (m, 1H), 2.9-3.1 (m, 1H), 2.86 (s, 1H), 2.74 (br s, 1H), 2.62 (s, 2H), 2.54 (br s, 1H), 2.35 (br s, 1H), 1.7-1.9 (m, 1H), 1.61 (qd, 2H, J=7.2, 14.2 Hz), 1.31 (br s, 2H), 1.1-1.3 (m, 6H), 0.9-1.0 (m, 1H), 0.8-0.9 (m, 6H).

Intermediate 31

To a 100 mL Schlenk flask equipped with a stir bar was added isopropyl (S)-2-(5- bromo-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-hydroxyacetate (2.395 g, 6.00 mmol) as a solution in DMF (40 mL). The flask was placed under argon atm. The flask was placed in a 60 °C oil bath. To the solution was added sodium hydride (60% dispersion in oil, 0.480 g, 12.00 mmol), then l-iodobutane (1.365 mL, 12.00 mmol). The solution was stirred for 1 h. To the solution was added iPrOH (10 mL) to quench the reaction. The solution was stirred for 15 minutes, then was transfered to a 500 mL separatory funnel. The solution was diluted with water (50 mL), then extracted with EtOAc (150 mL). The organic solution was dried over MgSCb: filtered; then concentrated in vacuo. The residue liquid residue was adsorbed onto celite in vacuo. The resulting powder was subjected to SiCh chromatography (80 g silica gel column, gradient of hexanes: EtOAc 100:0

65:35 over 11 column volumes, detected by UV at 254 nm and by ESI) to afford isopropyl (S)-2-(5-bromo-4-(4,4- dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-butoxyacetate as a pale yellow oil, 2.3924 g (88%). Ή NMR (CHLOROFORM-d) d: 8.47 (s, 1H), 6.01 (s, 1H), 5.08 (dt, J=l2.3, 6.2 Hz, 1H), 3.87 (br t, J=l l . l Hz, 1H), 3.58-3.67 (m, 1H), 3.53 (br t, J=l l .0 Hz, 1H), 3.26-3.33 (m, 1H), 2.77 (br d, J=9.2 Hz, 1H), 2.55-2.64 (m, 1H), 2.51 (s, 3H), 1.24-1.62 (m, 8H), 1.19 (d, J=6. l Hz, 3H), 1.12 (d, J=5.8 Hz, 3H), 1.05 (br s, 3H), 1.00 (br s, 3H), 0.88 (br t, J=7.2 Hz, 3H).

Intermediate 32

To a 100 mL RB flak equipped with a stir bar was added: tripotassium phosphate (5.36 g, 25.3 mmol),diacetoxycopper (0.459 g, 2.53 mmol), 2-(5-(benzyloxy)pyridin-2-yl)-6- methyl-l,3,6,2-dioxazaborocane-4,8-dione (2.58 g, 7.58 mmol), isopropyl (S)-2-(5-bromo-4- (4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-butoxyacetate (2.3 g, 5.05 mmol), Pd(Ph3p)4 (1.167 g, 1.010 mmol). The flask was equipped with an internal thermometer and was sealed and degassed with argon (vacuum and back fill with argon x 3). Then to the flask was added 2,2'-azanediylbis(ethan-l-ol) (0.531 g, 5.05 mmol) in anhydrous DMF (38.8 ml). The flask was degassed with argon (vacuum and back fill with argon x 3). The flask was placed in a 100 °C heating block and stirred for 16 hr overnight. The reaction mixture was transfered to a 1 L Erylnmyer. The mixture was diluted with water (125 mL), brine (125 mL), and EtOAc (200 mL). The mixture was vigorously mixed, then was filtered through a pad of celite (in order to clear a significant and persistent emulsion). The filtrate was transfered back to the separatory funnel and, without further mixing, the phases were partitioned. The aq. phase was vigoursly mixed with EtOAc (200 mL), then was through the same celite pad as before, and the mixture was partitioned in the separatory funnel without further mixing. The combined organics were washed with waterbrine (125 mL: 125 mL), then brine (125 mL). The combined organics were dried over Na2SOr: were filtered; then were concentrated in vauco. The resutling residue was dissolved in a minimum of acetone and then was concentrated onto celite in vacuo. The resulting powder was subjected to SiCh purification as described (see attached ISCO). The pure product fractions and mixed fractions containing a significant amount of the desired product were pooled and concentrated in vacuo to afford residue with ppt (likely PPh3 oxide). The material was taken up in 30 mL of MeOH and allowed to sit for 30 min. The slurry was filtered through a pad of celite washing with MeOH to remove the PPh3oxide. The resulting filtrate was concentrated to afford the expected product isopropyl (S)-2-(5-(benzyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)-2-butoxyacetate (2 g, 3.57 mmol, 70.8 % yield) consistent by LCMS.

LCMS: Wavelengthl : 220 nm, Wavelength2: 254 nm, Injection Vok: 5.00 mΐ, Stop Time: 4.00, Grad. Time: 3.0, Start %B: 0, End %B: 100, Total Flow: 0.80 ml/min, Solvent A: 95:5 WaterMeCN 0.1% TFA, Solvent B: 5:95 WaterMeCN 0.1% TFA, Col. Name: 1 - Acquity UPLC BEH C18 l .7um, rt: 1.598 min, M+H: 560.35

Intermediate 33

To a 250 mL r.b. flask equipped with a stir bar and charged with isopropyl (S)-2-(5- (benzyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-butoxyacetate (2 g, 3.57 mmol) and Methanol (21.27 ml) under argon. Then palladium on carbon (Degussa type E101 NE/W, 10% dry basis Pd, 50% wt water, Pd/C (0.380 g, 0.357 mmol)) was added. The flask was sealed with a rubber septum, and the atmosphere was replaced with argon (vaccuum and back fill with argon 3x). Then the atmosphere was replaced with H2 (g) by vacuum and back fill with a H2 (g) ballon. The reaction was stirred under a static balloon- pressure Eh atm until reaction was complete as monitored by LCMS (4 hrs). The mixture was sparged with argon for 5 minutes, and then the reaction mixture was filtered through a pad of celite washing with MeOH. The filtrate was concentrated and adsorbed onto celite. The resulting powder was subjected to Si02 purification (330 g column) running EtOAc 100% over 3CVs and then 10% EtOH/DCM over 5 CVs (see attached ISCO Purification). The pure fractions were combined and concentrated. The residue was co-evaporated twice with PhMe (2X, 50 mL ea) to ensure that no EtOH remains (EtOH would be a problem in the downstream step). The material was further concentrated under high vacuum to afford a colorless solid foam, isopropyl (S)-2-butoxy-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy-6'- methyl-[2,3'-bipyridin]-5'-yl)acetate (1.09 g, 2.205 mmol, 61.7 % yield) consistent by LCMS and NMR. LCMS: Wave length 1 : 220 nm, Wavelength2: 254 nm, Injection Vok: 5.00 mΐ, Stop Time: 4.00, Grad. Time: 3.0, Start %B: 0, End %B: 100, Total Flow: 0.80 ml/min, Solvent A: 95:5 Water: MeCN 0.1% TFA, Solvent B: 5:95 WaterMeCN 0.1% TFA, Col. Name: 1 - Acquity UPLC BEH C18 l .7um, rt: 1.340 min, M+H: 470.3. ¾ NMR (CHLOROFORM-d, 500 MHz) d 8.37 (d, 1H, J=2.4 Hz), 8.21 (s, 1H), 7.2-7.3 (m, 3H), 5.83 (s, 1H), 5.14 (td, 1H, J=6.3, 12.5 Hz), 3.6-3.7 (m, 1H), 3.3-3.3 (m, 1H), 2.86 (br s, 1H), 2.75 (br s, 1H), 2.63 (s, 3H), 2.4-2.6 (m, 1H), 1.5-1.7 (m, 4H), 1.2-1.4 (m, 12H), 0.8-0.9 (m, 9H).

Analysis Methods:

LCMS Method 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm).

LCMS Method 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm).

LCMS Method 3: Column: Waters Acquity UPLC BEH Cl 8, 2.1 x 50 mm, l .7-pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C;

Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

General Procedure A : To a 1 dram vial equipped with a stir bar was added the alcohol (0.080 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy-6'- methyl-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.053 mmol), and triphenylphosphine (20.9 mg, 0.080 mmol) as a solution in THF (0.25 mL). To the solution was added DIAD (0.016 mL, 0.080 mmol) as a solution in THF (0.25 mL). The solution was stirred at r.t. for 30 min to 18h. The reaction solution was concentrated under a N2 stream. The residue was dissolved in EtOH (1.0 mL). To the solution was added aq. NaOH (5.0 M, 0.110 mL, 0.532 mmol). The vial was capped, then placed in a 85 °C heating block with stirring for 4 h to 18 h. The mixture was cooled to r.t., then was filtered through a 0.4 micron syringe filter and the filtrate was directly subjected to HPLC purification to afford the purified product.

General Procedure B: To a 1 dram vial equipped with a stir bar was added the alcohol (0.080 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy-6'- methyl-[2,3'-bipyridin]-5'-yl)acetate as a solution in THF (0.355 M, 0.150 mL, 0.053 mmol), and triphenylphosphine as a solution in THF (0.535 M, 0.150 mL, 0.080 mmol). To the stirred solution was added diisopropyl diazene-l,2-dicarboxylate (“DIAD”) as a solution in THF (0.535 M, 0.150 mL, 0.080 mmol). The solution was stirred at r.t. for 30 min to 18 h. The reaction solution was concentrated under a N2 stream. The residue was dissolved in EtOH (1.0 mL). To the solution was added aq. sodium hydroxide (5.0 M, 0.160 mL, 0.795 mmol). The vial was capped, then placed in a 85 °C heating block with stirring for 4h to 18h. The mixture was cooled to r.t. and to the mixture was added AcOH (0.050 mL). The mixture was filtered through a 0.4 micron syringe filter and the filtrate was directly subjected to HPLC purification to afford the purified product.

General Procedure C: To a 1 dram vial equipped with a stir bar was added the alcohol (0.080 mmol), a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)- 5-(4-hydroxyphenyl)-2-methylpyridin-3-yl)acetate (0.355 M, 0.150 ml, 0.053 mmol) in THF, a solution of triphenylphosphine (0.535 M, 0.150 ml, 0.080 mmol) in THF, then a solution of diisopropyl diazene-l,2-dicarboxylate (0.535 M, 0.150 ml, 0.080 mmol) in THF. Alternately, to a 1 dram vial equipped with a stir bar was added the alcohol (0.080 mmol), then a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5-(4-hydroxyphenyl)-2- methylpyridin-3-yl)acetate (0.355 M, 0.053 mmol), triphenylphosphane (0.535 M, 0.080 mmol) and diisopropyl diazene-l,2-dicarboxylate (0.535 M, 0.080 mmol) in THF (0.450 mL). In either preparation, the reaction solution was then stirred at r.t. for 18 h. The reaction solution was concentrated under a N2 gas stream. To each vial was added EtOH (1.0 mL), then sodium hydroxide (aq.) (5.0 M, 0.160 ml, 0.795 mmol). The vial was capped, then placed in a 85 °C heating block for 4 h. The reaction mixture was cooled to r.t. and then filtered through a 0.4 micron syringe filter. The filtrate was subjected to HPLC purification to afford the purified product.

General Procedure D: To a 1 dram vial equipped with a stir bar was added the alcohol (0.080 mmol), and isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)- 5',6'-difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate as a solution in THF (0.105 M, 0.500 ml, 0.053 mmol), then potassium tert-butoxide in THF (1.00 M, 0.077 mL, 0.077 mmol). The solution was stirred at r.t. for 15 min, then the volatiles were evaporated under a N2 gas stream. The residue was dissolved in EtOH (1.0 mL). To the solution was added aq. sodium hydroxide (5.0 M, 0.160 ml, 0.795 mmol). The vial was capped, then placed in a 85 °C heating block with stirring for 1 h. The mixture was cooled to r.t. To the mixture was added acetic acid (0.050 mL). The mixture was filtered through a 0.4 micron syringe filter. The filtrate directly subjected to HPLC purification to afford the purified product. Example 1

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’ -(4,4-dimethylpiperidin- 1 -yl)-5 -(3 -hydroxy-3 -methylbutoxy)-6’ - methyl-[2,3’-bipyridine]-5’-yl]acetic acid (0 mg, 0% yield, 95.3% purity). LCMS Method 2: retention time = 1.64 min.; observed ion = 514.2. 1H NMR (500 MHz, METHANOL-d4) d 8.35 (d, J=3. l Hz, 1H), 8.11 (s, 1H), 7.56 (dd, J=8.7, 2.9 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 5.78 (s, 1H), 4.59 (br s, 4H), 4.30 (t, J=6.9 Hz, 2H), 2.68 - 2.63 (m, 4H), 2.05 (t, J=7.0 Hz, 2H), 1.43 (br s, 4H), 1.32 (s, 6H), 1.19 (s, 9H), 0.90 (s, 6H).

Example 2

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’ -(4,4-dimethylpiperidin- 1 -yl)-5-[2-( lH-imidazol- 1 -yl)ethoxy]-6’ - methyl-[2,3’-bipyridine]-5’-yl]acetic acid (22.3 mg, 80% yield, 98.8% purity). LCMS Method 2: retention time = 1.3 min.; observed ion = 522.2. 1H NMR (500 MHz,

METHAN OL-d4) d 9.13 (s, 1H), 8.50 (d, J=2.7 Hz, 1H), 8.35 (s, 1H), 7.82 (s, 1H), 7.66 - 7.59 (m, 3H), 5.70 (s, 1H), 4.79 (t, J=4.9 Hz, 2H), 4.58 (t, J=4.9 Hz, 2H), 2.95 (br s, 4H), 2.79 (s, 3H), 1.48 (br s, 4H), 1.24 (s, 9H), 0.95 (s, 6H).

Example 3

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[2-(piperidin-l- yl)ethoxy]-[2,3’-bipyridine]-5’-yl]acetic acid (35.3 mg, 123% yield, 99.1% purity). LCMS Method 1 : retention time = 1.29 min.; observed ion = 539.2. 1H NMR (500 MHz,

METHAN OL-d4) d 8.54 (d, J=2.7 Hz, 1H), 8.37 (s, 1H), 7.69 (dd, J=8.9, 3.1 Hz, 1H), 7.63 (d, J=8.9 Hz, 1H), 5.71 (s, 1H), 4.57 (t, J=4.7 Hz, 2H), 3.74 - 3.65 (m, 4H), 3.13 (br t, J=l 1.6 Hz, 2H), 2.97 (br s, 4H), 2.80 (s, 3H), 2.01 (br d, J=l2.2 Hz, 2H), 1.88 (br d, J=l 1.9 Hz, 3H), 1.65 - 1.45 (m, 5H), 1.25 (s, 9H), 0.97 (s, 6H).

Example 4

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[2-(pyrrolidin-l- yl)ethoxy]-[2,3’-bipyridine]-5’-yl]acetic acid (23.6 mg, 84% yield, 98.2% purity). LCMS Method 1 : retention time = 1.21 min.; observed ion = 525.2. 1H NMR (500 MHz,

METHAN OL-d4) d 8.55 (d, J=2.7 Hz, 1H), 8.37 (s, 1H), 7.70 (dd, J=8.5, 3.1 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 5.71 (s, 1H), 4.54 (t, J=4.3 Hz, 2H), 3.86 - 3.70 (m, 4H), 3.31 - 3.16 (m, 2H), 2.97 (br s, 4H), 2.80 (s, 3H), 2.22 (br s, 2H), 2.12 (br s, 2H), 1.50 (br s, 4H), 1.25 (s, 9H), 0.97 (s, 6H).

Example 5

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-(3-methoxypropoxy)-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (25.1 mg, 94% yield, 100% purity). LCMS Method 1 : retention time = 1.58 min.; observed ion = 500.3. 1H NMR (500 MHz, METHANOL-d4) d 8.44 (d, J=2.4 Hz, 1H), 8.36 (s, 1H), 7.62 - 7.58 (m, 1H), 7.58 - 7.54 (m, 1H), 5.72 (s, 1H), 4.24 (t, J=6.3 Hz, 2H), 3.62 (t, J=6. l Hz, 2H), 3.38 (s, 3H), 2.96 (br s, 4H), 2.78 (s, 3H), 2.12 (quin, J=6.0 Hz, 2H), 1.49 (br d, J=3.7 Hz, 4H), 1.25 (s, 9H), 0.97 (s, 6H). Example 6

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[5-(cyclohexylmethoxy)-4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (17.6 mg, 63% yield, 100% purity). LCMS Method 1 : retention time = 2.25 min.; observed ion = 524.3. 1H NMR (500 MHz, METHANOL-d4) d 8.36 (d, J=2.7 Hz, 1H), 8.18 (s, 1H), 7.55 (dd, J=8.5, 2.7 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 5.84 (s, 1H), 3.96 (d, J=6. l Hz, 2H), 2.83 (br s, 4H), 2.66 (s, 3H), 1.95 - 1.80 (m, 5H), 1.75 (br d, J=l 1.9 Hz, 1H), 1.44 (br s, 4H), 1.36 (br td, J=l2.8, 2.7 Hz, 2H), 1.29 (tt, J=l2.2, 3.0 Hz, 1H), 1.21 (s, 9H), 1.17 (br qd, J=l 1.9, 2.4 Hz, 2H), 0.92 (s, 6H).

Example 7

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-(2-ethoxyethoxy)-6’-methyl-[2,3’- bipyridine]-5’-yl]acetic acid (28.1 mg, 106% yield, 100% purity). LCMS Method 1 : retention time = 1.73 min.; observed ion = 500.2. lH NMR (500 MHz, METHANOL-d4) d 8.48 (d, J=2.7 Hz, 1H), 8.37 (s, 1H), 7.63 (dd, J=8.5, 2.7 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 5.71 (s,

1H), 4.33 - 4.29 (m, 2H), 3.89 - 3.85 (m, 2H), 3.64 (q, J=7.0 Hz, 2H), 2.97 (br s, 4H), 2.80 (s, 3H), 1.50 (br d, J=4.0 Hz, 4H), 1.27 - 1.23 (m, 12H), 0.97 (s, 6H).

Example 8

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[2-(morpholin-4- yl)ethoxy]-[2,3’-bipyridine]-5’-yl]acetic acid (34 mg, 118% yield, 98.7% purity). LCMS Method 2: retention time = 1.39 min.; observed ion = 541.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.55 (d, J=2.7 Hz, 1H), 8.36 (s, 1H), 7.69 (dd, J=8.7, 2.9 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 5.71 (s, 1H), 4.62 - 4.57 (m, 2H), 4.00 (br s, 4H), 3.76 - 3.72 (m, 2H), 3.50 (br s, 4H), 3.02 (br s, 2H), 2.97 (br s, 2H), 2.80 (s, 3H), 1.50 (br s, 4H), 1.25 (s, 9H), 0.97 (s, 6H).

Example 9

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[2-(oxetan-3-yl)ethoxy]- [2,3’-bipyridine]-5’-yl]acetic acid (21.7 mg, 80% yield, 100% purity). LCMS Method 1 : retention time = 1.61 min.; observed ion = 512.3. 1H NMR (500 MHz, METHANOL-d4) d 8.32 (d, J=2.7 Hz, 1H), 8.09 (s, 1H), 7.52 (dd, J=8.7, 2.9 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H),

5.76 (s, 1H), 4.88 (t, J=6.3 Hz, 2H), 4.56 (t, J=6.3 Hz, 2H), 4.16 (t, J=6. l Hz, 2H), 3.32 (quin, J=7.0 Hz, 1H), 2.77 (br s, 2H), 2.64 (s, 3H), 2.28 - 2.23 (m, 2H), 1.43 (br s, 4H), 1.19 (s, 9H), 0.89 (s, 6H).

Example 10

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[5-(cyclopentylmethoxy)-4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (15.6 mg, 57% yield, 100% purity). LCMS Method 1 : retention time = 2.04 min.; observed ion = 510.3. 1H NMR (500 MHz, METHANOL-d4) d 8.37 (d, J=2.7 Hz, 1H), 8.17 (s, 1H), 7.55 (dd, J=8.5, 2.7 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 5.84 (s, 1H), 4.04 (d, J=6.7 Hz, 2H), 3.16 - 2.72 (m, 4H), 2.66 (s, 3H), 2.44 (dt, J=l5.0, 7.5 Hz, 1H), 1.91 (br d, J=7.6 Hz, 2H), 1.76 - 1.62 (m, 4H), 1.50 - 1.34 (m, 6H), 1.21 (s, 9H), 0.91 (s, 6H). Example 11

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-(2-methoxyethoxy)-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (15.8 mg, 61% yield, 98.9% purity). LCMS Method 1: retention time = 1.48 min.; observed ion = 486.1. 1H NMR (500 MHz, METHANOL-d4) d 8.41 (d, J=2.7 Hz, 1H), 8.17 (s, 1H), 7.59 (dd, J=8.5, 2.7 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.84 (s, 1H), 4.31 - 4.28 (m, 2H), 3.84 - 3.80 (m, 2H), 3.46 (s, 3H), 3.14 - 2.71 (m, 4H), 2.66 (s, 3H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 12

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[5 -(2,3 -dihydro- lH-inden-2-yloxy)-4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ - methyl-[2,3’-bipyridine]-5’-yl]acetic acid (12.1 mg, 42% yield, 99.2% purity). LCMS Method 1 : retention time = 2.05 min.; observed ion = 544.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.37 (d, J=3. l Hz, 1H), 8.19 (s, 1H), 7.60 (dd, J=8.7, 2.9 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.29 - 7.25 (m, 2H), 7.22 - 7.18 (m, 2H), 5.85 (s, 1H), 5.42 - 5.38 (m, 1H), 3.48 (dd, J=l6.9, 6.0 Hz, 2H), 3.18 (br dd, J=l6.8, 9.2 Hz, 2H), 3.13 - 2.72 (m, 4H), 2.66 (s, 3H), 1.45 (br s, 4H), 1.22 (s, 9H), 0.93 (s, 6H).

Example 13

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-[2-(l-hydroxycyclobutyl)ethoxy]- 6’-methyl-[2,3’-bipyridine]-5’-yl]acetic acid (9.9 mg, 35% yield, 98.1% purity). LCMS Method 2: retention time = 1.59 min.; observed ion = 526.2. 1H NMR (500 MHz,

METHAN OL-d4) d 8.34 (d, J=2.7 Hz, 1H), 8.09 (s, 1H), 7.55 (dd, J=8.5, 2.7 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 5.75 (s, 1H), 4.30 (t, J=6.7 Hz, 2H), 3.27 - 2.66 (m, 4H), 2.64 (s, 3H), 2.24 - 2.10 (m, 6H), 1.82 (br d, J=l0.7 Hz, 1H), 1.70 - 1.63 (m, 1H), 1.42 (br s, 4H), 1.18 (s, 9H), 0.89 (s, 6H).

Example 14

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[2-(4-methylpiperidin-l- yl)ethoxy]-[2,3’-bipyridine]-5’-yl]acetic acid (15 mg, 51% yield, 99.2% purity). LCMS Method 2: retention time = 1.42 min.; observed ion = 553.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.40 (d, J=2.7 Hz, 1H), 8.04 (s, 1H), 7.57 (dd, J=8.5, 2.7 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 5.73 (s, 1H), 4.46 (t, J=5.0 Hz, 2H), 3.50 (br d, J=l 1.3 Hz, 2H), 3.41 (t, J=4.6 Hz, 2H), 2.87 (br t, J=l2.5 Hz, 2H), 2.64 (s, 3H), 2.96 - 2.54 (m, 2H), 1.88 (br d,

J= 12.8 Hz, 2H), 1.69 (br s, 1H), 1.55 - 1.33 (m, 6H), 1.18 (s, 9H), 1.03 (d, J=6.4 Hz, 3H), 0.88 (s, 6H).

Example 15

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[2-(thiomorpholin-4- yl)ethoxy]-[2,3’-bipyridine]-5’-yl]acetic acid (19.8 mg, 67% yield, 98.3% purity). LCMS Method 2: retention time = 1.55 min.; observed ion = 557.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.38 (d, J=3. l Hz, 1H), 8.09 (s, 1H), 7.58 (dd, J=8.5, 3.1 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 5.74 (s, 1H), 4.31 (t, J=5.0 Hz, 2H), 2.97 - 2.91 (m, 6H), 2.75 - 2.72 (m, 4H), 2.64 (s, 3H), 2.86 - 2.59 (m, 2H), 1.43 (br s, 4H), 1.18 (s, 9H), 0.89 (s, 6H). Example 16

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[2-(l-methyl-lH- pyrazol-3-yl)ethoxy] -[2,3’-bipyridine] -5’-yl] acetic acid (10.3 mg, 36% yield, 100% purity).

LCMS Method 1 : retention time = 1.49 min.; observed ion = 536.3. 1H NMR (500 MHz, METHAN OL-d4) d 8.36 (d, J=2.7 Hz, 1H), 8.13 (s, 1H), 7.56 (dd, J=8.7, 2.9 Hz, 1H), 7.52 (d, J=2. l Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.25 (d, J=2. l Hz, 1H), 5.78 (s, 1H), 4.38 (t, J=6.6 Hz, 2H), 3.87 (s, 3H), 3.15 (t, J=6.7 Hz, 2H), 2.78 (br s, 2H), 2.65 (s, 3H), 1.43 (br s, 4H), 1.19 (s, 9H), 0.90 (s, 6H).

Example 17

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-{5-[2-(l, 3-dimethyl- lH-pyrazol-4-yl)ethoxy]-4’-(4, 4- dimethylpiperidin-l-yl)-6’-methyl-[2,3’-bipyridine]-5’-yl}acetic acid (7.4 mg, 25% yield, 100% purity). LCMS Method 1 : retention time = 1.56 min.; observed ion = 550.3. 1H NMR (500 MHz, METHAN OL-d4) d 8.36 (d, J=2.7 Hz, 1H), 8.12 (s, 1H), 7.55 (dd, J=8.7, 2.9 Hz, 1H), 7.47 - 7.45 (m, 2H), 5.78 (s, 1H), 4.25 (t, J=6.4 Hz, 2H), 3.80 (s, 3H), 2.95 (t, J=6.6 Hz, 2H), 2.78 (br s, 2H), 2.65 (s, 3H), 2.24 (s, 3H), 1.43 (br s, 4H), 1.19 (s, 9H), 0.90 (s, 6H).

Example 18

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[2-(propan-2- yloxy)ethoxy]-[2,3’-bipyridine]-5’-yl]acetic acid (10.8 mg, 39% yield, 97.4% purity). LCMS Method 1 : retention time = 1.77 min.; observed ion = 514.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.41 (d, J=2.7 Hz, 1H), 8.19 (s, 1H), 7.60 (dd, J=8.7, 2.9 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 5.81 (s, 1H), 4.30 - 4.26 (m, 2H), 3.88 - 3.86 (m, 2H), 3.75 (quin, J=6. l Hz, 1H), 2.84 (br s, 4H), 2.67 (s, 3H), 1.45 (br s, 4H), 1.23 - 1.20 (m, 15H), 0.92 (s, 6H).

Example 19

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[5-(2-cyclopentylethoxy)-4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ -methyl - [2,3’-bipyridine]-5’-yl]acetic acid (11.9 mg, 42% yield, 100% purity). LCMS Method 1 : retention time = 2.28 min.; observed ion = 524.3. 1H NMR (500 MHz, METHANOL-d4) d 8.37 (d, J=2.7 Hz, 1H), 8.18 (s, 1H), 7.56 (dd, J=8.7, 2.9 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.81 (s, 1H), 4.18 (t, J=6.6 Hz, 2H), 2.83 (br s, 4H), 2.66 (s, 3H), 2.06 (quin, J=7.6 Hz, 1H), 1.88 (q, J=6.7 Hz, 4H), 1.70 (br s, 2H), 1.67 - 1.57 (m, 2H), 1.44 (br s, 4H), 1.28 - 1.20 (m, 11H), 0.92 (s, 6H).

Example 20

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[5 -(cyclopropylmethoxy)-4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ -methyl- [2,3’-bipyridine]-5’-yl]acetic acid (7.4 mg, 29% yield, 99.1% purity). LCMS Method 2: retention time = 1.89 min.; observed ion = 482.3. 1H NMR (500 MHz, METHANOL-d4) d 8.37 (d, J=2.7 Hz, 1H), 8.18 (s, 1H), 7.55 (dd, J=8.7, 2.9 Hz, 1H), 7.47 (d, J=8.9 Hz, 1H), 5.81 (s, 1H), 4.00 (d, J=7.0 Hz, 2H), 2.84 (br s, 4H), 2.67 (s, 3H), 1.45 (br s, 4H), 1.37 - 1.30 (m, 1H), 1.21 (s, 9H), 0.92 (s, 6H), 0.70 - 0.66 (m, 2H), 0.45 - 0.41 (m, 2H). Example 21

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-(2-phenoxyethoxy)- [2,3’-bipyridine]-5’-yl]acetic acid (13.1 mg, 45% yield, 100% purity). LCMS Method 1 : retention time = 1.91 min.; observed ion = 548.3. 1H NMR (500 MHz, METHANOL-d4) d 8.46 (d, J=2.7 Hz, 1H), 8.20 (s, 1H), 7.65 (dd, J=8.5, 2.7 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.31 (t, J=7.9 Hz, 2H), 7.01 - 6.96 (m, 3H), 5.81 (s, 1H), 4.55 - 4.49 (m, 2H), 4.42 - 4.39 (m, 2H), 2.84 (br s, 4H), 2.67 (s, 3H), 1.45 (br s, 4H), 1.22 (s, 9H), 0.91 (s, 6H).

Example 22

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’ -(4,4-dimethylpiperidin- 1 -yl)-5-(3-fluoropropoxy)-6’ -methyl-[2,3’ - bipyridine]-5’-yl]acetic acid (12.4 mg, 48% yield, 96.3% purity). LCMS Method 1 : retention time = 1.6 min.; observed ion = 488.2. 1H NMR (500 MHz, METHAN OL-d4) d 8.41 (d, J=2.7 Hz, 1H), 8.19 (s, 1H), 7.60 (dd, J=8.7, 2.9 Hz, 1H), 7.50 (d, J=8.9 Hz, 1H), 5.81 (s,

1H), 4.74 - 4.71 (m, 2H), 4.63 (br t, J=5.8 Hz, 2H), 4.28 (t, J=6.3 Hz, 2H), 2.83 (br s, 4H), 2.67 (s, 3H), 2.25 (dquin, J=25.3, 6.1 Hz, 2H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.92 (s, 6H). Example 23

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[(3-methylbut-3-en-l- yl)oxy]-[2,3’-bipyridine]-5’-yl]acetic acid (8.4 mg, 32% yield, 97.4% purity). LCMS Method 1 : retention time = 1.89 min.; observed ion = 496.3. 1H NMR (500 MHz, METHANOL-d4) d 8.37 (d, J=2.7 Hz, 1H), 8.19 (s, 1H), 7.58 (dd, J=8.7, 2.9 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H),

5.81 (s, 1H), 4.85 (br s, 2H), 4.28 (t, J=6.6 Hz, 2H), 2.83 (br s, 4H), 2.67 (s, 3H), 2.59 (t,

J=6.6 Hz, 2H), 1.85 (s, 3H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.92 (s, 6H).

Example 24

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[3-(propan-2- yloxy)propoxy]-[2,3’-bipyridine]-5’-yl]acetic acid (13.6 mg, 49% yield, 96.1% purity). LCMS Method 2: retention time = 1.83 min.; observed ion = 528.3. 1H NMR (500 MHz, METHAN OL-d4) d 8.39 (d, J=2.4 Hz, 1H), 8.19 (s, 1H), 7.58 (dd, J=8.5, 2.7 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 5.82 (s, 1H), 4.24 (t, J=6.3 Hz, 2H), 3.69 - 3.62 (m, 3H), 2.84 (br s, 4H), 2.67 (s, 3H), 2.09 (quin, J=6. l Hz, 2H), 1.45 (br s, 4H), 1.21 (s, 9H), 1.17 (d, J=6. l Hz, 6H), 0.92 (s, 6H).

Example 25

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-(3-ethoxypropoxy)-6’-methyl-[2,3’- bipyridine]-5’-yl]acetic acid (1.2 mg, 4% yield, 90.1% purity). LCMS Method 2: retention time = 1.68 min.; observed ion = 514.3. 1H NMR (500 MHz, METHANOL-d4) d 8.44 (d, J=2.7 Hz, 1H), 8.35 (s, 1H), 7.61 (dd, J=8.9, 2.7 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 5.72 (s,

1H), 4.25 (t, J=6.3 Hz, 2H), 3.67 (t, J=6.3 Hz, 2H), 3.55 (q, J=7.0 Hz, 2H), 3.13 - 2.86 (m, 4H), 2.78 (s, 3H), 2.12 (quin, J=6.2 Hz, 2H), 1.48 (br s, 4H), 1.24 (s, 9H), 1.21 (t, J=7.0 Hz, 3H), 0.96 (s, 6H).

Example 26

General Procedure B was followed. The experiment afforded the title compound,

(2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-(4-fluorobutoxy)-6’-methyl-[2,3’- bipyridine]-5’-yl]acetic acid (3.5 mg, 13% yield, 97.6% purity). LCMS Method 1 : retention time = 1.84 min.; observed ion = 502.3. lH NMR (500 MHz, METHANOL-d4) d 8.44 (d, J=2.4 Hz, 1H), 8.35 (s, 1H), 7.60 (dd, J=8.5, 2.4 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 5.72 (s, 1H), 4.59 (t, J=5.5 Hz, 1H), 4.50 (t, J=5.8 Hz, 1H), 4.22 (t, J=6. l Hz, 2H), 2.95 (br s, 4H),

2.78 (s, 3H), 2.02 - 1.88 (m, 4H), 1.48 (br s, 4H), 1.24 (s, 9H), 0.96 (s, 6H).

Example 27

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2- { 5- [2-(cyclohex- 1 -en- 1 -yl)ethoxy] -4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ - methyl- [2, 3’-bipyridine] -5’-yl} acetic acid (18.9 mg, 67% yield, 100% purity). LCMS Method 1 : retention time = 2.26 min.; observed ion = 536.3. 1H NMR (500 MHz, DMSO-d6) d 8.38 (d, J=2.7 Hz, 1H), 8.13 (s, 1H), 7.52 (dd, J=8.5, 3.1 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 5.86 (s, 1H), 5.52 (br s, 1H), 4.23 - 4.13 (m, 2H), 2.49 - 2.47 (m, 3H), 2.40 (br t, J=6.7 Hz, 2H), 2.08 (br s, 2H), 1.98 (br d, J=5.8 Hz, 4H), 1.62 - 1.56 (m, 2H), 1.54 - 1.48 (m, 2H), 1.31

(br s, 2H), 1.12 (s, 9H), 0.89 (br s, 3H), 0.78 (br s, 3H). Example 28

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[(5,5,5- trifluoropentyl)oxy]-[2,3’-bipyridine]-5’-yl]acetic acid (5.3 mg, 18% yield, 99.2% purity). LCMS Method 2: retention time = 2 min.; observed ion = 552.2. 1H NMR (500 MHz, METHAN OL-d4) d 8.39 (d, J=2.7 Hz, 1H), 8.18 (s, 1H), 7.58 (dd, J=8.7, 2.9 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 5.82 (s, 1H), 4.19 (t, J=6. l Hz, 2H), 2.84 (br s, 4H), 2.67 (s, 3H), 2.29 (br dd, J=l6.2, 10.7 Hz, 2H), 1.99 - 1.93 (m, 2H), 1.84 - 1.78 (m, 2H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.92 (s, 6H).

Example 29

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[5-(cyclobutylmethoxy)-4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (12.9 mg, 50% yield, 100% purity). LCMS Method 1 : retention time = 2.01 min.; observed ion = 496.3. 1H NMR (500 MHz, METHANOL-d4) d 8.37 (d, J=2.4 Hz, 1H), 8.17 (s, 1H), 7.56 (dd, J=8.5, 2.7 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.81 (s, 1H), 4.12 (d, J=6.7 Hz, 2H), 3.25 - 2.71 (m, J=6.4 Hz, 4H), 2.66 (s, 3H), 2.20 (br d, J=7.0 Hz, 2H), 2.07 - 1.95 (m, 5H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.92 (s, 6H).

Example 30

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-{5-[(cyclopent-3-en-l-yl)methoxy]-4’-(4,4-dimethylpiperidin-l-yl)-6’- methyl- [2, 3’-bipyridine] -5’-yl} acetic acid (10.7 mg, 39% yield, 98.2% purity). LCMS Method 2: retention time = 2.01 min.; observed ion = 508.2. 1H NMR (500 MHz,

METHAN OL-d4) d 8.38 (d, J=2. l Hz, 1H), 8.18 (s, 1H), 7.57 (dd, J=8.7, 2.6 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.82 (s, 1H), 5.74 (s, 2H), 4.06 (br d, J=7.0 Hz, 2H), 3.21 - 2.82 (m, 2H), 2.92 - 2.71 (m, 3H), 2.66 (s, 3H), 2.62 (br dd, J=l4.5, 9.0 Hz, 2H), 2.33 - 2.26 (m, 2H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.92 (s, 6H).

Example 31

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2- { 5- [(cyclopent- 1 -en- 1 -yl)methoxy] -4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ - methyl- [2, 3’-bipyridine] -5’-yl} acetic acid (11.3 mg, 42% yield, 98.7% purity). LCMS Method 2: retention time = 2.02 min.; observed ion = 508.2. 1H NMR (500 MHz,

METHAN OL-d4) d 8.38 (d, J=2.4 Hz, 1H), 8.18 (s, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 5.82 (s, 2H), 4.82 - 4.79 (m, 2H), 2.82 (br s, 4H), 2.66 (s, 3H), 2.43 (br d, J=7.0 Hz, 4H), 1.97 (quin, J=7.4 Hz, 2H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 32

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-[2-(2-methoxyethoxy)ethoxy]-6’- methyl-[2,3’-bipyridine]-5’-yl]acetic acid (10 mg, 35% yield, 100% purity). LCMS Method 1 : retention time = 1.61 min.; observed ion = 530.3. 1H NMR (500 MHz, METHANOL-d4) d 8.42 (d, J=2.7 Hz, 1H), 8.21 (s, 1H), 7.61 (dd, J=8.5, 3.1 Hz, 1H), 7.50 (d, J=8.9 Hz, 1H),

5.81 (s, 1H), 4.33 - 4.29 (m, 2H), 3.93 - 3.90 (m, 2H), 3.75 - 3.72 (m, 2H), 3.62 - 3.58 (m, 2H), 3.39 (s, 3H), 3.04 (br s, 2H), 2.84 (br s, 2H), 2.68 (s, 3H), 1.45 (br s, 4H), 1.22 (s, 9H), 0.92 (s, 6H).

Example 33

General Procedure B was followed. The experiment afforded the title compound,

(2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[(2-methylprop-2-en-l- yl)oxy]-[2,3’-bipyridine]-5’-yl]acetic acid (15.2 mg, 59% yield, 100% purity). LCMS Method 1 : retention time = 1.89 min.; observed ion = 482.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.40 (s, 1H), 8.19 (s, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.82 (s, 1H), 5.14 (s, 1H), 5.08 - 5.03 (m, 1H), 4.68 - 4.66 (m, 2H), 3.21 - 2.72 (m, 4H), 2.66

(s, 3H), 1.87 (s, 3H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 34

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[5-(3-cyclohexylpropoxy)-4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (15.7 mg, 53% yield, 99% purity). LCMS Method 2:

retention time = 2.59 min.; observed ion = 552.3. 1H NMR (500 MHz, DMSO-d6) d 8.38 (d, J=2.7 Hz, 1H), 8.13 (s, 1H), 7.50 (dd, J=8.9, 3.4 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 5.87 (s, 1H), 4.13 - 4.04 (m, 2H), 2.49 - 2.47 (m, 3H), 2.08 (br s, 2H), 1.77 - 1.63 (m, 6H), 1.61 (br s, 2H), 1.35 - 1.26 (m, 5H), 1.23 (s, 3H), 1.21 - 1.15 (m, 2H), 1.12 (s, 9H), 0.93 - 0.81 (m, 6H),

0.77 (br s, 3H). Example 35

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-{[(2E)-2-methylbut-2- en-l-yl]oxy}-[2,3’-bipyridine]-5’-yl]acetic acid (11.9 mg, 45% yield, 100% purity). LCMS Method 1 : retention time = 1.99 min.; observed ion = 496.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.38 (br s, 1H), 8.20 (br s, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.47 (br d, J=8.5 Hz, 1H), 5.80 (br s, 1H), 5.72 (br d, J=6.7 Hz, 1H), 4.61 (s, 2H), 3.14 - 2.82 (m, 2H), 2.83 (br s, 2H), 2.67 (br s, 3H), 1.77 (s, 3H), 1.70 (br d, J=6.7 Hz, 3H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.92 (s, 6H).

Example 36

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-(4,4,4-trifluorobutoxy)- [2,3’-bipyridine]-5’-yl]acetic acid (12.3 mg, 43% yield, 98.7% purity). LCMS Method 2: retention time = 1.88 min.; observed ion = 538.2. 1H NMR (500 MHz, METHANOL-d4) d 8.41 (br s, 1H), 8.20 (br s, 1H), 7.59 (br d, J=8.2 Hz, 1H), 7.50 (br d, J=8.2 Hz, 1H), 5.79 (br s, 1H), 4.24 (br s, 2H), 3.00 (br s, 2H), 2.84 (br s, 2H), 2.67 (br s, 3H), 2.50 - 2.39 (m, 2H), 2.13 (br d, J=7.9 Hz, 2H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.92 (s, 6H).

Example 37

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2- { 5 -[2-(tert-butoxy)ethoxy] -4’ -(4, 4-dimethylpiperidin- 1 -yl)-6’ -methyl- [2,3’-bipyridine]-5’-yl}acetic acid (12.4 mg, 44% yield, 99% purity). LCMS Method 1 : retention time = 1.9 min.; observed ion = 528.3. 1H NMR (500 MHz, METHANOL-d4) d 8.47 (d, J=2. l Hz, 1H), 8.37 (s, 1H), 7.63 (d, J=8. l Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 5.71 (s, 1H), 4.27 (br d, J=2.4 Hz, 2H), 3.83 (t, J=4.4 Hz, 2H), 2.96 (br s, 4H), 2.78 (s, 3H), 1.49 (br s, 4H), 1.27 (s, 9H), 1.24 (s, 9H), 0.97 (s, 6H).

Example 38

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-(3-phenoxypropoxy)- [2,3’-bipyridine]-5’-yl]acetic acid (16 mg, 53% yield, 100% purity). LCMS Method 1 : retention time = 2.04 min.; observed ion = 562.2. 1H NMR (500 MHz, METHANOL-d4) d 8.39 (d, J=2.4 Hz, 1H), 8.14 (s, 1H), 7.59 (dd, J=8.4, 2.6 Hz, 1H), 7.46 (d, J=8.9 Hz, 1H), 7.28 (br t, J=7.9 Hz, 2H), 6.98 - 6.91 (m, 3H), 5.79 (s, 1H), 4.36 (br t, J=6.0 Hz, 2H), 4.22 (t, J=6.0 Hz, 2H), 2.78 (br s, 2H), 2.88 - 2.71 (m, 2H), 2.65 (s, 3H), 2.33 (br quin, J=5.9 Hz, 2H), 1.42 (br s, 4H), 1.20 (s, 9H), 0.89 (s, 6H).

Example 39

General Procedure B was followed. The experiment afforded the title compound, (2S)-2- { 5 -[2-(benzyloxy)ethoxy] -4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ -methyl-[2,3’ - bipyridine]-5’-yl}-2-(tert-butoxy)acetic acid (14.8 mg, 49% yield, 100% purity). LCMS Method 1 : retention time = 1.93 min.; observed ion = 562.2. 1H NMR (500 MHz,

METHAN OL-d4) d 8.41 (d, J=2. l Hz, 1H), 8.17 (s, 1H), 7.60 (dd, J=8. l, 2.3 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.40 - 7.34 (m, 4H), 7.30 (d, J=7. l Hz, 1H), 5.82 (s, 1H), 4.65 (s, 2H), 4.34 (br s, 2H), 3.92 (br d, J=4.3 Hz, 2H), 2.97 (br s, 2H), 2.82 (br s, 2H), 2.66 (s, 3H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.90 (s, 6H). Example 40

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[(pyridin-3-yl)methoxy]- [2,3’-bipyridine]-5’-yl]acetic acid (12.3 mg, 44% yield, 100% purity). LCMS Method 1 : retention time = 1.71 min.; observed ion = 519.2. 1H NMR (500 MHz, METHANOL-d4) d 8.72 (br s, 1H), 8.57 (br s, 1H), 8.49 (s, 1H), 8.18 (s, 1H), 8.04 (br d, J=7.9 Hz, 1H), 7.68 (br d, J=6.7 Hz, 1H), 7.55 - 7.50 (m, 2H), 5.82 (s, 1H), 5.36 (s, 2H), 2.96 (br s, 2H), 2.81 (br s, 2H), 2.66 (s, 3H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.90 (s, 6H).

Example 41

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[(pyrimidin-2- yl)methoxy]-[2,3’-bipyridine]-5’-yl]acetic acid (1.4 mg, 5% yield, 78.9% purity). LCMS Method 2: retention time = 1.46 min.; observed ion = 520.2.

Example 42

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[(pyridin-4-yl)methoxy]- [2,3’-bipyridine]-5’-yl]acetic acid (7.4 mg, 26% yield, 99.1% purity). LCMS Method 2: retention time = 1.24 min.; observed ion = 519.2. 1H NMR (500 MHz, METHANOL-d4) d 8.58 (br s, 2H), 8.47 (s, 1H), 8.09 (s, 1H), 7.64 (dd, J=8.4, 2.6 Hz, 1H), 7.60 (br d, J=4.9 Hz, 2H), 7.48 (d, J=8.5 Hz, 1H), 5.74 (s, 1H), 5.39 (s, 2H), 2.74 (br s, 2H), 2.64 (s, 3H), 1.41 (br s, 4H), 1.18 (s, 9H), 0.87 (s, 6H).

Example 43

General Procedure B was followed. The experiment afforded the title compound,

(2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-(2-propoxyethoxy)-[2,3’- bipyridine]-5’-yl]acetic acid (9.1 mg, 33% yield, 97.7% purity). LCMS Method 2: retention time = 1.85 min.; observed ion = 514.3. lH NMR (500 MHz, METHANOL-d4) d 8.47 (s, 1H), 8.35 (s, 1H), 7.65 - 7.62 (m, 1H), 7.56 (d, J=8.5 Hz, 1H), 5.72 (s, 1H), 4.31 (br s, 2H), 3.87 (br d, J=4.0 Hz, 2H), 3.54 (t, J=6.6 Hz, 2H), 2.95 (br s, 4H), 2.78 (s, 3H), 1.68 - 1.61 (m,

2H), 1.49 (br s, 4H), 1.24 (s, 9H), 0.99 - 0.94 (m, 9H).

Example 44

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-[(5-methoxypentyl)oxy]-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (11.5 mg, 4l% yield, 100% purity). LCMS Method 1 : retention time = 1.86 min.; observed ion = 528.3. 1H NMR (500 MHz, METHANOL-d4) d 8.38 (d, J=2.4 Hz, 1H), 8.21 (s, 1H), 7.57 (d, J=8. l Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 5.80 (s, 1H), 4.16 (br t, J=6.4 Hz, 2H), 3.46 (t, J=6.3 Hz, 2H), 3.37 - 3.35 (m, 3H), 2.99 (br s, 2H), 2.85 (br s, 2H), 2.68 (s, 3H), 1.92 - 1.86 (m, 2H), 1.71 - 1.57 (m, 4H), 1.45 (br s, 4H), 1.22 (s,

9H), 0.92 (s, 6H).

Example 45

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-(4-ethoxybutoxy)-6’-methyl-[2,3’- bipyridine]-5’-yl]acetic acid (12 mg, 42% yield, 100% purity). LCMS Method 1 : retention time = 1.88 min.; observed ion = 528.3. 1H NMR (500 MHz, METHANOL-d4) d 8.38 (br s, 1H), 8.19 (br s, 1H), 7.60 - 7.52 (m, 1H), 7.51 - 7.43 (m, 1H), 5.79 (s, 1H), 4.20 - 4.15 (m, J=5.5 Hz, 2H), 3.57 - 3.50 (m, J=6.7, 4.0 Hz, 4H), 2.86 (br s, 2H), 2.66 (br s, 3H), 1.97 - 1.89 (m, 2H), 1.83 - 1.75 (m, 2H), 1.44 (br s, 4H), 1.22 - 1.18 (m, 9H), 0.92 (br d, J=3.4 Hz, 6H).

Example 46

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-{5-[(4,4-dimethylcyclohexyl)methoxy]-4’-(4,4-dimethylpiperidin-l- yl)-6’-methyl-[2,3’-bipyridine]-5’-yl}acetic acid (15.4 mg, 52% yield, 98.7% purity). LCMS Method 1 : retention time = 2.38 min.; observed ion = 552.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.37 (d, J=2.4 Hz, 1H), 8.19 (s, 1H), 7.56 (dd, J=8.5, 2.4 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.81 (s, 1H), 4.00 (br d, J=5.8 Hz, 2H), 2.99 (br s, 2H), 2.83 (br s, 2H), 2.67 (s, 3H), 1.76 (br d, J=l2.8 Hz, 3H), 1.53 - 1.42 (m, 6H), 1.42 - 1.31 (m, 4H), 1.21 (s, 9H), 0.97 (s, 6H), 0.92 (s, 6H).

Example 47

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-{5-[2-(cyclohexyloxy)ethoxy]-4’-(4,4-dimethylpiperidin-l-yl)-6’- methyl- [2, 3’-bipyridine] -5’-yl} acetic acid (15.9 mg, 54% yield, 100% purity). LCMS Method 1 : retention time = 1.92 min.; observed ion = 554.2. 1H NMR (500 MHz,

METHAN OL-d4) d 8.43 (br s, 1H), 8.22 (s, 1H), 7.61 (br d, J=8.5 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 5.79 (s, 1H), 4.29 (br s, 2H), 3.90 (br s, 2H), 3.43 (br s, 1H), 2.98 (br s, 2H), 2.86 (br s, 2H), 2.69 (s, 3H), 1.96 (br s, 2H), 1.77 (br s, 2H), 1.58 (br d, J=l0. l Hz, 1H), 1.46 (br s, 4H), 1.33 (br d, J=l7. l Hz, 5H), 1.22 (s, 9H), 0.93 (s, 6H). Example 48

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[5-(2-cyclobutoxyethoxy)-4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (13.7 mg, 49% yield, 99% purity). LCMS Method 1 : retention time = 1.84 min.; observed ion = 526.2. 1H NMR (500 MHz, METHANOL-d4) d 8.42 (br s, 1H), 8.21 (br s, 1H), 7.61 (br d, J=8.2 Hz, 1H), 7.50 (br d, J=8.2 Hz, 1H), 5.77 (br s, 1H), 4.27 (br s, 2H), 4.09 (br t, J=7.3 Hz, 1H), 3.81 - 3.77 (m, 2H), 2.99 (br s, 2H), 2.84 (br s, 2H), 2.68 (br s, 3H), 2.27 (br d, J=7.0 Hz, 2H), 2.02 - 1.93 (m, 2H), 1.73 (q, J=l0.4 Hz, 1H), 1.63 - 1.50 (m, 1H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.92 (s, 6H).

Example 49

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[5-(cycloheptylmethoxy)-4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (12.3 mg, 43% yield, 100% purity). LCMS Method 1 : retention time = 2.33 min.; observed ion = 538.3. 1H NMR (500 MHz, METHANOL-d4) d 8.37 (br s, 1H), 8.20 (br s, 1H), 7.56 (br d, J=8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 5.79 (br s, 1H), 3.94 (d, J=6.4 Hz, 2H), 3.02 (br s, 2H), 2.83 (br s, 2H), 2.67 (br s, 3H), 2.05 (br s, 1H), 1.96 - 1.90 (m, 2H), 1.78 (br d, J=7.0 Hz, 2H), 1.70 - 1.52 (m, 6H), 1.49 - 1.37 (m, 6H), 1.21 (s, 9H), 0.92 (s, 6H).

Example 50

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-{2-[2-(2- methoxyethoxy)ethoxy]ethoxy}-6’-methyl-[2,3’-bipyridine]-5’-yl]acetic acid (16 mg, 52% yield, 100% purity). LCMS Method 1 : retention time = 1.6 min.; observed ion = 574.3. 1H NMR (500 MHz, METHANOL-d4) d 8.41 (br s, 1H), 8.17 (br s, 1H), 7.60 (dd, J=8.7, 2.3 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 5.79 (br s, 1H), 4.31 (br s, 2H), 3.93 (br d, J=4.0 Hz, 2H), 3.76 - 3.73 (m, 2H), 3.70 - 3.65 (m, 4H), 3.58 - 3.55 (m, 2H), 3.38 (s, 3H), 2.97 (br s, 2H), 2.82 (br s, 2H), 2.66 (s, 3H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 51

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[3-(morpholin-4- yl)propoxy]-[2,3’-bipyridine]-5’-yl]acetic acid (14.9 mg, 50% yield, 100% purity). LCMS Method 1 : retention time = 1.25 min.; observed ion = 555.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.39 (br s, 1H), 8.14 (br s, 1H), 7.57 (br d, J=8.5 Hz, 1H), 7.48 (d, J=8.9 Hz, 1H), 5.79 (br s, 1H), 4.24 (br t, J=5.5 Hz, 2H), 3.84 (br s, 4H), 2.99 - 2.94 (m, 2H), 2.92 (br s, 4H), 2.98 (br s, 2H), 2.80 (br s, 2H), 2.66 (s, 3H), 2.22 - 2.16 (m, 2H), 1.44 (br s, 4H), 1.20 (s, 9H), 0.90 (s, 6H).

Example 52

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-(4-methoxybutoxy)-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (19.4 mg, 71% yield, 97.8% purity). LCMS Method 2: retention time = 1.74 min.; observed ion = 514.2. 1H NMR (500 MHz, METHANOL-d4) d 8.44 (s, 1H), 8.36 (s, 1H), 7.61 - 7.54 (m, 2H), 5.71 (s, 1H), 4.19 (t, J=6.4 Hz, 2H), 3.51 (t, J=6. l Hz, 2H), 3.37 (s, 3H), 2.96 (br s, 4H), 2.78 (s, 3H), 1.96 - 1.90 (m, 2H), 1.83 - 1.77 (m, 2H), 1.49 (br s, 4H), 1.24 (s, 9H), 0.97 (s, 6H). Example 53

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2- { 5 -[2-(cyclopentyloxy)ethoxy] -4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ - methyl- [2, 3’-bipyridine] -5’-yl} acetic acid (14.5 mg, 50% yield, 100% purity). LCMS

Method 1 : retention time = 1.93 min.; observed ion = 540.4. 1H NMR (500 MHz,

METHAN OL-d4) d 8.42 (br s, 1H), 8.21 (s, 1H), 7.61 (br d, J=8.5 Hz, 1H), 7.50 (br d, J=8.5 Hz, 1H), 5.79 (br s, 1H), 4.28 (br s, 2H), 4.06 (br s, 1H), 3.83 (br s, 2H), 3.02 (br s, 2H), 2.86 (br s, 2H), 2.69 (s, 3H), 1.79 (br s, 2H), 1.72 (br s, 4H), 1.58 (br s, 2H), 1.46 (br s, 4H), 1.22 (s, 9H), 0.93 (s, 6H).

Example 54

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[(oxan-4-yl)methoxy]- [2,3’-bipyridine]-5’-yl]acetic acid (15.8 mg, 56% yield, 100% purity). LCMS Method 1 : retention time = 1.71 min.; observed ion = 526.3. 1H NMR (500 MHz, METHANOL-d4) d 8.36 (d, J=2.4 Hz, 1H), 8.12 (s, 1H), 7.56 (d, J=8. l Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 5.77 (s, 1H), 4.05 - 4.00 (m, J=6. l Hz, 4H), 3.51 (br t, J=l 1.7 Hz, 2H), 2.96 (br s, 2H), 2.78 (br s, 2H), 2.65 (s, 3H), 2.16 (br s, 1H), 1.83 (br d, J=l3. l Hz, 2H), 1.57 - 1.46 (m, 3H), 1.44 (br s, 3H), 1.19 (s, 9H), 0.90 (s, 6H).

Example 55

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[(3-methylbut-2-en-l- yl)oxy]-[2,3’-bipyridine]-5’-yl]acetic acid (10.6 mg, 40% yield, 100% purity). LCMS Method 1 : retention time = 1.86 min.; observed ion = 496.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.36 (d, J=2. l Hz, 1H), 8.21 (s, 1H), 7.55 (dd, J=8.5, 2.4 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 5.80 (s, 1H), 5.51 (t, J=6.7 Hz, 1H), 4.73 (d, J=6.7 Hz, 2H), 2.99 (br s, 2H), 2.86 (br s, 2H), 2.68 (s, 3H), 1.82 (d, J=5.5 Hz, 6H), 1.45 (br s, 4H), 1.22 (s, 9H), 0.93 (s, 6H).

Example 56

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-(pent-l-en-3-yloxy)- [2,3’-bipyridine]-5’-yl]acetic acid (10 mg, 38% yield, 96.6% purity). LCMS Method 1 : retention time = 1.99 min.; observed ion = 496.3. 1H NMR (500 MHz, METHANOL-d4) d 8.36 (br s, 1H), 8.18 (br d, J=4.6 Hz, 1H), 7.55 (br d, J=8.5 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 5.93 - 5.83 (m, 1H), 5.81 (br s, 1H), 5.35 (br d, J=l7.7 Hz, 1H), 5.30 (br d, J=l 1.0 Hz, 1H), 4.84 - 4.78 (m, 1H), 2.96 (br s, 2H), 2.82 (br s, 2H), 2.66 (s, 3H), 1.92 - 1.78 (m, 2H), 1.44 (br s, 4H), 1.21 (s, 9H), 1.07 (br t, J=6.9 Hz, 3H), 0.91 (br d, J=5.2 Hz, 6H).

Example 57

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(5-{[l-(benzyloxy)propan-2-yl]oxy}-4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-[2,3’- bipyridine] -5’-yl)-2-(tert-butoxy)acetic acid (16.7 mg, 54% yield, 100% purity). LCMS Method 1 : retention time = 1.99 min.; observed ion = 576.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.40 (br s, 1H), 8.21 (br s, 1H), 7.62 (br d, J=8.2 Hz, 1H), 7.47 (br d, J=8.2 Hz, 1H), 7.36 - 7.27 (m, 5H), 5.77 (br s, 1H), 4.60 (br s, 2H), 3.71 (t, J=5.2 Hz, 2H), 3.01 (br s, 2H), 2.85 (br s, 2H), 2.69 (s, 3H), 1.43 (br s, 4H), 1.38 (br t, J=5.0 Hz, 3H), 1.21 (s, 9H), 0.90 (br d, J=4.9 Hz, 6H).

Example 58

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-(2-methoxy-3-methylbutoxy)-6’- methyl-[2,3’-bipyridine]-5’-yl]acetic acid (19 mg, 67% yield, 100% purity). LCMS Method 1 : retention time = 1.94 min.; observed ion = 528.3. 1H NMR (500 MHz, METHANOL-d4) d 8.39 (d, J=2.4 Hz, 1H), 8.13 (s, 1H), 7.60 (dd, J=8.5, 2.4 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H),

5.75 (s, 1H), 4.28 (br dd, J=l0. l, 2.1 Hz, 1H), 4.20 - 4.14 (m, J=l0.4, 4.6 Hz, 1H), 3.52 (d,

J= 1.2 Hz, 3H), 3.41 - 3.37 (m, J=3.4 Hz, 1H), 3.00 (br s, 2H), 2.79 (br s, 2H), 2.65 (s, 3H), 2.05 (sxt, J=6.4 Hz, 1H), 1.43 (br s, 4H), 1.19 (s, 9H), 1.04 (t, J=7.8 Hz, 6H), 0.90 (s, 6H).

Example 59

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’-methyl-5-[(4- methylcyclohexyl)methoxy]-[2,3’-bipyridine]-5’-yl]acetic acid (12.8 mg, 44% yield, 100% purity). LCMS Method 1 : retention time = min.; observed ion = 538.35, 538.35. The spectrum is of an approximate 1 : 1 mixture of diastereomers. The spectrum is reported as observed. For Example, overlapping signals such as a Me from each compound group, will produce a singlet integrating to 6H. 1H NMR (500 MHz, METHANOL-d4) d 8.38 (dd, J=7.5, 2.3 Hz, 2H), 8.20 (s, 2H), 7.60 - 7.54 (m, 2H), 7.50 - 7.47 (m, 2H), 5.78 (s, 2H), 4.07 (d,

J=6.7 Hz, 2H), 3.96 (d, J=6. l Hz, 2H), 3.03 (br s, 4H), 2.85 (br s, 4H), 2.68 (s, 6H), 2.07 - 2.01 (m, 1H), 1.94 (br d, J=l4.0 Hz, 1H), 1.81 (br d, J=l l .9 Hz, 2H), 1.74 (br s, 1H), 1.71 - 1.57 (m, 8H), 1.45 (br s, 8H), 1.41 - 1.35 (m, 4H), 1.21 (s, 18H), 1.20 - 1.12 (m, 2H), 1.10 - 1.01 (m, 2H), 1.00 (d, J=6.7 Hz, 3H), 0.95 (br d, J=6.4 Hz, 3H), 0.92 (s, 12H). Example 60

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-[(4-methoxybutan-2-yl)oxy]-6’- methyl-[2,3’-bipyridine]-5’-yl]acetic acid (17.6 mg, 64% yield, 99.4% purity). LCMS Method 1 : retention time = 1.65 min.; observed ion = 514.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.42 (br s, 1H), 8.37 (br s, 1H), 7.63 - 7.59 (m, 1H), 7.56 (d, J=8.5 Hz, 1H), 5.71 (s, 1H), 4.81 - 4.78 (m, 1H), 3.60 - 3.53 (m, J=5.8 Hz, 2H), 3.35 - 3.34 (m, 3H), 2.97 (br s, 4H), 2.79 (s, 3H), 2.04 (br dd, J=l3.6, 6.9 Hz, 1H), 1.95 (br d, J=6.4 Hz, 1H), 1.49 (br s, 4H), 1.42 - 1.38 (m, 3H), 1.24 (s, 9H), 0.97 (s, 6H).

Example 61

General Procedure B was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-[(l-ethoxypropan-2-yl)oxy]-6’- methyl-[2,3’-bipyridine]-5’-yl]acetic acid (16.5 mg, 60% yield, 100% purity). LCMS Method 1 : retention time = 1.81 min.; observed ion = 514.3. 1H NMR (500 MHz, METHANOL-d4) d 8.45 (d, J=2.4 Hz, 1H), 8.37 (d, J=4.6 Hz, 1H), 7.65 (dd, J=8.7, 2.6 Hz, 1H), 7.56 (br dd, J=8.9, 1.8 Hz, 1H), 5.71 (s, 1H), 4.84 - 4.78 (m, 1H), 3.67 (dd, J=4.7, 2.0 Hz, 2H), 3.63 - 3.55 (m, 2H), 2.97 (br s, 4H), 2.79 (s, 3H), 1.49 (br s, 4H), 1.37 (dd, J=6.3, 2.9 Hz, 3H), 1.24 (s, 9H), 1.20 (td, J=7.0, 2.1 Hz, 3H), 0.97 (s, 6H).

Example 62

General Procedure C was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-{5-[4-(cyclohexylmethoxy)phenyl]-4-(4,4-dimethylpiperidin-l-yl)-2- methylpyridin-3-yl} acetic acid (11.7 mg, 42% yield, 98% purity). LCMS Method 1 : retention time = 2.41 min.; observed ion = 523.4.

Example 63

General Procedure C was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5-[4-(3-methoxypropoxy)phenyl]-2- methylpyridin-3-yl]acetic acid (1.9 mg, 7% yield, 95.4% purity). LCMS Method 2: retention time = 1.75 min.; observed ion = 499.3. lH NMR (500 MHz, METHANOL-d4) d 8.08 (s,

1H), 7.28 (br d, J=7.9 Hz, 2H), 7.09 (br d, J=8.9 Hz, 2H), 5.67 (s, 1H), 4.14 (t, J=6.3 Hz, 2H), 3.62 (t, J=6. l Hz, 2H), 3.38 (s, 3H), 2.78 (br s, 2H), 2.69 (s, 3H), 2.08 (quin, J=6.2 Hz, 2H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.92 (s, 6H).

Example 64

General Procedure C was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-{5-[4-(2-cyclohexylethoxy)phenyl]-4-(4,4-dimethylpiperidin-l-yl)-2- methylpyridin-3-yl}acetic acid (8.1 mg, 28% yield, 98.2% purity). LCMS Method 2:

retention time = 2.54 min.; observed ion = 537.3. 1H NMR (500 MHz, METHANOL-d4) d 8.12 (s, 1H), 7.28 (br d, J=7.3 Hz, 2H), 7.08 (br d, J=8.5 Hz, 2H), 5.67 (s, 1H), 4.11 (t, J=6.6

Hz, 2H), 2.98 (br s, 2H), 2.80 (br s, 2H), 2.71 (s, 3H), 1.82 (br d, J=l2.2 Hz, 2H), 1.79 - 1.68 (m, 5H), 1.57 (br s, 1H), 1.46 (br s, 4H), 1.36 - 1.27 (m, 3H), 1.21 (s, 9H), 1.08 - 0.99 (m, 2H), 0.93 (s, 6H). Example 65

To a 1 dram vial equipped with a stir bar was added isopropyl (S)-2-(tert-butoxy)-2- (4-(4,4-dimethylpiperidin- l-yl)-5',6'-difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (25 mg, 0.051 mmol), butane- 1 -thiol (13.81 mg, 0.153 mmol), and THF (0.350 mL). To the solution was added potassium 2-methylpropan-2-olate in THF (0.153 mL, 0.153 mmol) upon which a fine white solid immediately ppt'd. The suspension was stirred at r.t. for 1.5 h. The volatiles were evaporated under a N2 gas stream. The residue was dissolved in EtOH (1.0 mL). To the solution was added aq. sodium hydroxide (5M, 0.153 mL, 0.766 mmol). The vial was capped, then placed in a 85 deg C heating block with for 1 h. The mixture was filtered through a 0.4 micron syringe filter. The filtrate was directly subjected to HPLC purification with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 -pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 36% B, 36- 76% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 C. This purification afforded (S)-2-(tert-butoxy)-2-(6'-(butylthio)-4-(4,4- dimethylpiperidin-l-yl)-5'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (10.3 mg, 38 % yield, 96.5% purity). LCMS Method 1 : retention time = 2.17 min.; observed ion = 518.2. 1H NMR (500 MHz, METHANOL-d4) d 8.29 (s, 1H), 8.16 (s, 1H), 7.51 (br d, J=l0.4 Hz, 1H),

5.81 (s, 1H), 3.40 - 3.34 (m, 1H), 3.27 - 3.19 (m, 1H), 3.11 (br s, 2H), 2.78 (br s, 2H), 2.65 (s, 3H), 1.77 - 1.70 (m, 2H), 1.55 - 1.41 (m, 6H), 1.21 (s, 9H), 0.98 (t, J=7.3 Hz, 3H), 0.92 (s, 6H).

Example 66

To a 1 dram vial equipped with a stir bar was added isopropyl (S)-2-(tert-butoxy)-2- (4-(4,4-dimethylpiperidin- l-yl)-5',6'-difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (25 mg, 0.051 mmol), 2-methylpropane-l -thiol (13.81 mg, 0.153 mmol), and THF (0.350 mL). To the solution was added potassium 2-methylpropan-2-olate in THF (0.153 mL, 0.153 mmol) upon which a fine white solid immediately ppt'd. The suspension was stirred at r.t. for 1.5 h. The volatiles were evaporated under a N2 gas stream. The residue was dissolved in EtOH (1.0 mL). To the solution was added aq. sodium hydroxide (5M, 0.153 mL, 0.766 mmol). The vial was capped, then placed in a 85 deg C heating block with for 1 h. The mixture was filtered through a 0.4 micron syringe filter. The filtrate was directly subjected to HPLC purification with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 -pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 37% B, 37-77% B over 20 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 C. This purification afforded (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-5'-fluoro-6'-(isobutylthio)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (11.6 mg, 42 % yield, 96.4% purity). LCMS Method 1 : retention time = 2.17 min.; observed ion = 518.2. 1H NMR (500 MHz, METHANOL-d4) d 8.28 (s, 1H), 8.16 (s, 1H), 7.5 l (br d, J=9.5 Hz, 1H), 5.80 (br s, 1H), 3.33 - 3.28 (m, J=l .2 Hz, 1H), 3.16 - 3.16 (m, 1H), 3.20 - 3.12 (m, J= 13.3, 6.6 Hz, 1H), 2.85 - 2.71 (m, 2H), 2.65 (s, 3H), 1.97 (br d, J=6.4 Hz, 1H), 1.46 (br s, 4H), 1.21 (s, 9H), 1.07 (d, J=6.7 Hz, 6H), 0.92 (s, 6H), 0.87 (br s, 1H).

Example 67

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5’-fhioro-6-methyl-6’-[2-(morpholin- 4-yl)ethoxy]-[3,3’-bipyridine]-5-yl]acetic acid (20.5 mg, 36% yield). LCMS Method 2: retention time = 1.52 min.; observed ion = 559.3. 1H NMR (500 MHz, METHANOL-d4) d 8.03 (s, 1H), 7.93 (s, 1H), 7.57 (br d, J=l0.7 Hz, 1H), 5.71 (s, 1H), 4.66 (br t, J=5.5 Hz, 2H), 3.77 - 3.73 (m, 4H), 2.94 (br t, J=5.5 Hz, 2H), 2.70 (br s, 6H), 2.64 (s, 3H), 1.44 (br s, 4H), 1.18 (s, 9H), 0.91 (s, 6H). Example 68

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[6’-(cyclohexylmethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6- methyl-[3,3’-bipyridine]-5-yl]acetic acid (15.7 mg, 28% yield). LCMS Method 1 : retention time = 2.32 min.; observed ion = 542.3. lH NMR (500 MHz, DMSO-d6) d 8.10 (s, 1H), 7.92 (s, 1H), 7.75 (br d, J=l l.3 Hz, 1H), 5.81 (s, 1H), 4.28 (dd, J=l0.4, 6.1 Hz, 1H), 4.20 (dd, J=l0.5, 6.3 Hz, 1H), 2.20 (br s, 2H), 1.79 (br d, J=l2.8 Hz, 3H), 1.74 - 1.62 (m, 3H), 1.52 (br s, 1H), 1.40 - 1.15 (m, 9H), 1.13 (s, 9H), 1.10 - 1.03 (m, 2H), 0.87 (br s, 3H), 0.75 (br s, 3H).

Example 69

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6’-(3-methoxypropoxy)-6- methyl-[3,3’-bipyridine]-5-yl]acetic acid (18.5 mg, 35% yield). LCMS Method 2: retention time = 1.79 min.; observed ion = 518.3. 1H NMR (500 MHz, METHANOL-d4) d 8.11 (s, 1H), 7.92 (s, 1H), 7.57 (br d, J=l0.7 Hz, 1H), 5.77 (br s, 1H), 4.54 (br t, J=6.3 Hz, 2H), 3.61 (t, J=6.3 Hz, 2H), 3.38 (s, 3H), 2.76 (br s, 2H), 2.65 (s, 3H), 2.11 (quin, J=6.3 Hz, 2H), 1.46 (br s, 4H), 1.20 (s, 9H), 0.92 (s, 6H).

Example 70

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[6’-(2-cyclohexylethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6- methyl-[3,3’-bipyridine]-5-yl]acetic acid (16.5 mg, 29% yield). LCMS Method 1 : retention time = 2.41 min.; observed ion = 556.3. lH NMR (500 MHz, METHANOL-d4) d 8.13 (s, 1H), 7.92 (s, 1H), 7.57 (br d, J=l 1.0 Hz, 1H), 5.79 (br s, 1H), 4.57 - 4.47 (m, 2H), 2.78 (br s, 2H), 2.65 (s, 3H), 1.83 (br d, J=l2.5 Hz, 2H), 1.79 - 1.72 (m, 4H), 1.70 (br d, J=l3. l Hz, 1H), 1.54 (br s, 1H), 1.46 (br s, 4H), 1.36 - 1.23 (m, 4H), 1.21 (s, 9H), 1.09 - 1.00 (m, 2H), 0.93 (s, 6H).

Example 71

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-{6’-[2-(tert-butylamino)ethoxy]-4-(4,4-dimethylpiperidin-l-yl)-5’- fluoro-6-methyl-[3,3’-bipyridine]-5-yl}acetic acid (20 mg, 36% yield). LCMS Method 2: retention time = 1.35 min.; observed ion = 545.3.

Example 72

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin- 1 -yl)-5’ -fluoro-6-methyl-6’ -[( 1 - methylpiperidin-4-yl)methoxy]-[3,3’-bipyridine]-5-yl]acetic acid (24.5 mg, 43% yield). LCMS Method 1 : retention time = 1.35 min.; observed ion = 557.3.

Example 73

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin- 1 -yl)-5’ -fluoro-6-methyl-6’ -[3 -(piperidin- 1 - yl)propoxy]-[3,3’-bipyridine]-5-yl]acetic acid (27.1 mg, 47% yield). LCMS Method 1 :

retention time = 1.42 min.; observed ion = 571.4. 1H NMR (500 MHz, METHANOL-d4) d 7.98 (s, 1H), 7.93 (s, 1H), 7.58 (br d, J=l0.4 Hz, 1H), 5.67 (s, 1H), 4.57 (br t, J=5.6 Hz, 2H), 3.31 - 3.28 (m, 2H), 3.26 (br s, 4H), 2.63 (s, 3H), 2.68 (br s, 2H), 2.32 (br d, J=6. l Hz, 2H), 1.89 (br s, 4H), 1.70 (br s, 2H), 1.43 (br s, 4H), 1.17 (s, 9H), 0.89 (s, 6H).

Example 74

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin- 1 -yl)-5’ -fluoro-6-methyl-6’ -(2- phenoxyethoxy)-[3,3’-bipyridine]-5-yl]acetic acid (15.7 mg, 27% yield). LCMS Method 2: retention time = 1.97 min.; observed ion = 566.3. 1H NMR (500 MHz, METHANOL-d4) d 8.18 (br s, 1H), 7.96 (s, 1H), 7.62 (br d, J=9.8 Hz, 1H), 7.30 (t, J=7.2 Hz, 2H), 7.00 - 6.95 (m,

3H), 5.75 (br s, 1H), 4.41 (br t, J=4.4 Hz, 2H), 2.82 (br s, 2H), 2.68 (s, 3H), 1.46 (br s, 4H), 1.22 (s, 9H), 0.93 (s, 6H).

Example 75

General Procedure D was followed. The experiment afforded the title compound,

(2S)-2-(tert-butoxy)-2-[6’-(2,2-difluoropropoxy)-4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6- methyl-[3,3’-bipyridine]-5-yl]acetic acid (7.7 mg, 14% yield). LCMS Method 2: retention time = 1.9 min.; observed ion = 524.2. 1H NMR (500 MHz, METHAN OL-d4) d 8.16 (s, 1H), 7.97 (s, 1H), 7.67 (br d, J=l0. l Hz, 1H), 5.77 (br s, 1H), 4.78 - 4.62 (m, 2H), 3.12 (br s, 2H), 2.80 (br s, 2H), 2.67 (s, 3H), 1.78 (t, J=l8.8 Hz, 3H), 1.46 (br s, 4H), 1.21 (s, 9H), 0.93 (s,

6H).

Example 76

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2- { 6’ -[2-(cyclohex- 1 -en- 1 -yl)ethoxy] -4-(4,4-dimethylpiperidin- 1 -yl)-5’ - fluoro-6-methyl-[3,3’-bipyridine]-5-yl}acetic acid (8.9 mg, 16% yield). LCMS Method 1 : retention time = 2.33 min.; observed ion = 554.3. 1H NMR (500 MHz, METHANOL-d4) d 8.14 (s, 1H), 7.92 (s, 1H), 7.57 (br d, J=l0.4 Hz, 1H), 5.74 (br s, 1H), 5.53 (br s, 1H), 4.55 (br t, J=6.9 Hz, 2H), 2.80 (br s, 2H), 2.67 (s, 3H), 2.47 (br t, J=6.6 Hz, 2H), 2.07 (br s, 2H), 2.01 (br s, 2H), 1.66 (br d, J=5.8 Hz, 2H), 1.61 - 1.54 (m, 2H), 1.46 (br s, 4H), 1.21 (s, 9H), 0.93 (s, 6H).

Example 77

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6-methyl-6’-[2- (trimethylsilyl)ethoxy]-[3,3’-bipyridine]-5-yl]acetic acid (11.3 mg, 20% yield). LCMS Method 1 : retention time = 2.29 min.; observed ion = 546.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.16 (br s, 1H), 7.93 (s, 1H), 7.57 (br d, J=l0.7 Hz, 1H), 5.73 (br s, 1H), 4.69 - 4.54 (m, 2H), 3.13 (br s, 2H), 2.80 (br s, 2H), 2.67 (br s, 3H), 1.46 (br s, 4H), 1.24 - 1.22 (m, 2H), 1.21 (s, 9H), 0.93 (s, 6H), 0.11 (s, 9H).

Example 78

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin- 1 -yl)-6’ -[( 1 -ethoxypropan-2-yl)oxy] -5 - fluoro-6-methyl-[3,3’-bipyridine]-5-yl]acetic acid (17.7 mg, 33% yield). LCMS Method 1: retention time = 1.9 min.; observed ion = 532.3. 1H NMR (500 MHz, METHANOL-d4) d 8.15 (br d, J=3.4 Hz, 1H), 7.93 (br s, 1H), 7.58 (br d, J=l0. l Hz, 1H), 5.77 (br s, 1H), 5.59 - 5.50 (m, 1H), 3.76 - 3.69 (m, 1H), 3.69 - 3.56 (m, 3H), 3.14 (br s, 2H), 2.80 (br s, 2H), 2.66 (s, 3H), 1.46 (br s, 4H), 1.40 (dd, J=8.9, 6.7 Hz, 3H), 1.23 - 1.18 (m, 12H), 0.93 (s, 6H). Example 79

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6’-[(3-methoxybutan-2- yl)oxy]-6-methyl-[3,3’-bipyridine]-5-yl]acetic acid (16.3 mg, 30% yield). LCMS Method 2: retention time = 1.83 min.; observed ion = 532.3. 1H NMR (500 MHz, METHANOL-d4) d 8.16 (br s, 1H), 7.93 (s, 1H), 7.59 (br d, J=l l .0 Hz, 1H), 5.77 (br s, 1H), 5.44 (br dd, J=l l .4, 5.6 Hz, 1H), 3.62 (br d, J=3. l Hz, 1H), 3.43 (d, J=5.5 Hz, 3H), 3.14 (br s, 2H), 2.81 (br s, 2H), 2.67 (s, 3H), 1.46 (br s, 4H), 1.38 (br t, J=6.4 Hz, 3H), 1.26 (t, J=6.0 Hz, 3H), 1.21 (s, 9H), 0.93 (s, 6H).

Example 80

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(6’-{[l-(benzyloxy)propan-2-yl]oxy}-4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6- methyl- [3, 3’-bipyridine] -5 -yl)-2-(tert-butoxy)acetic acid (13 mg, 21% yield). LCMS Method

2: retention time = 2.09 min.; observed ion = 594.3. 1H NMR (500 MHz, METHANOL-d4) d 8.13 (br d, J=8.5 Hz, 1H), 7.91 (br s, 1H), 7.58 (br d, J=9.8 Hz, 1H), 7.36 - 7.31 (m, 4H), 7.30 - 7.26 (m, 1H), 5.76 (br s, 1H), 5.65 - 5.56 (m, 1H), 4.66 - 4.58 (m, 2H), 3.81 - 3.69 (m, 2H), 3.12 (br s, 2H), 2.79 (br s, 2H), 2.66 (s, 3H), 1.49 - 1.37 (m, 7H), 1.21 (s, 9H), 0.90 (br d, J=8.5 Hz, 6H).

Example 81

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6-methyl-6’-[(4- methy ley clohexyl)methoxy]- [3, 3’-bipyridine] -5 -yl] acetic acid (10.7 mg, 19% yield). LCMS Method 2: retention time = 2.4 min.; observed ion = 556.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.15 (s, 1H), 7.92 (s, 1H), 7.58 (br d, J=l0.7 Hz, 1H), 5.76 (s, 1H), 4.48 - 4.42 (m, 1H), 4.40 - 4.35 (m, 1H), 3.15 (br s, 2H), 2.80 (br s, 2H), 2.67 (s, 3H), 2.10 - 2.01 (m, 1H), 1.71 (br s, 1H), 1.66 - 1.55 (m, 6H), 1.46 (br s, 4H), 1.39 - 1.33 (m, 2H), 1.21 (s, 9H), 0.98 (d, J=7.0 Hz, 3H), 0.93 (s, 6H).

Example 82

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin- 1 -yl)-5’ -fluoro-6’ -[(4-methoxybutan-2- yl)oxy]-6-methyl-[3,3’-bipyridine]-5-yl]acetic acid (15.6 mg, 29% yield). LCMS Method 1 : retention time = 1.88 min.; observed ion = 532.3. 1H NMR (500 MHz, METHANOL-d4) d 8.16 (br s, 1H), 7.92 (s, 1H), 7.58 (br d, J=l0.4 Hz, 1H), 5.73 (br s, 1H), 5.54 - 5.46 (m, J=5.8 Hz, 1H), 3.56 (q, J=5.8 Hz, 2H), 3.33 (s, 3H), 3.14 (br s, 2H), 2.80 (br s, 2H), 2.67 (br s, 3H), 2.07 (dt, J=l3.6, 6.9 Hz, 1H), 2.01 - 1.93 (m, 1H), 1.46 (br s, 4H), 1.42 (t, J=6.4 Hz, 3H),

1.21 (s, 9H), 0.93 (s, 6H).

Example 83

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6’-(2-methoxy-3- methylbutoxy)-6-methyl-[3,3’-bipyridine]-5-yl]acetic acid (15.6 mg, 28% yield). LCMS Method 1 : retention time = 2.05 min.; observed ion = 546.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.18 (br s, 1H), 7.94 (br s, 1H), 7.61 (br d, J=l0. l Hz, 1H), 5.70 (br s, 1H), 4.72 - 4.61 (m, 1H), 4.52 - 4.42 (m, 1H), 3.52 (d, J=l .8 Hz, 3H), 3.41 (br d, J=3.4 Hz, 1H), 3.14 (br s, 2H), 2.81 (br s, 2H), 2.67 (br s, 3H), 2.01 (sxt, J=6.4 Hz, 1H), 1.46 (br s, 4H), 1.21 (s, 9H), 1.03 (br t, J=5.6 Hz, 6H), 0.93 (s, 6H).

Example 84

General Procedure D was followed. The experiment afforded the title compound,

(2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin- 1 -yl)-5’ -fluoro-6-methyl-6’-[(1,1,1- trifluoro-3-phenylpropan-2-yl)oxy]-[3,3’-bipyridine]-5-yl]acetic acid (13.8 mg, 22% yield). LCMS Method 2: retention time = 2.24 min.; observed ion = 618.2. The NMR spectrum is a mixture of two diastereomers in an approximate 1 : 1 ratio. The spectrum is reported as observed, with apparent splitting patterns. 1H NMR (500 MHz, METHANOL-d4) d 8.07 (br s, 1H), 7.81 (br d, J=l8.3 Hz, 1H), 7.59 (br dd, J=l6.2, 10.7 Hz, 1H), 7.34 (br d, J=7.0 Hz, 2H), 7.27 - 7.14 (m, 3H), 6.30 (d, J=30.2 Hz, 1H), 5.74 (br s, 1H), 3.33 - 3.29 (m, 1H), 3.26 - 3.18 (m, 1H), 2.70 (br s, 2H), 2.64 (br s, 3H), 1.42 (br s, 4H), 1.19 (s, 9H), 0.90 (br d, J=l6.2 Hz, 6H).

Example 85

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6-methyl-6’-(3,3,3- trifluoropropoxy)-[3,3’-bipyridine]-5-yl]acetic acid (7.7 mg, 14% yield). LCMS Method 1 : retention time = 1.93 min.; observed ion = 542.2. 1H NMR (500 MHz, METHANOL-d4) d 8.09 (br s, 1H), 7.95 (s, 1H), 7.60 (br d, J=l0.4 Hz, 1H), 5.73 (br s, 1H), 4.76 - 4.68 (m, 2H), 3.16 (br s, 2H), 2.85 - 2.69 (m, 4H), 2.65 (s, 3H), 1.45 (br s, 4H), 1.19 (s, 9H), 0.91 (s, 6H). Example 86

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6-methyl-6’-[2-(propan-2- yloxy)ethoxy]-[3,3’-bipyridine]-5-yl]acetic acid (18 mg, 33% yield). LCMS Method 2:

retention time = 1.98 min.; observed ion = 532.3. 1H NMR (500 MHz, METHANOL-d4) d 8.17 (s, 1H), 7.94 (s, 1H), 7.60 (br d, J=l0.7 Hz, 1H), 5.77 (s, 1H), 4.62 - 4.57 (m, 2H), 3.90 - 3.86 (m, 2H), 3.75 (quin, J=6. l Hz, 1H), 2.82 (br s, 2H), 2.67 (s, 3H), 1.47 (br s, 4H), 1.22 (s, 9H), 1.20 (br d, J=6.4 Hz, 6H), 0.94 (s, 6H).

Example 87

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[6’-(2,3-dihydro-lH-inden-2-yloxy)-4-(4,4-dimethylpiperidin-l-yl)-5’- fluoro-6-methyl-[3,3’-bipyridine]-5-yl]acetic acid (18.6 mg, 33% yield). LCMS Method 2: retention time = 2.24 min.; observed ion = 562.3. 1H NMR (500 MHz, METHANOL-d4) d 8.17 (s, 1H), 7.98 (s, 1H), 7.58 (br d, J=l0.4 Hz, 1H), 7.27 (br d, J=4.3 Hz, 2H), 7.22 - 7.18 (m, 2H), 5.94 (br s, 1H), 5.80 (br s, 1H), 3.50 (dd, J=l6.8, 6.4 Hz, 2H), 3.19 (br t, J=l8.2 Hz, 2H), 3.15 (br s, 2H), 2.82 (br s, 2H), 2.67 (s, 3H), 1.47 (br s, 4H), 1.22 (s, 9H), 0.95 (s, 6H).

Example 88

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2- { 6’ -[(cyclopent-3 -en- 1 -yl)methoxy] -4-(4,4-dimethylpiperidin- 1 -yl)-5’ - fluoro-6-methyl-[3,3’-bipyridine]-5-yl}acetic acid (15.3 mg, 29% yield). LCMS Method 2: retention time = 2.21 min.; observed ion = 526.3. 1H NMR (500 MHz, METHANOL-d4) d 8.07 (s, 1H), 7.91 (s, 1H), 7.56 (br d, J=l0.7 Hz, 1H), 5.75 (br s, 1H), 5.74 (s, 2H), 4.41 - 4.33 (m, 2H), 2.90 - 2.82 (m, 1H), 2.73 (br s, 2H), 2.64 (s, 3H), 2.59 (br dd, J=l4.3, 8.5 Hz, 2H), 2.28 (br d, J=l4.6 Hz, 2H), 1.44 (br s, 4H), 1.20 (s, 9H), 0.91 (s, 6H).

Example 89

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6-methyl-6’-[(piperidin-4- yl)methoxy]-[3,3’-bipyridine]-5-yl]acetic acid (22.4 mg, 41% yield). LCMS Method 2: retention time = 1.31 min.; observed ion = 543.3. 1H NMR (500 MHz, METHANOL-d4) d 8.02 (br s, 1H), 7.90 (s, 1H), 7.47 (br d, J=l0. l Hz, 1H), 5.69 (br s, lH), 4.3 l (br dd, J=l0.4, 5.8 Hz, 1H), 4.17 (br s, 1H), 3.45 (br t, J= 11.1 Hz, 2H), 3.07 - 2.99 (m, 2H), 2.65 (s, 3H),

2.21 (br s, 1H), 2.12 (br d, J=l3.7 Hz, 1H), 2.04 (d, J=l3.7 Hz, 1H), 1.64 - 1.47 (m, 2H), 1.44 (br s, 4H), 1.18 (s, 9H), 0.90 (s, 6H).

Example 90

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6-methyl-6’-[2- (thiomorpholin-4-yl)ethoxy]-[3,3’-bipyridine]-5-yl]acetic acid (20 mg, 34% yield). LCMS Method 1 : retention time = 1.45 min.; observed ion = 575.3. 1H NMR (500 MHz,

METHAN OL-d4) d 8.02 (s, 1H), 7.93 (s, 1H), 7.57 (br d, J=l0.4 Hz, 1H), 5.70 (s, 1H), 4.70 4.61 (m, 2H), 3.02 - 2.94 (m, 6H), 2.74 - 2.70 (m, 4H), 2.70 (br s, 2H), 2.64 (s, 3H), 1.44 (br s, 4H), 1.18 (s, 9H), 0.91 (s, 6H). Example 91

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2- { 6’ - [2-(tert-butoxy)ethoxy] -4-(4,4-dimethylpiperidin- 1 -yl)-5’ -fluoro- 6-methyl-[3,3’-bipyridine]-5-yl}acetic acid (11.9 mg, 21% yield). LCMS Method 2: retention time = 2.79 min.; observed ion = 546.3. 1H NMR (500 MHz, METHANOL-d4) d 8.16 (s, 1H), 7.93 (s, 1H), 7.59 (br d, J=l0. l Hz, 1H), 5.78 (s, 1H), 4.56 (t, J=4.7 Hz, 2H), 3.83 (t, J=4.9 Hz, 2H), 2.80 (br s, 2H), 2.67 (s, 3H), 1.47 (br s, 4H), 1.26 (s, 9H), 1.21 (s, 9H), 0.93 (s, 6H).

Example 92

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[6’-(cyclopentylmethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6- methyl-[3,3’-bipyridine]-5-yl]acetic acid (15.1 mg, 28% yield). LCMS Method 2: retention time = 2.3 min.; observed ion = 528.3. 1H NMR (500 MHz, METHAN OL-d4) d 8.12 (s, 1H), 7.91 (s, 1H), 7.57 (br d, J=l l .0 Hz, 1H), 5.78 (br s, 1H), 4.40 - 4.32 (m, 2H), 2.78 (br s, 2H), 2.65 (s, 3H), 2.46 (dt, J=l5. l, 7.4 Hz, 1H), 1.92 - 1.85 (m, 2H), 1.75 - 1.60 (m, 4H), 1.52 - 1.38 (m, J=6.7 Hz, 6H), 1.21 (s, 9H), 0.92 (s, 6H).

Example 93

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(6’ - { [3 -(benzyloxy)butan-2-yl]oxy } -4-(4,4-dimethylpiperidin- 1 -yl)-5’ -fluoro-6- methyl-[3,3’-bipyridine] -5 -yl)-2-(tert-butoxy)acetic acid (15.2 mg, 24% yield). LCMS Method 1 : retention time = 2.31 min.; observed ion = 608.3. 1H NMR (500 MHz, DMSO-d6) d 8.11 - 8.06 (m, 1H), 7.89 (br s, 1H), 7.78 - 7.73 (m, J=7.0 Hz, 1H), 7.33 - 7.23 (m, 5H),

5.79 (br s, 1H), 5.44 - 5.36 (m, 1H), 4.64 - 4.47 (m, 3H), 3.76 (br s, 1H), 2.49 (s, 3H), 2.20 (br s, 2H), 1.51 (br s, 1H), 1.33 (br dd, J=l3. l, 6.4 Hz, 3H), 1.30 (br s, 1H), 1.26 - 1.18 (m, 4H), 1.12 (s, 9H), 0.86 (br s, 3H), 0.68 (br d, J=l9.2 Hz, 3H).

Example 94

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6-methyl-6’-[(3-methylbut- 3-en-l-yl)oxy]-[3,3’-bipyridine]-5-yl]acetic acid (16.5 mg, 32% yield). LCMS Method 1 : retention time = 2.15 min.; observed ion = 514.3. 1H NMR (500 MHz, METHANOL-d4) d 8.15 (s, 1H), 7.93 (s, 1H), 7.57 (br d, J=l0.7 Hz, 1H), 5.78 (br s, 1H), 4.83 (d, J=l8.6 Hz, 2H), 4.67 - 4.54 (m, 2H), 3.14 (br s, 2H), 2.79 (br s, 2H), 2.66 (s, 3H), 2.58 (t, J=6.6 Hz, 2H), 1.85 (s, 3H), 1.46 (br s, 4H), 1.21 (s, 9H), 0.93 (s, 6H).

Example 95

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6-methyl-6’-(3- phenoxypropoxy)-[3,3’-bipyridine]-5-yl]acetic acid (24.6 mg, 42% yield). LCMS Method 1 : retention time = 2.21 min.; observed ion = 580.3. 1H NMR (500 MHz, METHANOL-d4) d 8.12 (s, 1H), 7.92 (s, 1H), 7.57 (br d, J=l 1.0 Hz, 1H), 7.27 (t, J=8. l Hz, 2H), 6.96 - 6.91 (m, 3H), 5.78 (s, 1H), 4.68 (br dd, J=6. l, 4.3 Hz, 2H), 4.20 (t, J=6. l Hz, 2H), 2.78 (br s, 2H), 2.65 (s, 3H), 2.33 (quin, J=6. l Hz, 2H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.91 (s, 6H). Example 96

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[6’-(cyclobutylmethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6- methyl-[3,3’-bipyridine]-5-yl]acetic acid (13.1 mg, 25% yield). LCMS Method 2: retention time = 2.9 min.; observed ion = 514.2. 1H NMR (500 MHz, METHAN OL-d4) 5 8.13 (br s, 1H), 7.91 (s, 1H), 7.57 (br d, J=l0.4 Hz, 1H), 5.77 (br s, 1H), 4.49 - 4.40 (m, 2H), 3.14 (br s, 2H), 2.87 (quin, J=7.2 Hz, 1H), 2.78 (br s, 2H), 2.65 (br s, 3H), 2.17 (br d, J=8.2 Hz, 2H), 2.05 - 1.92 (m, 4H), 1.46 (br s, 4H), 1.21 (s, 9H), 0.93 (s, 6H).

Example 97

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[6’-(2-cyclopropylethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6- methyl-[3,3’-bipyridine]-5-yl]acetic acid (20.2 mg, 39% yield). LCMS Method 1 : retention time = 2.14 min.; observed ion = 514.3. 1H NMR (500 MHz, METHANOL-d4) 5 8.09 (s, 1H), 7.92 (s, 1H), 7.56 (br d, J=l l .0 Hz, lH), 5.75 (s, 1H), 4.58 - 4.51 (m, 2H), 2.75 (br s, 2H), 2.65 (s, 3H), 1.75 (q, J=6.9 Hz, 2H), 1.45 (br s, 4H), 1.20 (s, 9H), 0.92 (s, 6H), 0.91 - 0.85 (m, 1H), 0.53 - 0.48 (m, 2H), 0.18 - 0.14 (m, 2H).

Example 98

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[6’-(cyclopropylmethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6- methyl-[3,3’-bipyridine]-5-yl]acetic acid (13.6 mg, 27% yield). LCMS Method 2: retention time = 2.04 min.; observed ion = 500.3. lH NMR (500 MHz, METHANOL-d4) d 8.14 (br s, 1H), 7.91 (s, 1H), 7.57 (br d, J=l 1.0 Hz, 1H), 5.75 (br s, 1H), 4.37 - 4.27 (m, 2H), 2.79 (br s, 2H), 2.66 (br s, 3H), 1.46 (br s, 4H), 1.40 - 1.35 (m, 1H), 1.21 (s, 9H), 0.93 (s, 6H), 0.65 (br d, J=7.9 Hz, 2H), 0.42 (br d, J=4.6 Hz, 2H).

Example 99

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[6’-(2-cyclopentylethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5’-fluoro-6- methyl-[3,3’-bipyridine]-5-yl]acetic acid (17 mg, 31% yield). LCMS Method 1: retention time = 2.36 min.; observed ion = 542.3. 1H NMR (500 MHz, METHANOL-d4) d 8.13 (br s, 1H), 7.92 (s, 1H), 7.57 (br d, J=l 1.0 Hz, 1H), 5.75 (br s, 1H), 4.56 - 4.45 (m, 2H), 2.78 (br s, 2H), 2.65 (br s, 3H), 2.05 - 1.98 (m, 1H), 1.88 (q, J=7.0 Hz, 4H), 1.69 (br s, 2H), 1.66 - 1.53 (m, 2H), 1.46 (br s, 4H), 1.27 - 1.22 (m, 2H), 1.21 (s, 9H), 0.92 (s, 6H).

Example 100

General Procedure D was followed. The experiment afforded the title compound, (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin- 1 -yl)-5’ -fluoro-6’ -(3-fluoropropoxy)-6- methyl-[3,3’-bipyridine]-5-yl]acetic acid (11.8 mg, 23% yield). LCMS Method 1 : retention time = 1.77 min.; observed ion = 506.2. 1H NMR (500 MHz, METHANOL-d4) d 8.14 (br s, 1H), 7.94 (s, 1H), 7.59 (br d, J=l0.4 Hz, 1H), 5.77 (br s, 1H), 4.72 - 4.69 (m, 2H), 4.64 - 4.55

(m, 2H), 3.16 (br s, 2H), 2.78 (br s, 2H), 2.66 (s, 3H), 2.30 - 2.19 (m, 2H), 1.46 (br s, 4H), 1.21 (s, 9H), 0.93 (s, 6H). Example 101

To a 1 dram vial equipped with a stir bar and charged with isopropyl (S)-2-(tert- butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.053 mmol) was added 2-cyclohexylethan-l-ol (10.24 mg, 0.080 mmol). To the vial was added triphenylphosphine (20.94 mg, 0.080 mmol) as a solution in THF (0.25 mL). To the solution was added DIAD (0.016 mL, 0.080 mmol) as a solution in THF (0.25 mL). The solution was stirred at r.t. LCMS analysis after 5 h found clean and complete conversion to the desired ester intermediate. The reaction solution was concentrated under an N2 stream. The residue was dissolved in EtOH (1.0 mL). To the solution was added aq. 1M NaOH (0.106 mL, 0.532 mmol). The solution was stirred at 75 °C for 18 hrs. LCMS analysis after 18 hrs found disappearance of the ester peak and a large expected product peak (acid). The mixture was filtered through a syringe filter and the filtrate was purified via preparative LC/MS. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the product (S)-2-(tert-butoxy)-2-(5-(2-cyclohexylethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (13.5 mg, 0.025 mmol, 46.7 % yield). ¾ NMR (500 MHz, methanol-d*) d 8.38 (d, J=2.7 Hz, 1H), 8.21 (s, 1H), 7.56 (dd, .7=8.5, 3.1 Hz, 1H), 7.51 - 7.45 (m, 1H), 5.82 (s, 1H), 4.20 (t, J=6.6 Hz, 2H), 3.21 - 2.74 (m, 4H), 2.68 (s, 3H), 1.88 - 1.70 (m, 7H), 1.64 - 1.56 (m, 1H), 1.52 - 1.41 (m, 4H), 1.37 - 1.30 (m, 4H), 1.22 (s, 9H), 1.11 - 0.99 (m, 2H), 0.92 (s, 6H). ESI-MS(+) m/z = 538.2 (M+l).

Absolute stereochemistry is

arbitrarily assigned

To a 50 mL flask equipped with a stir bar was added (tetrahydrofuran-3-yl)methanol (250 mg, 2.448 mmol), 6-chloropyridin-3-ol (317 mg, 2.448 mmol), triphenylphosphine (642 mg, 2.448 mmol) and THF (15 mL). To the solution was added DIAD (0.476 mL, 2.448 mmol). The yellow solution was stirred at r.t. LCMS analysis after 18 h found nearly complete conversion. The reaction solution was concentrated in vacuo. The residue was dissolved in a minimum of acetone, then was concentrated onto celite in vacuo. The resutling powder was subjected to Si02 purification on the Biotage (40 g column, 0-75% EtOAc:Hex). Fractions of the major peak were analyzed by TLC to find a spot consistent with the desired product. All product-containing fractions were pooled and concentrated in vacuo to afford a soft white solid. SFC separation provided two fractions. The first compound to elute was arbitrarily assigned as (S)-2-chloro-5-((tetrahydrofuran-3-yl)methoxy)pyridine, and the second compound was arbitrarily assigned as (R)-2-chloro-5-((tetrahydrofuran-3- yl)methoxy)pyridine. The absolute stereochemistry assigned is arbitrary and was not estabilished experimentally. The fractions were concentrated in vacuo. The resulting residue was transfered in DCM and concentrated under an N2 stream for several hours to afford the products (S)-2-chloro-5-((tetrahydrofuran-3-yl)methoxy)pyridine (174.8 mg, 0.818 mmol, 33.4 % yield) and (R)-2-chloro-5-((tetrahydrofuran-3-yl)methoxy)pyridine (181.7 mg, 0.850 mmol, 34.7 % yield).

First eluting isomer: (S)-2-Chloro-5-((tetrahydrofuran-3-yl)methoxy)pyridine: Ή NMR (500 MHz, chloroform-d) d 8.07 (d, J= 3.0 Hz, 1H), 7.26 - 7.24 (m, 1H), 7.22 - 7.18 (m, 1H), 4.00 - 3.91 (m, 4H), 3.84 - 3.78 (m, 1H), 3.73 (dd, J= 9.0, 5.2 Hz, 1H), 2.83 - 2.69 (m, 1H), 2.15 (dtd, J=l3.0, 8.0, 5.4 Hz, 1H), 1.80 - 1.70 (m, 1H)

Second eluting isomer: (R)-2-Chloro-5-((tetrahydrofuran-3-yl)methoxy)pyridine: Ή NMR (500 MHz, chloroform-d) d 8.07 (d, J= 3.0 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.22 - 7.18 (m, 1H), 3.99 - 3.90 (m, 4H), 3.84 - 3.78 (m, 1H), 3.73 (dd, J= 8.9, 5.1 Hz, 1H), 2.82 - 2.72 (m, 1H), 2.15 (dtd, J=l3.0, 8.0, 5.4 Hz, 1H), 1.79 - 1.71 (m, 1H).

First eluting isomer2

Step 1 : To a 14 mF test tube equipped with a stir bar and (S)-(5-(l-(tert-butoxy)-2- isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-l-yl)-6-methylpyridin-3-yl)boronic acid (210 mg, 0.500 mmol) was added (S)-2-chloro-5-((tetrahydrofuran-3-yl)methoxy)pyridine (53.4 mg, 0.250 mmol), potassium phosphate tribasic (954 mg, 4.50 mmol) and SPhos-Pd-G3 (19.46 mg, 0.025 mmol) . The flask was sealed with a rubber septum, then was placed under N2 atm (vac/fill x 3). To the flask was added degassed (N2 bubbling for 5 min) dioxane (1873 mΐ) and water (624 mΐ). The test tube was placed in a 60 °C heating block with stirring for 18 h. The reaction was cooled to RT and diluted with EtOAc and water. The organic layer was washed with brine, collected, dried over MgSCri. filtered and volatiles evaporated to afford the crude product. The crude product was purified via silica gel chromatography (24 g column, 20-100% EtOAc:Hex) to afford the product isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((S)-tetrahydrofuran-3-yl)methoxy)-[2,3'-bipyridin]-5'- yl)acetate (41 mg, 0.074 mmol, 14.82 % yield) as a red/brown oil. ESI-MS(+) m/z = 554.5 (M+l).

Step 2: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((S)-tetrahydrofuran-3-yl)methoxy)-[2,3'-bipyridin]-5'-yl)acetate (41 mg, 0.074 mmol) in EtOH (494 mΐ) was added sodium hydroxide (148 mΐ, 0.740 mmol) then heated at 75°C for 24 hrs. The reaction was cooled to RT, filtered through a nylon 0.45 m frit filter and purified via preparative LC/MS. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the product (S)-2-(tert-butoxy)-2- (4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(((S)-tetrahydrofuran-3-yl)methoxy)-[2,3'- bipyridin]-5'-yl)acetic acid (l9.7mg, 0.039 mmol, 52.0 % yield). ¾ NMR (500 MHz, methanol-d₄) d 8.39 (br s, 1H), 8.16 (br s, 1H), 7.58 (dd, J=8.4, 2.3 Hz, 1H), 7.48 (br d, J=8.5 Hz, 1H), 5.80 (br s, 1H), 4.17 - 4.05 (m, 2H), 3.98 - 3.91 (m, 2H), 3.86 - 3.71 (m, 2H), 3.15 - 2.70 (m, 4H), 2.66 (s, 3H), 2.24 - 2.13 (m, 1H), 1.84 (dq, J=13.2, 6.7 Hz, 1H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.91 (s, 6H) 1 proton on one of the methylenes closest to the piperidine N was not observed in the HNMR spectrum. ESI-MS(+) m/z = 512.3 (M+l).

Example 103

Step 1 : To a 14 mL test tube equipped with a stir bar and (S)-(5-(l-(tert-butoxy)-2- isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-l-yl)-6-methylpyridin-3-yl)boronic acid (210 mg, 0.500 mmol) was added (R)-2-chloro-5-((tetrahydrofuran-3-yl)methoxy)pyridine (53.4 mg, 0.250 mmol), potassium phosphate tribasic (954 mg, 4.50 mmol) and SPhos-Pd-G3 (19.46 mg, 0.025 mmol) . The flask was sealed with a rubber septum, then was placed under N2 atm (vac/fill x 3). To the flask was added degassed (N2 bubbling for 5 min) dioxane (1873 mΐ) and water (624 mΐ). The test tube was placed in a 60 °C heating block with stirring for 18h. The reaction was cooled to RT and diluted with EtOAc and water. The organic layer was washed with brine, collected, dried over MgSOi. filtered and volatiles evaporated to afford the crude product. The crude product was purified via silica gel chromatography (24 g column, 20-100% EtOAc:Hex) to afford the product isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((R)-tetrahydrofuran-3-yl)methoxy)-[2,3'-bipyridin]-5'- yl)acetate (49 mg, 0.088 mmol, 17.71 % yield) as a red/brown oil. ESI-MS(+) m/z = 554.5 (M+l).

Step 2: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((R)-tetrahydrofuran-3-yl)methoxy)-[2,3'-bipyridin]-5'-yl)acetate (49 mg, 0.088 mmol) in EtOH (590 pl) was added sodium hydroxide (177 mΐ, 0.885 mmol) then heated at 75°C for 24 hrs. The reaction was cooled to RT, filtered througha nylon 0.45 m frit filter and purified via preparative LC/MS. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the product (S)-2-(tert-butoxy)-2- (4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(((R)-tetrahydrofuran-3-yl)methoxy)-[2,3'- bipyridin]-5'-yl)acetic acid (36.4 mg, 0.071 mmol, 80 % yield). Ή NMR (500 MHz, methanol-d₄) d 8.37 (d, J=l .8 Hz, 1H), 8.11 (s, 1H), 7.60 - 7.54 (m, 1H), 7.47 (d, J=8.5 Hz, 1H), 5.75 (s, 1H), 4.17 - 4.11 (m, 1H), 4.11 - 4.04 (m, 1H), 3.99 - 3.91 (m, 2H), 3.82 (q,

J= 7.6 Hz, 1H), 3.75 (dd, J=8.5, 5.5 Hz, 1H), 3.21 - 2.69 (m, 4H), 2.65 (s, 3H), 2.24 - 2.14 (m, 1H), 1.89 - 1.78 (m, 1H), 1.43 (br s, 4H), 1.19 (s, 9H), 0.90 (s, 6H). 1 proton on one ofthe methylenes closest to the piperidine N was not observed in the HNMR spectrum. ESI-MS(+) m/z— 512.3 (M+l).

Absolute stereochemistry is arbitrarily assigned

To a 50 mL flask equipped with a stir bar was added (tetrahydrofuran-2-yl)methanol (250 mg, 2.448 mmol), 6-chloropyridin-3-ol (317 mg, 2.448 mmol), triphenylphosphine (642 mg, 2.448 mmol) and THF (10 mL). To the solution was added DIAD (0.476 mL, 2.448 mmol). The yellow solution was stirred at r.t. for 4 h. The reaction solution was concentrated in vacuo. The resulting residue was dissolved in a minimum of acetone, then was concentrated onto celite in vacuo. The resulting powder was subjected to Si02 purification on the Biotage (40 g column, 0-50% EtOAc :Hex). purity. The material was concentrated in vacuo to afford a colorless liquid. SFC separation to afford two separate, homochiral enantiomers: (S)-2-chloro-5-((tetrahydrofuran-2-yl)methoxy)pyridine (202.3 mg, 0.947 mmol, 38.7 % yield) and (R)-2-chloro-5-((tetrahydrofuran-2-yl)methoxy)pyridine (200.2 mg, 0.937 mmol, 38.3 % yield) which have been arbitrarily assigned.

First eluting isomer: (S)-2-chloro-5-((tetrahydrofuran-2-yl)methoxy)pyridine: Ή NMR (500 MHz, chloroform-d) d 8.10 (dd, J= 2.5, 1.1 Hz, 1H), 7.25 (t, J= 2.0 Hz, 2H), 4.32 - 4.26 (m, 1H), 4.06 - 3.99 (m, 2H), 3.95 (dt, J= 8.3, 6.7 Hz, 1H), 3.89 - 3.83 (m, 1H), 2.15 -

2.07 (m, 1H), 2.04 - 1.93 (m, 2H), 1.83 - 1.74 (m, 1H).

Second eluting isomer: (R)-2-chloro-5-((tetrahydrofuran-2-yl)methoxy)pyridine: Ή NMR (500 MHz, chloroform-d) d 8.10 (dd, J= 2.6, 1.0 Hz, 1H), 7.26 - 7.22 (m, 2H), 4.32 -

4.26 (m, 1H), 4.06 - 3.99 (m, 2H), 3.95 (dt, J= 8.3, 6.7 Hz, 1H), 3.89 - 3.83 (m, 1H), 2.15 -

2.07 (m, 1H), 2.05 - 1.93 (m, 2H), 1.83 - 1.73 (m, 1H).

Example 104

Step 1 : To a 14 mL test tube equipped with a stir bar and (S)-(5-(l-(tert-butoxy)-2- isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-l-yl)-6-methylpyridin-3-yl)boronic acid (105 mg, 0.250 mmol) was added (R)-2-chloro-5-((tetrahydrofuran-2-yl)methoxy)pyridine (26.7 mg, 0.125 mmol), potassium phosphate tribasic (477 mg, 2.248 mmol) and SPhos-Pd- G3 (9.73 mg, 0.012 mmol). The flask was sealed with a rubber septum, then was placed under N2 atm (vac/fill x 3). To the flask was added degassed (N2 bubbling for 5 min) dioxane (937 pl) and water (312 mΐ). The test tube was placed in a 60 °C heating block with stirring for 18 h. The reaction was cooled to RT and diluted with EtOAc and water. The organic layer was washed with brine, collected, dried over MgSOi. filtered and volatiles evaporated to afford the crude product. The crude product was purified via silica gel chromatography (24 g column, 20-100% EtOAc:Hex) to afford the product isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((R)-tetrahydrofuran-2-yl)methoxy)-[2,3'-bipyridin]-5'- yl)acetate (22 mg, 0.040 mmol, 15.91 % yield) as a red/brown oil. ESI-MS(+) m/z = 554.5 (M+l). Step 2: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((R)-tetrahydrofuran-2-yl)methoxy)-[2,3'-bipyridin]-5'-yl)acetate (22 mg, 0.040 mmol) in EtOH (265 pl) was added sodium hydroxide (79 mΐ, 0.397 mmol) then heated at 75°C for 24 hrs. The reaction was cooled to RT, filtered through a nylon 0.45 m frit filter and purified via preparative LC/MS. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the product (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((R)-tetrahydrofuran-2-yl)methoxy)-[2,3'-bipyridin]-5'- yl)acetic acid (14.1 mg, 0.028 mmol, 69.4 % yield). ¾ NMR (500 MHz, methanol-d4) d 8.41 (d, .7=1.8 Hz, 1H), 8.18 (s, 1H), 7.60 (dd, J=8.5, 2.1 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 5.81 (s, 1H), 4.34 (br d, .7=3.4 Hz, 1H), 4.24 - 4.17 (m, 1H), 4.15 - 4.07 (m, 1H), 3.97 - 3.90 (m, 1H), 3.90 - 3.80 (m, 1H), 3.15 - 2.72 (m, 3H), 2.66 (s, 3H), 2.20 - 2.11 (m, 1H), 2.09 - 2.02 (m, 1H), 2.00 - 1.95 (m, 1H), 1.91 - 1.81 (m, 1H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.92 (s, 6H). 1 proton on one of the methylenes closest to the piperidine N was not observed in the HNMR spectrum. ESI-MS(+) m/z = 512.3 (M+l).

Example 105

Step 1 : To a 14 mL test tube equipped with a stir bar and (S)-(5-(l-(tert-butoxy)-2- isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-l-yl)-6-methylpyridin-3-yl)boronic acid (105 mg, 0.250 mmol) was added (S)-2-chloro-5-((tetrahydrofuran-2-yl)methoxy)pyridine (26.7 mg, 0.125 mmol), potassium phosphate tribasic (477 mg, 2.248 mmol) and SPhos-Pd- G3 (9.73 mg, 0.012 mmol). The flask was sealed with a rubber septum, then was placed under N2 atm (vac/fill x 3). To the flask was added degassed (N2 bubbling for 5 min) dioxane (937 mΐ) and water (312 mΐ). The test tube was placed in a 60 °C heating block with stirring for 18 h. The reaction was cooled to RT and diluted with EtOAc and water. The organic layer was washed with brine, collected, dried over MgSCri, filtered and volatiles evaporated to afford the crude product. The crude product was purified via silica gel chromatography (24 g column, 20-100% EtOAc:Hex) to afford the product isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[2,3'-bipyridin]-5'- yl)acetate (25 mg, 0.045 mmol, 18.07 % yield) as a red/brown oil. ESI-MS(+) m/z = 554.5 (M+l). Step 2: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.045 mmol) in EtOH (301 pl) was added sodium hydroxide (90 mΐ, 0.451 mmol) then heated at 75°C for 24 hrs. The reaction was cooled to RT, filtered through a nylon 0.45 m frit filter and purified via preparative. Fractions containing the desired product were combined and dried via centrifugal evaporation (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(((S)-tetrahydrofuran-2-yl)methoxy)-[2,3'-bipyridin]-5'-yl)acetic acid (14.4 mg, 0.028 mmol, 62.3 % yield). Tf NMR ^OO MHz, methanol-d*) d 8.42 (br s, 1H), 8.19 (s, 1H), 7.62 - 7.57 (m, 1H), 7.49 (br d, J=8.5 Hz, 1H), 5.80 (br s, 1H), 4.34 (br d, J= 3.7 Hz, 1H), 4.24 - 4.19 (m, 1H), 4.12 (br dd, .7=10.1, 6.4 Hz, 1H), 3.94 (q, J=7T Hz, 1H), 3.86 (q, J=7.2 Hz, 1H), 3.19 - 2.76 (m, 3H), 2.67 (s, 3H), 2.21 - 2.11 (m, 1H), 2.05 - 1.84 (m, 3H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.92 (s, 6H). 1 proton on one of the methylenes closest to piperidine N was not observed in the HNMR spectrum. ESI-MS(+) m/z = 512.3 (M+l).

Stereochemistry arbitrarily assigned

To a 10 mL Shlenk flask equipped with a stir bar was added 2-((6-bromopyridin-3- yl)oxy)-l-phenylethan-l-one (400 mg, 1.369 mmol). The flask was sealed with a rubber septum, then was placed under N2 atm (vac/fill x 3). To the flask was added dry and degassed THF (7 mL). The flask was cooled in a 0 °C ice bath. To the homogeneous yellow solution was added over 2 minutes methylmagnesium bromide in THF:PhMe (1 :3) (1.027 mL, 1.438 mmol). Slight effervescence was observed (likely quenching of the Grignard reagent with a proton source, but also could be metal exchange to afford MeBr). The cold bath was immediately removed and the solution was allowed to warm to r.t. with stirring. LCMS analysis after 1.5 h found full conversion to the desired product. To the solution was added sat. aq. NH₄C1 (0.25 mL). The mixture was allowed to stir overnight. The reaction mixture was transferred to a 125 mL separatory funnel using water (50 mL) and EtOAc (50 mL). Note: the reaction mixture had partially solidified upon the prolonged standing. The organic phase was isolated and reserved. The aq. phase was extracted with EtOAc (50 mL). The combined organics were washed with brine; dried over MgSOr: filtered; then concentrated in vacuo. The resulting residue was dissolved in a minimum of acetone and then was concentrated onto celite in vacuo. The resutling powder was subjected to Si02 purification on the Biotage (40 g column, 0-10% DCM:MeOH). For an unknown reason, the product eluted near the solvent front. The desired fractions were concentrated and subjected to a second round of purification. The second round of purification proceeded under the same conditions as the first, but provided the expected retention time and peak shape. The entirety of the material was submitted for chiral separation to afford the desired product as two pure enantiomers post SFC purification. The absolute configuration was arbitrarily assigned.

First eluting isomer: (S)-l-((6-bromopyridin-3-yl)oxy)-2-phenylpropan-2-ol (49 mg, 0.159 mmol, 11.61 % yield): ¾ NMR (500 MHz, chloroform-d) d 8.08 (d, J= 3.0 Hz, 1H), 7.54 (d, .7=7.6 Hz, 2H), 7.42 (t, 7=7.6 Hz, 2H), 7.40 - 7.32 (m, 2H), 7.12 (dd, 7=8.7, 3.2 Hz, 1H), 4.17 (d, 7=9.0 Hz, 1H), 4.07 (d, 7=9.0 Hz, 1H), 1.72 (s, 3H).

Second eluting isomer: (R)-l-((6-bromopyridin-3-yl)oxy)-2-phenylpropan-2-ol (44.7 mg, 0.145 mmol, 10.59 % yield): ¾ NMR (500 MHz, chloroform-d) d 8.08 (d, 7=3.2 Hz, 1H), 7.56 - 7.52 (m, 2H), 7.44 - 7.40 (m, 2H), 7.38 (d, 7=8.7 Hz, 1H), 7.36 - 7.31 (m, 1H), 7.12 (dd, 7=8.7, 3.2 Hz, 1H), 4.17 (d, 7=9.0 Hz, 1H), 4.07 (d, 7=9.0 Hz, 1H), 1.72 (s, 3H).

Example 106

Step 1 : To a 14 mL test tube equipped with a stir bar and added (S)-(5-(l-(tert- butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-l-yl)-6-methylpyridin-3- yl)boronic acid (105 mg, 0.250 mmol) and (R)-l-((6-bromopyridin-3-yl)oxy)-2- phenylpropan-2-ol (44.7 mg, 0.145 mmol), tribasic potassium phosphate (477 mg, 2.248 mmol) and SPhos-Pd-G3 (9.73 mg, 0.012 mmol). The flask was sealed with a rubber septum, then was placed under N2 atm (vac/fill x 3). To the flask was added degassed (N2 bubbling for 5 min) dioxane (937 pl) and water (312 mΐ). The test tube was placed in a 60 °C heating block with stirring. The reaction was stirred for 18 hrs. The reaction was cooled to RT and diluted with EtOAc and water. The organic layer was washed with brine, collected, dried over MgSCfi, filtered and the volatiles evaporated to afford the crude product. The crude product was purified via silca gel chromatography(24 g column, 20-100% EtAOc:Hex) to afford the product isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((R)-2 -hydroxy -2- phenylpropoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (32 mg, 0.053 mmol, 21.22 % yield) as a brown oil. ESI-MS(+) m/z = 604.5 (M+l). Step 2: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((R)-2-hydroxy-2-phenylpropoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (32 mg,

0.053 mmol) in EtOH (1 mL) was added sodium hydroxide (0.106 mL, 0.530 mmol) then heated at 75°C for 24 hrs. The reaction was cooled to RT, filtered through a nylon 0.45 m frit filter and purified via preparative LC/MS. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the product (S)-2-(tert-butoxy)-2- (4'-(4,4-dimethylpiperidin-l-yl)-5-((R)-2-hydroxy-2-phenylpropoxy)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (14.6 mg, 0.026 mmol, 49.0 % yield). ¹H NMR (600 MHz, DMSO-de) d 8.35 (br s, 1H), 8.08 (s, 1H), 7.58 (br d, J=7.3 Hz, 2H), 7.49 (dd, J=8.8, 2.6 Hz, 1H), 7.40 (d, .7=8.4 Hz, 1H), 7.35 (t, J=7.5 Hz, 2H), 7.29 - 7.21 (m, 1H), 5.78 (br s, 1H), 4.20 - 4.07 (m, 2H), 2.48 (s, 3H), 1.57 (s, 3H), 1.55 - 1.14 (m, 4H), 1.11 (s, 9H), 0.92 - 0.73 (m, 6H). 4 protons on methylenes closest to piperidine N were not observed in HNMR spectrum. ESI-MS(+) m/z = 562.2 (M+l).

Example 107

Step 1 : To a 14 mL test tube equipped with a stir bar and added (S)-(5-(l-(tert- butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-l-yl)-6-methylpyridin-3- yl)boronic acid (105 mg, 0.250 mmol) and (S)-l-((6-bromopyridin-3-yl)oxy)-2- phenylpropan-2-ol (44.7 mg, 0.145 mmol), tribasic potassium phosphate (477 mg, 2.248 mmol) and SPhos-Pd-G3 (9.73 mg, 0.012 mmol). The flask was sealed with a rubber septum, then was placed under N2 atm (vac/fill x 3). To the flask was added degassed (N2 bubbling for 5 min) dioxane (937 pl) and water (312 mΐ). The test tube was placed in a 60 °C heating block with stirring. The reaction was stirred for 18 hrs. The reaction was cooled to RT and diluted with EtOAc and water. The organic layer was washed with brine, collected, dried over MgSCri, filtered and the volatiles evaporated to afford the crude product. The crude product was purified via silica gel chromatography(24 g column, 20-100% EtAOc:Hex) to afford the product isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((S)-2- hydroxy-2-phenylpropoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (40 mg, 0.066 mmol, 26.5 % yield) as a brown oil. ESI-MS(+) m/z = 604.5 (M+l).

Step 2: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((S)-2-hydroxy-2-phenylpropoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (40 mg, 0.066 mmol) in EtOH (1 mL) was added sodium hydroxide (0.132 mL, 0.662 mmol) then heated at 75 °C for 24 hrs. The reaction was cooled to RT, filtered through a nylon 0.45 m frit filter and purified via preparative LC/MS. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the product (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-((S)-2-hydroxy-2-phenylpropoxy)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (21.2 mg, 0.038 mmol, 57.0 % yield). ¾ NMR (500 MHz, methanol-d4) d 8.15 (d, .7=2.7 Hz, 1H), 7.87 (s, 1H), 7.42 (d, 7=7.9 Hz, 2H), 7.34 (dd, 7=8.5, 2.7 Hz, 1H), 7.25 - 7.16 (m, 3H), 7.12 - 7.06 (m, 1H), 5.55 (s, 1H), 4.10 - 3.99 (m, 2H), 2.67 - 2.49 (m, 2H), 2.45 (s, 3H), 1.52 (s, 3H), 1.23 (br s, 4H), 0.99 (s, 9H), 0.69 (s, 6H). 2 Protons on methylenes closest to piperidine N were not observed in HNMR spectrum. ESI-MS(+) m/z = 562.3 (M+l).

Examples 108 to 127 are prepared according to one of the general Methods A-F outlined below.

Method A: To a 14 mL test tube equipped with a stir bar and (S)-(5-(l-(tert-butoxy)- 2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-l-yl)-6-methylpyridin-3-yl)boronic acid (0.500 mmol) OR (S)-(4-(4,4-dimethylpiperidin-l-yl)-5-(2-isopropoxy-2-oxo-l-(tert- pentyloxy)ethyl)-6-methylpyridin-3-yl)boronic acid (0.500 mmol) was added aryl halide ( 0.125 mmol), potassium phosphate tribasic (954 mg, 4.50 mmol) and SPhos-Pd-G3 (19.46 mg, 0.025 mmol) . The flask was sealed with a rubber septum, then was placed under N2 atm (vac/fill x 3). To the flask was added degassed (N2 bubbling for 5 min) dioxane (1.9 mL) and water (0.7 ml). The test tube was placed in a 60 °C heating block with stirring (t=0) for t=l8h. The reaction was cooled to RT and diluted with EtOAc and water. The organic layer was washed with brine, collected, dried over MgSOi. filtered and volatiles evaporated to afford the crude product. The crude product was purified via silica gel chromatography (24 g column, 20-100% EtOAc:Hex) to afford the product. To a solution of the product in EtOH (1 mL) was added 5 N aq. sodium hydroxide (10 eq) then heated at 75 °C for 18 hrs. The reaction was cooled to RT, filtered through a nylon 0.45 m frit filter, neutralized with acetic acid (10 eq) and purified accordingly and noted in individual Examples.

Method B: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin- l-yl)-5-(lH-indol-5-yl)-2-methylpyridin-3-yl)acetate (52 mg, 0.106 mmol) and alkyl halide (0.116 mmol) in DMF (1 mL) was added cesium carbonate (37.9 mg, 0.116 mmol) and stirred at RT. The reaction was stirred for 24 hrs. The reaction was quenched with water and diluted with EtOAc. The organic layer was washed with brine, collected, dried over MgSOi. filtered and volatiles evaporated to afford the crude product. The crude product was taken up in EtOH (1 mL) and added 5 N aq. sodium hydroxide (10 eq) and then heated to 75 °C for 18 hrs. The reaction was cooled to RT, filtered through a 0.45u nylon frit filter and purified accordingly and noted in individual Examples.

Method C: To a solution of heterocyclic nucleophile (1 eq) and alkyl bromide (1.1 eq) in DMF (5 mL) was added cesium carbonate (1.1 eq) and stirred at RT for 18 hrs. The reaction was diluted with water and EtOAc. The organic layer was washed with brine, collected, dried over MgSCri, filtered and the volatiles evaporated to afford the crude product. The crude product was purified via silica gel (24 g column, with varying gradients between 5- 100% EtOAc:Hex) to afford the product(s).

Method D: To a solution of amine (HC1 salt, 1 eq) in DCE (5 mL) and MeOH (5 ml) were added substituted benzaldehyde or alkyl aldehyde (1.1 eq), Hunig's Base (2 eq) and acetic acid (1 eq). Sodium triacetoxyborohydride (2.1 eq) was then added and the reaction mixture was stirred at rt overnight. The mixture was quenched with water and aq. 1.5 M potassium phosphate and extracted with EtOAc. The organic layer was washed with brine, dried over MgSOi and concentrated. The residue was purified on silica gel (24 or 40 g column, 5-100 % EtOAc:Hex) to afford the product.

Method E: To a solution of aryl-OH or heteroaryl-OH (-, 0.079 mmol), isopropyl (S)- 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-(2-hydroxyethoxy)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (27 mg, 0.053 mmol) in THF (0.5 mL) was added triphenylphosphine (20.68 mg, 0.079 mmol) followed by DIAD (0.015 mL, 0.079 mmol). The reaction was stirred at RT for 18 hrs. Extra eq of reagents (TPP and DIAD) were added if needed to progress starting material to product. Once the reactions were deemed complete via LMCS analysis, the reactions were dried down under a stream of N2 and taken up in EtOH (1 mL) and added aq. 5 N sodium hydroxide (20 eq), heated to 75 °C and stirred for 18 hrs. The reactions were cooled to RT, filtered through a 0.45 u nylon frit filter, neutralized with 20 eq of acetic acid purified accordingly via prep HPLC noted in individual Examples.

Method F: Cesium carbonate (19.08 mg, 0.059 mmol) was added to a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (25 mg, 0.053 mmol) and (2-bromoethoxy)aryl (0.059 mmol) and stirred at RT for 18 hrs. The reaction volatiles were evaporated under a stream of N2 to afford the product as a sticky oil. To the sticky oil was added Ethanol (1 mL) followed by aq. 5 N sodium hydroxide (10 eq) and stirred at 75 °C for 18 hrs. The reaction was cooled to RT and filtered through a 0.45 u nylon frit filter, neutralized with acetic acid (10 eq) and purified accordingly via prep HPLC noted in individual Examples.

Example 108

Method F. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 27% B, 27-67% B over 20 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2-(tert- butoxy)-2- [4’ -(4,4-dimethylpiperidin- 1 -yl)-5 -[2-(2-methoxyphenoxy)ethoxy] -6’ -methyl - [2,3’-bipyridine]-5’-yl]acetic acid (30.8 mg, 53.3 pmol, 100.6% yield). lH NMR (500 MHz, METHAN OL-d4) d 8.46 (br s, 1H), 8.21 (s, 1H), 7.67 (br d, J=8.2 Hz, 1H), 7.51 (br d, J=8.5 Hz, 1H), 7.08 - 6.89 (m, 4H), 5.81 (br s, 1H), 4.52 (br s, 2H), 4.42 (br s, 2H), 3.84 (s, 3H), 3.23 - 2.75 (m, 3H), 2.68 (s, 3H), 1.45 (br s, 4H), 1.22 (s, 9H), 0.91 (s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum.

Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95

acetonitrile: water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 578.29; Retention Time: 1.84 min.

Example 109

Method F. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with lO-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with lO-mM ammonium acetate; Gradient: a 0-minute hold at 24% B, 24-64% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-[2-(3-methoxyphenoxy)ethoxy]-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (21.5 mg, 37.2 pmol, 70.2% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.46 (br s, 1H), 8.23 (s, 1H), 7.65 (br d, J=8.5 Hz, 1H), 7.52 (br d, J=8.2 Hz, 1H), 7.20 (br t, J=8. l Hz, 1H), 6.63 - 6.50 (m, 3H), 5.80 (s, 1H), 4.51 (br s, 2H), 4.38 (br s, 2H), 3.79 (s, 3H), 3.24 - 2.77 (m, 3H), 2.69 (s, 3H), 1.45 (br s, 4H), 1.22 (s, 9H), 0.92 (s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 578.31; Retention Time: 1.9 min.

Example 110

Method F. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with lO-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with lO-mM ammonium acetate; Gradient: a 0-minute hold at 29% B, 29-69% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2- { 5- [2-(4-chlorophenoxy)ethoxy] -4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ -methyl - [2,3’-bipyridine]-5’-yl}acetic acid (23.4 mg, 40.2 pmol, 75.8% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.45 (br s, 1H), 8.19 (s, 1H), 7.64 (br d, J=8.2 Hz, 1H), 7.51 (br d, J=8.5 Hz, 1H), 7.29 (br d, J=8.5 Hz, 2H), 6.99 (br d, J=8.5 Hz, 2H), 5.82 (br s, 1H), 4.51 (br s, 2H), 4.40 (br s, 2H), 3.20 - 2.72 (m, 3H), 2.67 (s, 3H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.91 (s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95

acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 98.3 %; Observed Mass: 582.24; Retention Time: 2.04 min.

Example 111

To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5-(4- hydroxyphenyl)-2-methylpyridin-3-yl)acetate (31 mg, 0.066 mmol) and (2- bromoethoxy)benzene (14.6 mg, 0.073 mmol) in DMF (1 mL) was added cesium carbonate (23.71 mg, 0.073 mmol) and stirred at RT. The reaction progress was monitored via LCMS. After 72 hrs (time unoptimized), the reaction was diluted with 2 mL acetone and filtered through a 0.45 u nylon frit filter into a 1 dram vial. The solution was dried down under a stream of N2 until a sticky residue was left behind. To the crude material was added EtOH (1 mL) followed by sodium hydroxide (0.132 mL, 0.661 mmol). With stirring the reaction was heated to 75°C for 18 hrs. The reaction was cooled to RT and neutralized with acetic acid (0.038 mL, 0.661 mmol) and filtered through a 0.45 u nylon frit filter. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 30% B, 30-70% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-mhi particles; Mobile Phase A: 5:95 methanol: water with lO-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with lO-mM ammonium acetate; Gradient: a 0-minute hold at 60% B, 60-100% B over 25 minutes, then a 6-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2-(tert-butoxy)-2-[4-(4,4-dimethylpiperidin-l-yl)-2- methyl-5-[4-(2-phenoxyethoxy)phenyl]pyridin-3-yl]acetic acid (9.6 mg, 17.6 pmol, 26.6% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.09 (s, 1H), 7.31 (br s, 4H), 7.16 (br d, J=7.9 Hz, 2H), 7.02 - 6.92 (m, 3H), 5.69 (br s, 1H), 4.41 (br s, 2H), 4.38 (br d, J=4.0 Hz, 2H), 3.23 - 2.74 (m, 3H), 2.69 (s, 3H), 1.45 (br s, 4H), 1.21 (s, 9H), 0.91 (s, 6H) 1 proton on the methylenes closest to the piperidine N were not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 98.8 %; Observed Mass: 547.29; Retention Time: 2.09 min.

Example 112

Method E. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with lO-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with lO-mM ammonium acetate; Gradient: a 0-minute hold at 16% B, 16-56% B over 25 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2-[4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ -methyl-5 - [2-(2-oxo- 1 ,2-dihydropyridin- 1 - yl)ethoxy]-[2,3’-bipyridine]-5’-yl]acetic acid (9.7 mg, 17.7 pmol, 34.7% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.34 (br s, 1H), 8.07 (s, 1H), 7.78 (br d, J=6.4 Hz, 1H), 7.60 - 7.51 (m, 2H), 7.44 (br d, J=8.5 Hz, 1H), 6.60 (br d, J=9.2 Hz, 1H), 6.44 (br t, J=6. l Hz, 1H), 5.73 (br s, 1H), 4.48 (s, 4H), 3.24 - 2.68 (m, 2H), 2.64 (br s, 3H), 1.41 (br s, 4H), 1.18 (s,

9H), 0.88 (br s, 6H) 2 protons on the methylene closest to the piperidine N were not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 549.32; Retention Time: 1.36 min.

Example 113

Method E. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 16% B, 16-56% B over 25 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 16% B, 16-56% B over 25 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 methanol: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 40% B, 40-80% B over 25 minutes, then a 6-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’- methyl-5-[2-(pyridin-2-yloxy)ethoxy]-[2,3’-bipyridine]-5’-yl]acetic acid (0 mg, 0 pmol, 0% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.45 - 8.41 (m, 1H), 8.19 (s, 1H), 8.16 (br d, J=4.9 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.63 (br d, J=7.0 Hz, 1H), 7.50 (br d, J=8.2 Hz, 1H), 7.02 - 6.96 (m, 1H), 6.87 (br d, J=7.9 Hz, 1H), 5.81 (br s, 1H), 4.69 (br d, J=3.7 Hz, 2H), 4.52 (br s, 2H), 3.25 - 2.72 (m, 3H), 2.67 (br s, 3H), 1.44 (br s, 4H), 1.21 (br s, 9H), 0.91 (br s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 99.0 %; Observed Mass: 549.29; Retention Time: 1.75 min.

Example 114

Method E. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 29% B, 29-69% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2- { 5 -[2-(2,6-dimethylphenoxy)ethoxy] -4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ - methyl-[2,3’-bipyridine]-5’-yl}acetic acid (17.8 mg, 30.9 pmol, 59.5% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.43 (br s, 1H), 8.13 (br s, 1H), 7.65 (br d, J=8.2 Hz, 1H), 7.49 (br d, J=8.5 Hz, 1H), 7.03 (br d, J=7.3 Hz, 2H), 6.96 - 6.89 (m, 1H), 5.75 (br s, 1H), 4.56 - 4.42 (m, 2H), 4.22 (br s, 2H), 3.23 - 2.68 (m, 3H), 2.65 (s, 3H), 2.31 (s, 6H), 1.42 (br s, 4H), 1.19 (s, 9H), 0.87 (s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1 % trifluoroacetic acid; Mobile Phase B:

95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 99.2 %; Observed Mass: 576.34; Retention Time: 2.11 min.

Example 115

Method E. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 25% B, 25-65% B over 20 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2- { 5- [2-(2-chlorophenoxy)ethoxy] -4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ -methyl - [2,3’-bipyridine]-5’-yl}acetic acid (10.2 mg, 17.5 pmol, 33.1% yield). lH NMR (500 MHz, METHAN OL-d4) d 8.47 (br s, 1H), 8.20 (s, 1H), 7.69 (br d, J=8.2 Hz, 1H), 7.51 (br d, J=8.5 Hz, 1H), 7.38 (br d, J=7.6 Hz, 1H), 7.34 - 7.28 (m, 1H), 7.17 (br d, J=8.2 Hz, 1H), 6.97 (br t, J=7.2 Hz, 1H), 5.80 (br s, 1H), 4.58 (br s, 2H), 4.48 (br s, 2H), 3.21 - 2.73 (m, 3H), 2.68 (s, 3H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.90 (br s, 6H) 1 proton on the methylenes closest to the piperidine N was not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge Cl 8, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature:

50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 582.26;

Retention Time: 2.02 min. Example 116

Method E. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with lO-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with lO-mM ammonium acetate; Gradient: a 0-minute hold at 8% B, 8-48% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2-[4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ -methyl-5 - [2-(pyridin-4-yloxy)ethoxy] - [2,3’-bipyridine]-5’-yl]acetic acid (16 mg, 29.2 pmol, 57.2% yield). 1H NMR (500 MHz, METHAN OF-d4) d 8.43 (br s, 3H), 8.17 - 8.08 (m, 1H), 7.63 (br d, J=8.5 Hz, 1H), 7.50 (br d, J=8.2 Hz, 1H), 7.25 - 6.98 (m, 2H), 5.86 - 5.65 (m, 1H), 4.54 (br s, 4H), 3.24 - 2.68 (m, 3H), 2.65 (br s, 3H), 1.43 (br s, 4H), 1.20 (s, 9H), 0.90 (br s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical FC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge Cl 8, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature:

50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mF/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 549.28;

Retention Time: 1.29 min.

Example 117

Method E. The crude material was purified via preparative FC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with lO-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with lO-mM ammonium acetate; Gradient: a O-minute hold at 23% B, 23-63% B over 22 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2-(tert- butoxy)-2- [4’ -(4,4-dimethylpiperidin- 1 -yl)-5 -[2-(4-methoxyphenoxy)ethoxy] -6’ -methyl - [2,3’-bipyridine]-5’-yl]acetic acid (17.2 mg, 29.8 pmol, 56.2% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.44 (br s, 1H), 8.20 (br s, 1H), 7.64 (br d, J=8.2 Hz, 1H), 7.51 (br d, J=8.5 Hz, 1H), 6.96 - 6.90 (m, 2H), 6.90 - 6.84 (m, 2H), 5.81 (br s, 1H), 4.48 (br s, 2H), 4.35 (br s, 2H), 3.77 (s, 3H), 3.27 - 2.71 (m, 3H), 2.67 (br s, 3H), 1.44 (br s, 4H), 1.21 (s, 9H),

0.91 (br s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5

acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 578.3; Retention Time: 1.9 min.

Example 118

Method E. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with lO-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with lO-mM ammonium acetate; Gradient: a 0-minute hold at 9% B, 9-49% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2-[4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ -methyl-5 - [2-(pyridin-3 -yloxyjethoxy] - [2,3’-bipyridine]-5’-yl]acetic acid (9.1 mg, 16.6 pmol, 32.5% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.46 (br s, 1H), 8.18 (br s, 2H), 7.72 - 7.43 (m, 5H), 6.01 - 5.55 (m, 1H), 4.62 - 4.44 (m, 4H), 3.20 - 2.76 (m, 4H), 2.65 (br s, 3H), 1.43 (br s, 4H), 1.20 (br s, 9H), 0.91 (br s, 6H). Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 mih particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 549.29; Retention Time: 1.49 min.

Example 119

Method E. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 26% B, 26-66% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2-[4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ -methyl-5 - [2-(4-methylphenoxy)ethoxy] - [2,3’-bipyridine]-5’-yl]acetic acid (19.2 mg, 34.2 pmol, 64.5% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.45 (br s, 1H), 8.19 (br s, 1H), 7.67 - 7.60 (m, 1H), 7.50 (br d, J=8.2 Hz, 1H), 7.11 (br d, J=7.9 Hz, 2H), 6.88 (br d, J=8.2 Hz, 2H), 5.80 (br s, 1H), 4.49 (br s, 2H),

4.36 (br s, 2H), 3.26 - 2.73 (m, 3H), 2.67 (br s, 3H), 2.29 (s, 3H), 1.44 (br s, 4H), 1.21 (s,

9H), 0.91 (s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5

acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 562.3; Retention Time: 1.97 min. Example 120

Method E. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 26% B, 26-66% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2-[4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ -methyl-5 - [2-(3 -methylphenoxy)ethoxy] - [2,3’-bipyridine]-5’-yl]acetic acid (14.3 mg, 25.5 pmol, 48% yield). 1H NMR (500 MHz, METHAN OF-d4) d 8.45 (br s, 1H), 8.20 (br s, 1H), 7.67 - 7.62 (m, 1H), 7.51 (br d, J=8.5 Hz, 1H), 7.21 - 7.13 (m, 1H), 6.85 - 6.74 (m, 3H), 5.80 (br s, 1H), 4.50 (br s, 2H), 4.38 (br s, 2H), 3.27 - 2.76 (m, 3H), 2.67 (br s, 3H), 2.33 (s, 3H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.91 (s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical FC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95

acetonitrile: water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mF/min; Detection: MS and UV (220 nm). Purity: 99.3 %; Observed Mass: 562.31; Retention Time: 2.05 min.

Example 121

Method E. The crude material was purified via preparative FC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 26% B, 26-66% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2-[4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ -methyl-5 - [2-(2-methylphenoxy)ethoxy] - [2,3’-bipyridine]-5’-yl]acetic acid (16.3 mg, 29 pmol, 54.8% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.46 (br s, 1H), 8.20 (br s, 1H), 7.66 (br d, J=8.5 Hz, 1H), 7.51 (br d, J=8.5 Hz, 1H), 7.20 - 7.09 (m, 2H), 6.97 (br d, J=7.9 Hz, 1H), 6.87 (br t, J=7.2 Hz, 1H), 5.80 (br s, 1H), 4.56 (br d, J=4.0 Hz, 2H), 4.41 (br t, J=3.8 Hz, 2H), 3.27 - 2.75 (m, 3H), 2.67 (br s, 3H), 2.19 (s, 3H), 1.44 (br s, 4H), 1.22 (s, 9H), 0.90 (s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge Cl 8, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 562.3; Retention Time: 1.97 min.

Example 122

Method E. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 22% B, 22-62% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-[2-(4-fluorophenoxy)ethoxy]-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (17 mg, 30.1 pmol, 58.9% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.44 (br s, 1H), 8.19 (br s, 1H), 7.68 - 7.61 (m, 1H), 7.51 (br d, J=8.5 Hz, 1H), 7.07 - 6.96 (m, 4H), 5.82 (br s, 1H), 4.50 (br s, 2H), 4.38 (br s, 2H), 3.27 - 2.72 (m, 3H), 2.67 (br s, 3H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.91 (s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge Cl 8, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 566.3;

Retention Time: 1.96 min.

Example 123

Method E. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 26% B, 26-66% B over 22 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2-[4’ -(4,4-dimethylpiperidin- 1 -yl)-5-[2-(3 -fluorophenoxyjethoxy] -6’ -methyl- [2,3’-bipyridine]-5’-yl]acetic acid (15.7 mg, 27.8 pmol, 54.4% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.45 (br s, 1H), 8.19 (br s, 1H), 7.69 - 7.60 (m, 1H), 7.51 (br d, J=8.5 Hz, 1H), 7.31 (q, J=7.5 Hz, 1H), 6.86 - 6.75 (m, 2H), 6.72 (br t, J=7.3 Hz, 1H), 5.82 (br s, 1H), 4.52 (br s, 2H), 4.41 (br s, 2H), 3.28 - 2.72 (m, 3H), 2.67 (s, 3H), 1.45 (br s, 4H), 1.21 (s,

acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 99.0 %; Observed Mass: 566.28; Retention Time: 1.9 min. Example 124

Method E. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with lO-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with lO-mM ammonium acetate; Gradient: a 0-minute hold at 24% B, 24-64% B over 22 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-5-[2-(2-fluorophenoxy)ethoxy]-6’-methyl- [2,3’-bipyridine]-5’-yl]acetic acid (20.4 mg, 36.1 pmol, 70.7% yield). 1H NMR (500 MHz, METHAN OF-d4) d 8.45 (br s, 1H), 8.19 (br s, 1H), 7.65 (br d, J=8.5 Hz, 1H), 7.50 (br d, J=8.2 Hz, 1H), 7.22 - 7.16 (m, 1H), 7.15 - 7.07 (m, 2H), 6.98 (br d, J=4.3 Hz, 1H), 5.81 (br s, 1H), 4.54 (br s, 2H), 4.47 (br s, 2H), 3.24 - 2.72 (m, 3H), 2.67 (s, 3H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.91 (br s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical FC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mF/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 566.26; Retention Time: 1.84 min.

Example 125

Method E. The crude material was purified via preparative FC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with lO-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with lO-mM ammonium acetate; Gradient: a 0-minute hold at 32% B, 32-72% B over 20 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2- (tert-butoxy)-2- { 5- [2-(3 -chlorophenoxy)ethoxy] -4’ -(4,4-dimethylpiperidin- 1 -yl)-6’ -methyl - [2,3’-bipyridine]-5’-yl}acetic acid (13.4 mg, 23 pmol, 45. l% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.45 (br s, 1H), 8.19 (br s, 1H), 7.64 (br d, J=8.2 Hz, 1H), 7.51 (br d, J=8.2 Hz, 1H), 7.32 - 7.25 (m, 1H), 7.03 (br s, 1H), 6.97 (br dd, J=l9.5, 7.6 Hz, 2H), 5.81 (br s, 1H), 4.52 (br s, 2H), 4.41 (br d, J=3.7 Hz, 2H), 3.27 - 2.73 (m, 3H), 2.67 (br s, 3H), 1.44 (br s, 4H), 1.21 (s, 9H), 0.91 (br s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95 :5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 99.4 %; Observed Mass: 582.24; Retention Time: 2.02 min.

Example 126

Method A (Halide used for this compound was 2-chloro-9-(2-phenoxyethyl)-9H- purine. The hydrolysis step opened up the imidazole portion of the purine heterocycle to form the above product). The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 18% B, 18- 58% B over 20 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2-(5-{5-amino-4-[(2-phenoxyethyl)amino]pyrimidin-2-yl} -4-(4,4- dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetic acid (57.7 mg, 102.5 mhioΐ, 100.5% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.22 (s, 1H), 7.74 (s, 1H), 7.33 - 7.27 (m, 2H), 7.02 - 6.95 (m, 3H), 5.79 (br s, 1H), 4.28 (br t, J=4.7 Hz, 2H), 3.65 - 3.60 (m, 2H), 3.25 - 2.76 (m, 3H), 2.64 (s, 3H), 1.51 - 1.38 (m, 4H), 1.19 (s, 9H), 0.94 (br s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95

acetonitrile: water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 93.9 %; Observed Mass: 563.32; Retention Time: 1.51 min.

Example 127

Method A (Halide used for this compound was 2-chloro-7-(2-phenoxyethyl)-7H- purine. The hydrolysis step opened up the imidazole portion of the purine heterocycle to form the above productj.The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 12% B, 12- 52% B over 25 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with l0-mM ammonium acetate; Gradient: a 0-minute hold at 11% B, 11-51% B over 25 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2-(5-{4- amino-5-[(2-phenoxyethyl)amino]pyrimidin-2-yl}-4-(4,4-dimethylpiperidin-l-yl)-2- methylpyridin-3-yl)-2-(tert-butoxy)acetic acid (15.8 mg, 28.1 pmol, 30.9% yield). 1H NMR (500 MHz, METHANOL-d4) d 8.20 (s, 1H), 7.74 (s, 1H), 7.25 - 7.19 (m, 2H), 6.97 - 6.89 (m, 3H), 5.77 (br s, 1H), 4.22 - 4.15 (m, 2H), 4.10 - 4.01 (m, 1H), 3.91 - 3.81 (m, 1H), 3.21 - 3.11 (m, 1H), 3.19 - 2.76 (m, 2H), 2.65 (s, 3H), 1.52 - 1.37 (m, 4H), 1.19 (s, 9H), 0.91 (br s, 6H) 1 proton on the methylene closest to the piperidine N was not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 563.3; Retention Time: 1.55 min.

Example 128

Step 1: To a dry 10 mL Schlenk flask equipped with a stir bar was added 2-(5- (benzyloxy)pyridin-2-yl)-6-methyl-l,3,6,2-dioxazaborocane-4,8-dione (1.091 g, 3.21 mmol), isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2-vinylpyridin-3-yl)-2-(tert- butoxy)acetate (1 g, 2.139 mmol), palladium tetrakis (0.494 g, 0.428 mmol), diacetoxycopper (0.194 g, 1.070 mmol) and anhydrous tribasic potassium phosphate, finely ground (2.270 g, 10.70 mmol). The flask was sealed with a rubber septum, then placed under N2 atm (vac/fill x 3). To the flask was added a degassed (N2 sparging for 5 min) solution of DMF + diethanolamine (0.225 g, 2.139 mmol). The flask was placed in a 100 °C oil bath with stirring for t=l8h. The reaction mixture was transfered to a 125 mL separatory funnel and was diluted with water: brine (1: 1, 50 mL). The mixture was extracted with EtOAc (3 x 50 mL). The combined organics were washed with waterbrine (1: 1, 50 mL), then brine (50 mL). The organics were dried over MgSOu filtered; then concentrated in vacuo to afford an amber oil. This material was dissolved in a min of acetone, then was concentrated onto celite in vacuo. The resulting powder was subjected to Si02 purification (EtOAc:Hex). The pure fractions were pooled and concentrated in vacuo to afford the expected product isopropyl (S)-2-(5- (benzyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-vinyl-[2,3'-bipyridin]-5'-yl)-2-(tert- butoxy)acetate (670 mg, 1.172 mmol, 54.8 % yield). 1H NMR (400 MHz, CHLOROFORM- d) d 8.52 (d, J=2.7 Hz, 1H), 8.37 (s, 1H), 7.53 - 7.48 (m, 2H), 7.45 (t, J=7.5 Hz, 2H), 7.42 - 7.32 (m, 4H), 6.33 (dd, J=l6.8, 2.1 Hz, 1H), 6.10 (br s, 1H), 5.43 (dd, J=l0.6, 2.1 Hz, 1H), 5.21 (s, 2H), 5.10 (dt, J=l2.6, 6.2 Hz, 1H), 3.44 - 3.22 (m, 2H), 1.23 (d, J=6. l Hz, 3H), 1.19 (s, 9H), 1.17 (d, J=6.4 Hz, 3H), 0.98 - 0.80 (m, 6H). 6 protons of the methylenes on the piperidine were not observed in the HNMR spectrum. Observed Mass: 572.6.

Step 2: To an N2 sparged solution of isopropyl (S)-2-(5-(benzyloxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-vinyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (670 mg, 1.172 mmol) inMeOH (15 mL) was added Pd-C (125 mg, 0.117 mmol) and capped with a rubber septum. H2 was then bubbled through the solution for 10 minutes. The reaction was left under postiive pressure of H2 for 1 hr. The LCMS indicated the reaction was complete. The reaction was filtered through a 0.45 m nylon frit filter and volatiles evaporated to afford the crude oil. The reaction afforded the expected product isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-ethyl-5-hydroxy-[2,3'-bipyridin]-5'-yl)acetate (447 mg, 0.924 mmol, 79 % yield). 1H NMR (400 MHz, CHLOROFORM-d) d 8.39 (d, J=2.4 Hz, 1H), 8.26 (s, 1H), 7.31 (br d, J=2.7 Hz, 1H), 7.24 - 7.19 (m, 1H), 6.05 (br s, 1H), 5.17 - 5.08 (m, 1H), 3.05 (dq, J=l3.9, 7.1 Hz, 1H), 2.97 - 2.88 (m, 1H), 1.38 - 1.35 (m, 3H), 1.25 (d, J=6.4 Hz, 3H), 1.23 - 1.19 (m, 12H), 0.89 (br s, 6H) 8 protons on the methylenes on the piperidine ring were not observed in the HNMR spectrum. Observed Mass: 484.5.

Step 3 : To a 1 dram vial equipped with a stir bar and charged with isopropyl (S)-2- (tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-ethyl-5-hydroxy-[2,3'-bipyridin]-5'- yl)acetate (25 mg, 0.052 mmol) was added 2-phenoxyethan-l-ol (9.72 mΐ, 0.078 mmol). To the vial was added triphenylphosphane (20.34 mg, 0.078 mmol) as a solution in THF (0.25 mL). To the solution was added DIAD (0.015 mL, 0.078 mmol) as a solution in THF (0.25 mL). The solution was stirred at r.t. LCMS analysis at t=20min found clean and complete conversion to the desired ester intermediate. The reaction solution was concentrated under a N2 stream. The residue was dissolved in EtOH (1.0 mL). To the solution was added NaOH (0.207 mL, 1.034 mmol). The solution was stirred at 75 °C for 18 hrs. LCMS analysis after 18 hrs found disappearance of the ester peak and a large expected product peak (acid). The mixture was filtered through a syringe filter and the filtrate was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5-pm particles; Mobile Phase A: 5:95 acetonitrile: water with l0-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with lO-mM ammonium acetate; Gradient: a 0-minute hold at 29% B, 29-69% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 °C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the product (2S)-2-(tert-butoxy)-2-[4’-(4,4-dimethylpiperidin-l-yl)-6’- ethyl-5-(2-phenoxyethoxy)-[2,3’-bipyridine]-5’-yl]acetic acid (17.1 mg, 30.4 pmol, 58.5% yield). 1H NMR (500 MHz, METHAN OL-d4) d 8.46 (br s, 1H), 8.25 (br s, 1H), 7.66 (br d, J=8.9 Hz, 1H), 7.52 (br d, J=8.5 Hz, 1H), 7.31 (br t, J=7.6 Hz, 2H), 7.04 - 6.92 (m, 3H), 5.88 - 5.76 (m, 1H), 4.52 (br s, 2H), 4.41 (br s, 2H), 3.01 (br d, J=6.7 Hz, 2H), 2.95 - 2.71 (m, 2H), 1.51 - 1.39 (m, 4H), 1.34 - 1.30 (m, 3H), 1.23 (s, 9H), 0.91 (s, 6H) 2 protons on the methylenes closest to the piperidine N were not observed in the HNMR spectrum. Analytical LC/MS was used to determine the final purity. Injection conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1 % trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0 %B to 100 %B over 3 min, then a 0.75 min hold at 100 %B; Flow: 1 mL/min; Detection: MS and UV (220 nm). Purity: 100.0 %; Observed Mass: 562.32; Retention Time: 2.04 min.

Example 129

A mixture of 2-(pyridin-2-yl)ethan-l-ol (0.027 g, 0.223 mmol, 5 equiv), 60% NaH (8.90 mg, 0.223 mmol, 5 equiv), and isopropyl (.S)-2-(/ -butoxy)-2-(4-(4.4- dimethylpiperidin-l-yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (0.021 g, 0.045 mmol, 1 equiv) in THF (1.5 mL) was stirred at ambient temperature for 1 h. Upon complete addition, 5 M NaOH (0.089 mL, 0.445 mmol, 10 equiv) was added and the mixture was heated at 80 °C for 2 h. The reaction was allowed to cool to ambient temperature, filtered, and purified by preparative reverse phase HPLC to provide (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6-methyl-6'-(2-(pyridin-2-yl)ethoxy)-[3,3'-bipyridin]-5-yl)acetic acid (4 mg, 16%). ¾ NMR (500 MHz, DMSO-t/e) d 8.54 - 8.49 (m, 1H), 8.12 - 8.06 (m, 1H), 8.02 (s, 1H), 7.76 - 7.58 (m, 2H), 7.34 (d, J=8. l Hz, 1H), 7.24 (dd, J= 6.4, 5.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.78 (br d, = 5. l Hz, 1H), 4.78 - 4.66 (m, 2H), 1.37 - 1.26 (m, 3H), 1.20 - 1.08 (m, 10H), 0.91 - 0.76 (m, 6H) [note: not all piperidine protons not seen\. LCMS (M+l): 533.2.

Example 130

A mixture of 2-(pyridin-2-yl)ethan-l-ol (0.038 g, 0.306 mmol, 5 equiv), 60% NaH (0.012 g, 0.306 mmol, 5 equiv), and isopropyl (,S)-2-(to7-butoxy)-2-(4-(4.4- dimethylpiperidin-l-yl)-5',6'-difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (0.03 g, 0.061 mmol, 1 equiv) in THF (1.5 mL) was stirred for 1 h. After completion, 5 M NaOH (0.167 mL, 0.837 mmol, 10 equiv) was added and the mixture was heated at 80 °C for 2 h. Upon cooling to ambient temperature, the mixture was filtered and purified by reverse phase preparative HPLC to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5'-fhioro-6- methyl-6'-(2-(pyridin-2-yl)ethoxy)-[3,3'-bipyridin]-5-yl)acetic acid (3 mg, 9%). Ή NMR (500 MHz, DMSO-de) d 8.57 - 8.48 (m, 1H), 8.11 - 8.05 (m, 1H), 7.97 - 7.90 (m, 1H), 7.77 - 7.64 (m, 2H), 7.37 - 7.31 (m, 1H), 7.27 - 7.22 (m, 1H), 5.82 - 5.76 (m, 1H), 4.86 - 4.78 (m, 2H), 1.92 (s, 1H), 1.39 - 1.28 (m, 3H), 1.14 (s, 10H), 0.93 - 0.76 (m, 6H). LCMS (M+l): 551.3.

Example 131

diastereomer mixture A mixture of 6-fluoro-l,2,3,4-tetrahydronaphthalen-2-amine hydrochloride (0.047 g, 0.235 mmol, equiv), 60% NaH (9.39 mg, 0.235 mmol, 5 equiv), and isopropyl (S)-2-(tert- butoxy)-2-(4-(4,4-dimethylpiperidin- 1 -yl)-5 ',6'-difluoro-6-methyl- [3 ,3 '-bipyridin] -5 - yl)acetate (0.023 g, 0.047 mmol, 1 equiv) in NMP (1.5 mL) was heated at 100 °C for 2 h. After cooling to ambient temperature, 5 M NaOH (0.167 mL, 0.837 mmol, 10 equiv) was added and the mixture was heated at 80 °C for 2 h. Upon cooling to ambient temperature, the reaction was filtered and purified by reverse phase preparative HPLC to give (2S)-2-(tert- butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro-6'-((6-fluoro-l,2,3,4- tetrahydronaphthalen-2-yl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (10.6 mg, 37%). ¾ NMR (500 MHz, DMSO-de) d 8.06 (d, J= 2.2 Hz, 1H), 7.80 (s, 1H), 7.36 (d, J= 12.1 Hz, 1H), 7.17 - 7.01 (m, 1H), 6.98 - 6.86 (m, 2H), 6.57 - 6.45 (m, 1H), 5.81 (s, 1H), 4.32 (br s, 1H), 3.12 (br d, = 14.7 Hz, 1H), 2.97 - 2.70 (m, 3H), 2.51 (s, 12H), 2.19 - 2.07 (m, 1H), 1.89 - 1.71 (m, 1H), 1.58 - 1.38 (m, 1H), l .34 (br d, = 1.5 Hz, 3H), 1.14 (s, 9H), 0.86 (br s, 6H). ¹⁹F NMR (471 MHz, DMSO-de) d -117.88 (s, 1F, isomer 1), -117.92 (s, 1F, isomer 2), - 140.06 (s, 1F). LCMS (M+l): 593.3.

To a slurry of 4-fluorobenzaldehyde (0.47 g, 4.49 mmol, 1 equiv) and

cyclopropyldiphenylsulfonium tetrafluoroborate (1.02 g, 4.49 mmol, 1 equiv) in THF (45 mL) at -20 °C (IP A/dry ice) was added dropwise with a syringe 1 M KOtBu in THF (5.4 mL, 5.38 mmol, 1.2 equiv). After 30 min, 48% tetrafluoroboric acid (0.97 mL, 6.28 mmol, 1.4 equiv) was added. The reaction was allowed to warm to ambient temperature and stirred 1 h. The reaction was diluted with ether and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (NaiSOr) and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-40% EtO Ac/hexane) to provide 2- (4-fluorophenyl)cyclobutan-l-one (0.40 g, 54%) as a colorless oil.

; anthsyn, racemic

To a solution of 2-(4-fluorophenyl)cyclobutanone (0.40 g, 2.44 mmol, 1 equiv) in DCM (10 mL) and MeOH (2.5 mL) was added sodium borohydride (0.111 g, 2.92 mmol, 1.2 equiv). Slow gas evolution observed. After 1 h, the reaction was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (NaiSCb) and concentrated in vacuo to afford 2-(4-fluorophenyl)cyclobutan-l-ol as a 3: 1 anthsyn mixture (0.40 g, 99%) as a colorless oil. Anti isomer: Ή NMR (500 MHz, CDCb) d 7.25 - 7.17 (m, 1H), 7.02 (t, J= 8.7 Hz, 2H), 3.34 - 3.17 (m, 1H), 2.38 - 2.26 (m, 1H), 2.16 - 2.09 (m, 1H), 1.95 (br d, J= 6.9 Hz, 1H), 1.91 - 1.84 (m, 1H), 1.64 - 1.58 (m, 1H). ¾ NMR (500 MHz, CDCb) d 7.27 - 7.20 (m, 2H), 7.12 - 6.98 (m, 2H), 4.60 - 4.42 (m, 1H), 3.35 - 3.21 (m, 1H), 3.06 (dddd, J = 17.7, 9.9, 4.8, 2.7 Hz, 1H), 2.58 (qd, J= 10.8, 4.7 Hz, 1H), 2.22 (ddt, = 11.2, 9.8, 8.4 Hz, 1H).

Example 132 and 133

isomers

To a solution of 2-(4-fluorophenyl)cyclobutan-l-ol (0.062 g, 0.371 mmol, 1.5 equiv) and isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'-difluoro-6-methyl- [3,3'-bipyridin]-5-yl)acetate (.121 g, 0.247 mmol, 1 equiv) in THF (2.5 mL) was added 60% NaH (15 mg, 0.371 mmol, 1.5 equiv). After stirring 1 h, the reaction was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (NaiSCri) and concentrated in vacuo. The crude product was treated with EtOH (2 mL) and 10 N NaOH (0.2 mL). The reaction was heated at 80 °C for 4 h. After cooling to ambient temperature, the mixture was filtered and then purified by reverse phase preparative HPLC to give both diastereomers of (2S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro- 6'-(2-(4-fhiorophenyl)cyclobutoxy)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (42 mg, 29%) and (8 mg, 5%). Diastereomer 1 : ¾ NMR (500 MHz, DMSO-rie) d 8.06 (d, J= 12.5 Hz, 1H), 7.83 (dd, J= 12.5, 1.8 Hz, 1H), 7.70 (dd, J= 11.2, 1.7 Hz, 1H), 7.37 (ddd, J= 8.4, 5.9, 2.2 Hz, 2H), 7.12 (td, J= 8.9, 1.7 Hz, 2H), 5.78 (s, 1H), 5.45 - 5.33 (m, 1H), 3.70 (q, J= 9.2 Hz, 1H), 2.55 - 2.48 (m, 1H), 2.50 (s, 3H), 2.28 (q, J= 9.5 Hz, 1H), 2.03 (td, J= 19.0, 9.7 Hz, 1H), 1.78 (ddd, J= 10.3, 7.9, 2.8 Hz, 1H), 1.52 - 1.34 (m, 1H), 1.31 (br s, 3H), 1.13 (s, 9H), 0.81 (br s, 6H) [note: some piperidine protons not visible] LCMS (M+l): 594.3.

Diastereomer 2: ¾ NMR (500 MHz, DMSO-rie) d 8.08 - 7.94 (m, 1H), 7.89 - 7.79 (m, 1H), 7.56 (dd, J= 11.2, 1.7 Hz, 1H), 7.34 - 7.24 (m, 2H), 7.07 - 6.92 (m, 2H), 5.76 (br s, 1H), 5.74 - 5.65 (m, 1H), 4.11 - 3.95 (m, 1H), 2.65 - 2.53 (m, 1H), 2.50 (s, 3H), 2.46 - 2.36 (m, 1H), 2.33 - 2.24 (m, 2H), 1.32 (br d, J= 2.9 Hz, 4H), 1.13 (s, 9H), 0.85 (br s, 6H) [note: some piperidine protons not visible] LCMS (M+l): 594.3.

To a solution of 2-(4-fluorophenyl)cyclobutanol (0.36 g, 3: 1 anthsyn, 2.17 mmol, 1 equiv), 4-bromo-2-fluorophenol (0.496 g, 2.60 mmol, 1.2 equiv), and triphenylphosphine (0.795 g, 3.03 mmol, 1.4 equiv) in THF (4 mL) was added DIAD (0.59 mL, 3.03 mmol, 1.4 equiv) slowly with a syringe. After stirring 18 h, the reaction was diluted with ether and washed with 10% aqueous potasium carbonate and brine. The ether layer was dried (MgSCri) and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-30% EtOAc/hexane) to provide 4-bromo-l-(cyclopropyl(4-fluorophenyl)methoxy)-2- fluorobenzene (0.53 g, 72%) as a colorless oil. NMR clearly indicates a ring contraction has occured in addition to substitution. Ή NMR (500 MHz, CDC13) d 7.41 - 7.34 (m, 3H), 7.22 (dd, J= 10.6, 2.4 Hz, 1H), 7.09 - 7.00 (m, 3H), 6.67 (t, J= 8.7 Hz, 1H), 4.56 (d, J= 7.7 Hz, 1H), 1.45 - 1.32 (m, 1H), 0.77 - 0.67 (m, 1H), 0.64 - 0.57 (m, 1H), 0.54 (td, J= 9.9, 4.9 Hz, 1H), 0.46 - 0.37 (m, 1H).

A solution of 4-bromo-l -(cyclopropyl (4-fluorophenyl)methoxy)-2-fluorobenzene (0.53 g, 1.56 mmol, 1 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane)

(0.595 g, 2.344 mmol, 1.5 equiv), Pd(dppf)Ch (0.114 g, 0.156 mmol, 0.1 equiv), and KOAc (0.46 g, 4.69 mmol, 3 equiv) in dioxane (8 mL) was heated at 80 °C for 18 h. After cooling to ambient temperature, the reaction was diluted with EtOAc and washed with brine. The organic layer was dried (NaiSCri) and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-60% EtOAc in hexane) to provide 2-(4-(cyclopropyl(4- fhiorophenyl)methoxy)-3-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.42 g, 70%) as a viscous colorless oil. ¾ NMR (500 MHz, CDCh) d 7.48 (dd, J= 11.7, 1.4 Hz,

1H), 7.37 (dt, J= 8.4, 5.7 Hz, 3H), 7.03 (t, J= 8.7 Hz, 2H), 6.77 (t, J= 8.0 Hz, 1H), 4.68 (d, J = 7.7 Hz, 1H), 1.42 (tdd, J= 7.9, 5.0, 3.1 Hz, 1H), 1.32 (s, 12H), 0.71 (tdd, J= 8.3, 5.9, 4.3 Hz, 1H), 0.64 - 0.52 (m, 2H), 0.48 - 0.38 (m, 1H). Example 134

mixture of diastereomers A mixture of isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2- methylpyridin-3-yl)-2-(tert-butoxy)acetate (0.075 g, 0.165 mmol, 1 equiv), 2-(4- (cyclopropyl(4-fluorophenyl)methoxy)-3 -fluorophenyl)-4,4,5 ,5 -tetramethyl- 1 ,3 ,2- dioxaborolane (0.095 g, 0.247 mmol, 1.5 equiv), Pd(dppf)Ch (12 mg, 0.016 mmol, 0.1 equiv), and 2 M K3PO4 (0.49 ml, 0.988 mmol, 6 equiv) in dioxane (1.6 mL) was heated at 80 °C for 2 h. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried (NaiSOr) and concentrated in vacuo. The residue was taken up in ethanol (2 mL) and 10 M NaOH (0.2 mL) was added. The mixture was heated at 80 °C for 18 h. After cooling to ambient temperature, the mixture was filtered and purified by reverse phase preparative HPLC to provide (2S)-2-(tert-butoxy)-2-(5- (4-(cyclopropyl(4-fluorophenyl)methoxy)-3-fluorophenyl)-4-(4,4-dimethylpiperidin-l-yl)-2- methylpyridin-3-yl)acetic acid (40 mg, 38%) as a mixture of diastereomers. Diastereomeric mixture: 'H NMR (500 MHz, DMSO-de) d 7.99 (s, 1H), 7.54 - 7.41 (m, 2H), 7.22 - 7.05 (m, 4H), 6.97 - 6.85 (m, 1H), 5.76 (d, J= 3.7 Hz, 1H), 4.90 (t, J= 7.5 Hz, 1H), 2.48 (d, J= 1.5 Hz, 3H), 1.44 - 1.20 (m, 4H), 1.12 (d, J= 1.1 Hz, 9H), 0.90 - 0.74 (m, 4H), 0.71 - 0.58 (m, 3H), 0.57 - 0.40 (m, 4H) [note: some piperidine protons not visible}. LCMS (M+l): 593.3.

To a solution of 3-(4-fluorophenyl)cyclobutanone (0.13 g, 0.792 mmol, 1 equiv) in EtOH (8 mL) was added NaBfL (36 mg, 0.950 mmol, 1.2 equiv). After 2 h, reaction added to 1 M NaHSCU and extract with CHCb (x3). The organic layer was dried (NaiSCU) and concentrated in vacuo to give 3-(4-fluorophenyl)cyclobutan-l-ol (0.13 g, 10: 1 cisdrans, 99%) as a yellow oil. 'HNMR (500 MHz, CDCb) d 7.20 (dd, J= 8.4, 5.6 Hz, 2H), 7.10 - 6.94 (m, 2H), 4.37 - 4.24 (m, 1H), 3.01 - 2.89 (m, 1H), 2.85 - 2.74 (m, 2H), 2.05 - 1.94 (m, 2H).

To a solution of (ls,3s)-3-(4-fluorophenyl)cyclobutanol (0.13 g, 0.782 mmol, 1 equiv) and 5-bromo-l,2,3-trifluorobenzene (0.198 g, 0.939 mmol, 1.2 equiv) in DMF (8 mL) was added 60% NaH (0.038 g, 0.939 mmol, 1.2 equiv). After 1 h, the reaction was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (NaiSOr) and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-30% EtO Ac/hexane) to provide 5-bromo-l,2-difluoro-3-((3-(4- fluorophenyl)cyclobutoxy)benzene (0.17 g, 61%) as a colorless oil. Ή NMR (500 MHz, CDCb) d 7.26 - 7.20 (m, 2H), 7.07 - 7.01 (m, 2H), 6.98 (ddd, J= 9.3, 6.1, 2.3 Hz, 1H), 6.83 (dt, J= 6.3, 2.2 Hz, 1H), 4.69 (quin, J= 7.2 Hz, 1H), 3.24 - 3.11 (m, 1H), 3.04 - 2.92 (m,

2H), 2.40 - 2.29 (m, 2H).

A solution of 5-bromo-l,2-difluoro-3-((ls,3s)-3-(4-fluorophenyl)cyclobutoxy)- benzene (0.17 g, 0.476 mmol, 1 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (0.181 g, 0.714 mmol, 1.5 equiv), Pd(dppf)Ch (0.035 g, 0.048 mmol, 0.1 equiv), and KOAc (0.14 g, 1.43 mmol, 3 equiv) in dioxane (2.4 mL) was heated at 80 °C for 18 h. After cooling to ambient temperature, the reaction was diluted with EtOAc and washed with brine. The organic layer was dried (NaiSOr) and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-60% EtOAc in hexane) to provide 2-(3,4-difluoro-5-((3-(4-fluorophenyl)cyclobutoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (60 mg, 31%) as a colorless glass. ¾ NMR (500 MHz, CDCb) d 7.27 - 7.20 (m, 3H), 7.10 (br d, J= 13 Hz, 1H), 7.07 - 6.99 (m, 2H), 4.78 (quin, J= 7.2 Hz, 1H), 3.23 - 3.11 (m, 1H), 3.07 - 2.92 (m, 2H), 2.34 (br d, J= 9.3 Hz, 2H), 1.36 (s, 12H).

Example 135

A mixture of isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-l-yl)-2- methylpyridin-3-yl)-2-(tert-butoxy)acetate (0.075 g, 0.165 mmol, 1 equiv), 2-(3,4-difluoro-5- ((3-(4-fluorophenyl)cyclobutoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.073 g, 0.181 mmol, 1.1 equiv), Pd(dppf)Cl2 (12 mg, 0.016 mmol, 0.1 equiv), and 2 M K3PO4 (0.49 ml, 0.988 mmol, 6 equiv) in dioxane (1.6 mL) was heated at 80 °C for 2 h. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried (NaiSCL) and concentrated in vacuo. The residue was taken up in ethanol (2 mL) and 10 M NaOH (0.2 mL) was added. The mixture was heated at 80 °C for 18 h. After cooling to ambient temperature, the mixture was filtered and purified by reverse phase preparative HPLC to provide (S)-2-(tert-butoxy)-2-(5-(3,4-difluoro-5-((3-(4- fluorophenyl)cyclobutoxy)phenyl)-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3- yl)acetic acid (37 mg, 37%). ¾ NMR (500 MHz, DMSO-de) d 8.06 (s, 1H), 7.30 (dd, J= 8.6, 5.7 Hz, 2H), 7.17 - 7.05 (m, 2H), 7.02 - 6.94 (m, 1H), 6.87 (br d, J= 6.2 Hz, 1H), 5.76 (br dd, J= 12.7, 3.5 Hz, 1H), 4.95 - 4.82 (m, 1H), 3.24 - 3.07 (m, 1H), 3.02 - 2.80 (m, 2H), 2.51 (br s, 3H), 2.23 - 2.09 (m, 2H), 1.54 - 1.25 (m, J= 7.3 Hz, 4H), 1.15 (s, 9H), 0.83 (br s, 6H) [note: some piperidine protons not visible] LCMS (M+l): 611.3.

Example 136

To an ice-cold solution of cyclohexylmethanol (50.8 mg, 0.445 mmol) in DMF (10 mL) was added NaH (26.72 mg, 0.668 mmol) in portions and stirred for 30 min at 0 °C.

Then, (S)-2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fhioro-6-methyl-3,3'-bipyridin- 5-yl)acetic acid (70 mg, 0.148 mmol) was added and stirred for 5 hours at 90 °C. The mixture was poured into ice-water (20 mL), acidified with 1N HC1 (2 mL, 2 mmol) and extracted with EtOAc (15 mL). The organic layer was washed with brine (10 mL), dried over NaiSOi and concentrated to give a crude product which was purified by preparative HPLC (TFA as buffer) to give (S)-2-tert-butoxy-2-(6'-(cyclohexylmethoxy)-4-(4,4-dimethylpiperidin-l-yl)-6- methyl-3,3'-bipyridin-5-yl)acetic acid (43.6 mg, 55.7%). LCMS [M + H] = 524.2. Ή NMR (400 MHz, CD30D) d 8.31 (s, 1H), 8.16 (s, 1H), 7.72 (d, J = 7.0 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 5.68 (s, 1H), 4.23-4.14 (m, 2H), 3.14-3.11 (br s, 2H), 2.95-2.94 (br, 2H), 2.78 (s, 3H), 1.90-1.73 (m, 6H), 1.51-1.45 (m, 4H); 1.27-1.33 (m, 3H), 1.25 (s, 9H), 1.11-1.10 (m, 2H), 0.97 (s, 6H). Example 137

To an ice-cold solution of butane- 1 -thiol (40.2 mg, 0.445 mmol) in DMF (10 mL) was added NaH (26.72 mg, 0.668 mmol) in portions and stirred for 0.5 hour at 0 °C. Then, (S)-2- tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fluoro-6-methyl-3,3'-bipyridin-5-yl)acetic acid (70 mg, 0.148 mmol) was added to the mixture and stirred for 5 hours at 90 °C. The mixture was poured into ice-water (20 mL), acidified with 1N HC1 (2 mL, 2 mmol) and extracted with EtOAc (15 mL). The organic layer was washed with brine (10 mL), dried over Na2S04, and concentrated to give a crude product which was purified by preparative HPLC (TFA as buffer) to give (S)-2-tert-butoxy-2-(6'-(butylthio)-4-(4,4-dimethylpiperidin-l-yl)-6- methyl-3,3'-bipyridin-5-yl)acetic acid (45.5 mg, 60.5%). LCMS [M + H] = 500.2. Ή NMR (400 MHz, CD30D) d 8.44 (s, 1H), 8.33 (s, 1H), 7.65 (d, J = 7.1 Hz, 1H), 7.45 (dd, J = 8.3, 0.6 Hz, 1H), 5.68 (s, 1H), 3.31-3.06 (m, 4H), 2.96-2.93 (br, 2H), 2.78 (s, 3H), 1.73 (dt, J = 13.0, 7.1 Hz, 2H), 1.56-1.44 (m, 6H), 1.29 (s, 9H), 1.03-0.92 (m, 9H).

Example 138

To an ice-cold solution of 2-ethoxyethanol (40.1 mg, 0.445 mmol) in DMF (10 mL) was added NaH (26.72 mg, 0.668 mmol) in portions and stirred for 0.5 hour at 0 °C. Then, (S)-2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fhioro-6-methyl-3,3'-bipyridin-5- yl)acetic acid(70 mg, 0.148 mmol) was added and stirred for 5 hours at 90 °C. The mixture was poured into ice-water (20 mL), acidified with 1N HC1 (2 mL, 2 mmol) and extracted with EtOAc (15 mL). The organic layer was washed with brine (10 mL), dried over NaiSOi. and concentrated to give a crude product which was purified by preparative HPLC (TFA as buffer) to give (S)-2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-(2-ethoxyethoxy)-6- methyl-3,3'-bipyridin-5-yl)acetic acid (42.9 mg, 56.5%). LCMS [M + H] = 500.2. Ή NMR (400 MHz, CD30D) d 8.32 (s, 1H), 8.19 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 5.68 (s, 1H), 4.60-4.43 (m, 2H), 3.88-3.75 (m, 2H), 3.62 (q, J = 7.0 Hz, 2H), 3.15-3.11 (br, 2H), 2.96-2.93 (br, 2H), 2.79 (s, 3H), 1.49-1.43 (m, 4H), 1.29 (s, 9H); l . l7-l .30(m, 3H); 0.97 (s, 6H).

Example 139

To a stirred solution of 2-(oxetan-3-yl)ethanol (65 mg, 0.636 mmol) in THF (10 mL) was added sodium hydride (30 mg, 1.250 mmol) and stirred at room temperature for 30 mins. Then, (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin- 1 -yl)-6'-fluoro-6-methyl- [3,3'-bipyridin]-5-yl)acetate (120 mg, 0.254 mmol) was added and stirred overnight at 65 °C. Cooled, the pH was adjusted to 8 by acetic acid, concentrated and purified by Prep-HPLC to afford the desired product (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6-methyl-6'- (2-(oxetan-3-yl)ethoxy)-[3,3'-bipyridin]-5-yl)acetic acid (50 mg, 38.4 % yield). LCMS [M + H] = 512.2. ¾ NMR (400 MHz, CD30D) d 8.12 (d, J = 2.1 Hz, 1H), 8.10 (s, 1H), 7.68 (dd, J = 8.5, 2.5 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 5.78 (s, 1H), 4.88-4.83 (m, 2H), 4.54-4.51 (t,

2H), 4.40 - 4.36 (m, 2H), 3.27-3.25 (m, 1H), 3.15 (s, 2H), 2.76-2.65 (br, 2H), 2.66 (s, 3H), 2.24-2.19 (dd, 2H), 1.45 (br, 4H), 1.21 (s, 9H), 0.92 (s, 6H).

Example 140

Step 1 : To a stirred mixture of l-ethoxypropan-2-ol (133 mg, 1.272 mmol) and sodium hydride (30 mg, 1.250 mmol) in THF (10 mL) was stirred at rt for 30 mins. Then, (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fluoro-6-methyl-[3,3'- bipyridin]-5-yl)acetate (120 mg, 0.254 mmol) was added and stirred for 4 h at 25 °C, diluted with H2O (100 mL) and extracted with EtOAc (150 mL ^c 3). The organic phase was dried over Na2SC>4, concentrated and the residue was purified by silica gel chromatography (Pet. Ether: EtOAc/4: 1) to afford the desired product (2S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-((l-ethoxypropan-2-yl)oxy)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (100 mg, 59.4 % yield). LCMS [M + H] = 556.3. Step 2: To a stirred solution of (2S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-((l-ethoxypropan-2-yl)oxy)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (100 mg, 0.180 mmol) in methanol (10 mL) was added a solution of sodium hydroxide (216 mg, 5.40 mmol) in water (3.00 mL). The mixture was stirred overnight at 75 °C, cooled and the pH of the reaction mixture was adjusted to 8 by acetic acid. Then, concentrated and the residue was purified by Prep-HPLC to afford the desired product (2S)-2-(tert-butoxy)-2-(4- (4,4-dimethylpiperidin-l-yl)-6'-((l-ethoxypropan-2-yl)oxy)-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (60 mg, 64.9 % yield). LCMS [M + H] = 514.2. ¾ NMR (400 MHz, CD30D) d 8.32 (d, J = 5.1 Hz, 1H), 8.18 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 5.68 (s, 1H), 5.47 - 5.42 (m, 1H), 3.70 - 3.55 (m, 4H), 3.15 (br, 2H), 2.96 (br, 2H), 2.79 (s, 3H), 1.49 (br, 4H), 1.37 (m, 3H), 1.25 (s, 9H), 1.22-1.17 (m, 3H), 0.97 (s, 6H).

Example 141

To an ice-cold solution of 2-(2-chloro-6-methylphenoxy)ethanol (142 mg, 0.763 mmol) in DMF (5 mL) was added the sodium hydride (20.35 mg, 0.848 mmol) in portions. To this mixture was added at once (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin- l-yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (40 mg, 0.085 mmol) in DMF (1 mL) and stirred at 25 °C for 16 h. Then, the pH was adjusted to about 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC to afford the desired product (S)-2-(tert-butoxy)-2-(6'-(2-(2-chloro-6-methylphenoxy)ethoxy)-4-(4,4-dimethylpiperidin-l- yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (20 mg, 39.6 % yield). LCMS [M + H] = 596.3. ¾ NMR (400 MHz, MeOD) d 8.15 (d, J=2.5, 1H), 8T2(s, 1H); 7.72 (dd, J = 8.5, 2.4 Hz,

1H), 7.24 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 6.8 Hz, 1H), 7.01 (t, J = 8.3 Hz, 2H), 5.77 (s, 1H), 4.81 - 4.68 (m, 2H), 4.35 (m, 2H), 2.76 (m, 4H), 2.66 (s, 3H), 2.34 (b, 3H), 1.49-1.41 (br, 4H), 1.20 (s, 9H), 0.89 (s, 6H). Example 142

To an ice-cold solution of 2-(p-tolyloxy)ethanol (116 mg, 0.763 mmol) in DMF (6 mL) was added sodium hydride (20.35 mg, 0.848 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fluoro- 6-methyl-[3,3'-bipyridin]-5-yl)acetate (40 mg, 0.085 mmol) in DMF (1 mL) and stirred at 25 °C for 16 h. Then, cooled, pH was adjusted to about 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC to afford the desired product (S)-2-(tert- butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6-methyl-6'-(2-(p-tolyloxy)ethoxy)-[3,3'- bipyridin] -5 -yl)acetic acid (20 mg, 42.0 % yield). LCMS [M + H] = 562.3. Ή NMR (400 MHz, MeOD) d 8.14 (d, J = 2.1 Hz, 1H), 8.12 (s, 1H), 7.71 (dd, J = 8.5, 2.4 Hz, 1H), 7.10 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 5.77 (s, 1H), 4.70 (dd, J = 5.2, 2.8 Hz, 2H), 4.34 (t, J = 4.7 Hz, 2H), 2.78 (br, 4H), 2.66 (br, 3H), 2.29 (s, 3H), 1.45 (br, 4H), 1.20 (s, 9H), 0.91 (s, 6H). Example 143

To an ice-cold solution of cyclopropylmethanol (92 mg, l.272mmol) in DMF (4mL) was added NaH (50.9 mg, 1.272 mmol) in portions. To this mixture was added at once a solution of (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-hydroxy-6- methyl-3, 3 '-bipyridin-5-yl)acetate (60 mg, O. l27mmol) in DMF (lml) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPLC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(6'-(cyclopropylmethoxy)-4- (4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (6.0 mg, 0.012 mmol, 9.73 % yield). LCMS [M + H] = 482. ¾ NMR (400 MHz, CD30D) 5 8.11 (br, 2H), 7.68 (dd, J = 8.5, 2.5 Hz, 1H), 6.94(d, J = 8.5 Hz, 1H), 5.77 (s, 1H), 4.25-4.15 (m, 2H), 3.33-3.32 (br s, 1H), 3.17-3.14 (br s, 2H), 2.66 (s, 3H), 1.49 - 1.23 (m, 5H), 1.21 (s, 9H), 0.92 (s, 6H), 0.67 - 0.59 (m, 2H), 0.42 - 0.36 (m, 2H).

Example 144

To an ice-cold solution of (l-methylcyclopropyl) methanol (43.8 mg, 0.509 mmol) in DMF (4 mL) was added the NaH (23.75 mg, 0.594 mmol) in portions. To this mixture was added at once a solution of (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'- hydroxy-6-methyl-3,3'-bipyridin-5-yl)acetate (80 mg,0T70mmol) in DMF (lml) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPFC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6-methyl-6'-((l-methylcyclopropyl)methoxy)-[3,3'-bipyridin]-5- yl)acetic acid (20 mg, 0.039 mmol, 23.26 % yield). FCMS [M + H] = 496. ¾ NMR (400 MHz, CD30D) 5 7.99-7.98 (m, 2H), 7.57 (dd, J = 8.5, 2.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 5.66 (s, 1H), 4.05 (q, J = 10.7 Hz, 2H), 3.04 (br, 2H), 2.66 (br, 2H), 2.55 (s, 3H), 1.33 (br s, 4H), 1.14 (s, 3H), 1.10 (s, 9H), 0.81 (s, 6H), 0.50 (t, J = 4.9 Hz, 2H), 0.33 (q, J = 4.3 Hz, 2H).

Example 145

To an ice-cold solution of (2-methylcyclopropyl)methanol (146 mg, 1.696 mmol) in DMF (4 mF), was added the NaH (67.8 mg, 1.696 mmol) in portions. To this mixture was added at once a solution of (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'- hydroxy-6-methyl-3,3'-bipyridin-5-yl)acetate (80 mg, 0.170 mmol) in DMF (1 ml) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPFC (NH4HCO3 as buffer) to give (2S)-2-tert-butoxy-2-(4-(4,4- dimethylpiperidin-l-yl)-6-methyl-6'-((2-methylcyclopropyl)methoxy)-3,3'-bipyridin-5- yl)acetic acid(l6.2mg, 18.83%). LCMS [M + H] = 496. ¾ NMR (400 MHz, CD30D) d 7.98 (d, J=2.4, 1H), 7.97(s, 1H), 7.56 (dd, J = 8.5, 2.4 Hz, 1H), 6.82 (d, J = 6.7 Hz, 1H), 5.64 (s, 1H), 4.08-4.07 (m, 2H), 3.03-2.90 (br, 1H), 2.63-2.59 (br, 5H), 1.44-1.15 (br, 4H), 1.10 (s, 9H), 0.99-0.98 (m, 4H), 0.96-0.87 (m, 1H), 0.80 (s, 6H), 0.74-0.67 (m, 1H), 0.49-0.38 (m, 1H), 0.31-0.20 (m, 1H).

Example 146

Step 1 : To a stirred solution of 4-fluoro-3-methylphenol (1.2 g, 9.51 mmol) in water (22 mL) was added the 2-bromoethanol (1.783 g, 14.27 mmol) and NaOH (0.571 g, 14.27 mmol). The mixture was stirred at 90 °C for 16 h and cooled to room temperature. The pH was adjusted to about 7 with acetic acid and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. etherEtOAc (6: l~5 : 1) to give 2-(4-fluoro-3-methylphenoxy)ethanol (500 mg, 2.64 mmol, 27.8 % yield).

Step 2: To an ice-cold solution of 2-(4-fluoro-3-methylphenoxy)ethanol (162 mg, 0.954 mmol) in DMF (3 mL) was added the NaH (42.4 mg, 1.060 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-hydroxy-6-methyl-3,3'-bipyridin-5-yl)acetate (50 mg, 0.106 mmol) in DMF (1 ml) at once. The mixture was stirred at rt for 16 h and pH was adjusted to 7 with acetic acid. The mixture was filtered and purified by Prep-HPLC (NH4HC03 as buffer) to give (S)-2-(tert- butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-(2-(4-fluoro-3-methylphenoxy)ethoxy)-6- methyl-[3,3'-bipyridin]-5-yl)acetic acid (21.2 mg, 0.036 mmol, 33.9 % yield). LCMS [M +

H] = 580. ¾ NMR (400 MHz, CD30D) d 8.27 - 8.09 (m, 2H), 7.86 - 7.64 (m, 1H), 7.05 - 6.77 (m, 4H), 5.78 (s, 1H), 4.78 - 4.59 (m, 2H), 4.33 (t, J = 4.6 Hz, 2H), 3.16-3.14 (br, 2H), 2.79-2.77(br, 1H), 2.66 (s, 3H), 2.25 (s, 3H), 1.45 (br, 3H), 1.20 (s, 9H), 0.91 (s, 6H). Example 147

To an ice-cold solution of 2-phenoxyethanol (132 mg, 0.954 mmol) in DMF (3 mL) was added the NaH (42.4 mg, 1.060 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-hydroxy-6-methyl-3,3'- bipyridin-5-yl)acetate (50mg,0. l06mmol) in DMF (lml) at once. The mixture was stirred at rt for 16 h and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPFC (NHJTCCh as buffer) to give (S)-2-(tert-butoxy)-2-(4- (4,4-dimethylpiperidin-l-yl)-6-methyl-6'-(2-phenoxyethoxy)-[3,3'-bipyridin]-5-yl)acetic acid (20.2 mg, 0.037 mmol, 34.8 % yield). FCMS [M + H] = 548. ¾ NMR (400 MHz, CD30D) d 8.21 - 8.10 (m, 2H), 7.71 (dd, J = 8.5, 2.4 Hz, 1H), 7.34 - 7.25 (m, 2H), 6.99-6.94 (m, 4H), 5.78 (s, 1H), 4.80 - 4.68 (m, 2H), 4.42 - 4.34 (m, 2H), 3.16-3.14 (br, 2H), 2.79-2.77 (br, 2H), 2.66 (s, 3H), 1.46-1.44 (br, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 148

To an ice-cold solution of 2-(4-chlorophenoxy)ethanol (165 mg, 0.954 mmol) in DMF (3 mF) was added the NaH (42.4 mg, 1.060 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-hydroxy-6- methyl-3,3'-bipyridin-5-yl)acetate (50mg,0. l06mmol) in DMF (lml) at once. The mixture was stirred at rt for 16 h and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPFC (NH4HC03 as buffer) to give (S)-2-(tert-butoxy)-2- (6'-(2-(4-chlorophenoxy)ethoxy)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (22.3 mg, 0.038 mmol, 35.5 % yield). FCMS [M + H] = 582. ¾ NMR (400 MHz, CD30D) d 8.1 (d, J=2.4 Hz, 1H), 8.17 (s, 1H), 7.69-7.72 (dd, J=8.5, 2.4Hz, 1H), 7.26- 7.30 (d, J=8.5Hz, 2H), 6.97-7.00 (m, 3H), 5.78 (s, 1H), 4.70- 4.72 (m, 2H), 4.42 - 4.34 (m, 2H), 3.14-3.15 (m, 2H), 2.76-2.78 (m, 2H), 2.66 (s, 3H), 1.46-1.44 (br, 4H), 1.21 (s, 9H), 0.91 (s, 6H). Example 149

To an ice-cold solution of (R)-l-cyclobutylethanol (38.2 mg, 0.382 mmol) in DMF (3 mL), was added NaH (16.79 mg, 0.420 mmol) in portions. To this mixture was added rapidly a solution of (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-hydroxy-6- methyl-3,3'-bipyridin-5-yl)acetate (60mg,0. l27mmol) in DMF (1 ml). The mixture was stirred at rt for 16 h and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)- 2-(6'-((R)-l-cyclobutylethoxy)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (9.6 mg, 0.019 mmol, 14.80 % yield). LCMS [M + H] = 510. ¾ NMR (400 MHz, CD30D) d 8.06-7.94 (m, 2H), 7.55 (dd, J = 8.5, 2.4 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 5.64 (s, 1H), 5.09 (m, 1H), 3.04-3.02 (br, 2H), 2.66-2.64 (br, 2H), 2.58 - 2.45 (m, 1H), 2.50(s, 3H); 2.00 - 1.66 (m, 6H), 1.34-1.32 (br, 4H), U9(s, 9H); 1.18 - 1.04 (m, 3H), 0.79 (s, 6H).

Example 150

To an ice-cold solution of (R)-l-cyclopropylethanol (32.9 mg, 0.382 mmol) in DMF (3 mL) was added NaH (20.35 mg, 0.509 mmol) in portions. To this mixture was added rapidly a solution of (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'- hydroxy-6-methyl-3,3'-bipyridin-5-yl)acetate (60mg,0. l27mmol) in DMF (1 ml). The mixture was stirred at rt for 16 h and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC (NH4HCO3 as buffer) to give (S)-2- (tert-butoxy)-2-(6'-((R)-l-cyclopropylethoxy)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetic acid (10.0 mg, 0.020 mmol, 15.68 % yield). LCMS [M + H] = 496. ¾ NMR (400 MHz, CD30D) 5 8.16 - 8.03 (m, 2H), 7.66 (dd, J = 8.5, 2.4 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 5.77 (s, 1H), 4.73 (dq, J = 12.4, 6.1 Hz, 1H), 3.16-3.14 (br, 2H), 2.778-2.77 (br, 2H), 2.66 (s, 3H), l.43(m, 7H), 1.26 - 1.16 (m, 1H), 1.21-1.19 (br, 1H); 0.92 (s, 6H), 0.66 - 0.51 (m, 2H), 0.39 (dtd, J = 18.2, 8.9, 5.1 Hz, 2H).

Example 151

Step 1 : To a stirred solution of 3,5-dif uorophenol (1.2 g, 9.22 mmol) in water (22 mL) was added the 2-bromoethanol (1.729 g, 13.84 mmol) and NaOH (0.553 g, 13.84 mmol). The mixture was stirred at 90 °C for 16 h and cooled to room temperature. Then, the pH was adjusted to about 7 with acetic acid and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous NaiSOr and concentrated to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet.

etherEtOAc (6: l~5: 1) to give 2-(3,5-difluorophenoxy)ethanol (680 mg, 3.55 mmol, 38.5 % yield).

Step 2; To an ice-cold solution of 2-(3,5-difluorophenoxy)ethanol (103 mg, 0.594 mmol) in DMF (3 mL) was added NaH (27.1 mg, 0.679 mmol) in portions. To this mixture was rapidly added a solution of (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-hydroxy-6-methyl-3,3'-bipyridin-5-yl)acetate (40 mg, 0.085 mmol) in DMF (1 ml). The mixture was stirred at rt for 16 h and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC (NH4HCO3 as buffer) to give (S)-2- (tert-butoxy)-2-(6'-(2-(3,5-difluorophenoxy)ethoxy)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl- [3,3'-bipyridin]-5-yl)acetic acid (20.1 mg, 0.034 mmol, 40.6 % yield). LCMS [M + H] = 584. ¾ NMR (400 MHz, CD30D) d 8.25 - 8.08 (m, 2H), 7.71 (dd, J = 8.5, 2.3 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.64 (dd, J = 9.2, 2.1 Hz, 2H), 6.59 - 6.51 (m, 1H), 5.78 (s, 1H), 4.77 - 4.66 (m, 2H), 4.46 - 4.33 (m, 2H), 3.16-3.14 (br, 2H), 2.79-2.77 (br, 2H), 2.66 (s, 3H), 1.46-1.44 (br, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 152

Step 1 : To a stirred solution of 4-chloro-2-fluorophenol (1.2 g, 8.19 mmol) in water (22 mL) was added the 2-bromoethanol (1.729 g, 13.84 mmol) and NaOH (0.491 g, 12.28 mmol). The mixture was stirred at 90 °C for 16 h. The solution was cooled to room temperature, the pH was adjusted to about 7 with acetic acid and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous NaiSOr and concentrated to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. etherEtoAc (6: 1-5: 1) to 2-(4-chloro-2-fluorophenoxy)ethanol (500 mg, 2.413 mmol, 29.5 % yield).

Step 2: To an ice-cold solution of 2-(4-chloro-2-fluorophenoxy)ethanol (113 mg, 0.594 mmol) in DMF (3 mL) was added NaH (27.1 mg, 0.679 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-hydroxy-6-methyl-3,3'-bipyridin-5-yl)acetate (40 mg, 0.085 mmol) in DMF (1 ml) rapidly. The mixture was stirred at rt for 16 h and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(6'-(2-(4-chloro-2-fluorophenoxy)ethoxy)-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (7.3 mg, 0.012 mmol,

13.83 % yield). LCMS [M + H] = 600. ¾NMR (400 MHz, CD30D) d 8.23 - 8.02 (m, 2H),

7.71 (dd, J = 8.5, 2.4 Hz, 1H), 7.28 - 7.08 (m, 3H), 7.00 (d, J = 8.5 Hz, 1H), 5.77 (s, 1H),

4.82 - 4.70 (m, 2H), 4.50 - 4.40 (m, 2H), 3.16-3.14 (br, 2H), 2.78-2.76 (br, 2H), 2.66 (s, 3H), 1.46-1.44 (br, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 153

Step 1: To a solution of 4-chloro-2-methylphenol (1 g, 7.01 mmol) in water (22 mL) was added the 2-bromoethanol (1.139 g, 9.12 mmol) and NaOH (0.365 g, 9.12 mmol). The mixture was stirred at 90 °C for 16 h and cooled to room temperature. The pH was adjusted to about 7 with acetic acid and extracted with DCM (3x20 mL). The combined organic layers were dried over anhydrous NaiSOr and concentrated to give a yellow crude product. The crude product was purified by column silica gel chromatography eluting with PE:EtoAc (6: 1-5: 1) to 2-(4-chloro-2-methylphenoxy)ethanol (400 mg, 2.100 mmol, 29.9 % yield).

Step 2: To an ice-cold solution of 2-(4-chloro-2-methylphenoxy)ethanol (125 mg, 0.668 mmol) in DMF (3 mL) was added NaH (30.5 mg, 0.763 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-hydroxy-6-methyl-3,3'-bipyridin-5-yl)acetate (45 mg, 0.095 mmol) in DMF (1 ml). The mixture was stirred at rt for l6h and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC (NH4HCO3 as buffer) to give (S)-2- (tert-butoxy)-2-(6'-(2-(4-chloro-2-methylphenoxy)ethoxy)-4-(4,4-dimethylpiperidin-l-yl)-6- methyl-[3,3'-bipyridin]-5-yl)acetic acid (21.2 mg, 0.035 mmol, 36.8 % yield). LCMS [M +

H] = 596. Tf NMR (400 MHz, CD30D) d 8.20 - 8.06 (m, 2H), 7.71 (dd, J= 8.4, 2.4 Hz,

1H), 7.20 - 7.08 (m, 2H), 7.04 - 6.88 (m, 2H), 5.78 (s, 1H), 4.80 - 4.71 (m, 2H), 4.45 - 4.30 (m, 2H), 3.16-3.14 (br, 2H), 2.79-2.76 (br, 2H), 2.66 (s, 3H), 2.18 (s, 3H), 1.46-1.44 (br, 4H), l .20(s, 9H), 0.91 (s, 6H).

Example 154

Step 1 : To an ice-cold solution of l-(2-bromoethyl)-4-fluorobenzene (5 g, 24.62 mmol) in ethanol (50 mL) was added thiourea (1.874 g, 24.62 mmol) in portions. The mixture was stirred at reflux for 2 h and cooled to room temperature. The solvents were removed, NaOH (1.477 g, 36.9 mmol) in water (40 ml) was added and stirred at reflux for 2 h. The mixture was cooled to room temperature and the pH was adjusted to 7 with 1M H2SO4. The mixture was extraced with EtiO (30 mL x 2). The combined organic layers were washed with sat NaCl (20 mL), dried with Na2SC>4 and concentrated to give an oil. The residue was purified by silica gel column (pet. ether: EtOAc/6: 1) to afford 2-(4- fluorophenyl)ethanethiol (1.5 g, 9.60 mmol, 39.0 % yield) as an colorless oil. LCMS No aim mass.

Step 2: To an ice-cold solution of 2-(4-fluorophenyl)ethanethiol (166 mg, 1.060 mmol) in DMF (1 mL) was added NaH (42.4 mg, 1.060 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'- fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (100 mg, 0.212 mmol) and stirred at room temperature for 16 hr. Then, the pH was adjusted to about 7 with acetic acid and purified by preparative HPLC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-((4-fhiorophenethyl)thio)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (33 mg, 0.058 mmol, 44.1 % yield) as a white solid. LCMS [M + H] = 566.2. Ή NMR (400 MHz, DMSO-d6) d 13.39 (s, 1H), 8.50 (s, 1H), 8.38 (s, 1H), 7.69 (d, J = 6.0 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.31 (dd, J = 8.3, 5.8 Hz, 2H), 7.13 (t, J = 8.8 Hz, 2H), 5.60 (s, 1H), 3.53-3.44 (m, 1H), 3.44-3.34 (m, 1H), 2.92-2.90 (m, , 6H), 2.62 (s, 3H), 1.35 (s, 4H), 1.13 (s, 9H), 0.85 (s, 6H).

Example 155

Step 1 : To a stirred mixture of 2-(4-fluorophenyl)ethanethiol (104 mg, 0.664 mmol) in DMF (3 mF) was added sodium hydride (15.93 mg, 0.664 mmol) and stirred at rt for 20 min. Then (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'-difluoro-6-methyl- [3,3'-bipyridin]-5-yl)acetate (65 mg, 0.133 mmol) was added and stirred at rt for 60 min. The reaction was queched with ice water and extracted with EtOAc (30 ml ^c 3), dried with Na2SC>4 and concentrated. The residue was purified by Prep-TFC to afford (S)-isopropyl 2- (tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro-6'-((4-fluorophenethyl)thio)-6- methyl-[3,3'-bipyridin]-5-yl)acetate (70 mg, 0.101 mmol, 76 % yield). FCMS 626 [M+H]⁺.

Step 2: A mixture of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)- 5'-fluoro-6'-((4-fluorophenethyl)thio)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (70 mg, 0.112 mmol) and sodium hydroxide (89 mg, 2.237 mmol) in methanol (3 mF) was heated at 80 °C overnight. Then, the mixture was neutralized with aq. HC1 to pH = 7. The solvent was removed and the residue was purified by Prep-TFC (Pet. ether: EtOAc/ 1 : 1) to afford (S)-2- (tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro-6'-((4-fluorophenethyl)thio)-6- methyl-[3,3'-bipyridin]-5-yl)acetic acid (10.1 mg, 0.017 mmol, 15.47 % yield) as a white solid. FCMS 584 [M+H]⁺. ¾ NMR (400 MHz, CD30D) d 8.37 (d, J = 5.0 Hz, 2H), 7.59 (d,

J = 10.2 Hz, 1H), 7.42-7.24 (m, 2H), 7.09-6.93 (m, 2H), 5.68 (s, 1H), 3.57-3.50 (m, 2H), 3.21-2.87 (m, 6H), 2.78 (s, 3H), 1.55-1.48 (m, 4H), 1.25 (s, 9H), 0.97 (s, 6H).

Example 156

To an ice-cold solution of l-isopropoxypropan-2-ol (251 mg, 2.120 mmol) in DMF (3 mL) was added the NaH (85 mg, 2.120 mmol) in portions. The resulting mixture was stirred at room temperature for 30 min and (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (100 mg, 0.212 mmol) was added quickly to this mixture. The mixture was stirred at 70 °C for 16 hr, water (0.2 mL) was added and stirred additional 16 hr at 70 °C. The pH was adjusted to about 7 with acetic acid and purified by preparative HPLC (NH4HCO3 as buffer) to give (2S)-2-(tert- butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-((l-isopropoxypropan-2-yl)oxy)-6-methyl-[3,3'- bipyridin]-5-yl)acetic acid (41.8 mg, 0.078 mmol, 36.6 % yield) as a white solid. LCMS [M + H] = 528. ¾ NMR (500MHz, CD30D): 1H NMR (400 MHz, CD30D) d 8.26 (d, J=2.4 Hz, 1H), 8.14 (s, 1H), 7.69 - 7.47 (dd, J=8.5, 2.4 Hz, 1H), 6.94-6.92 (d, J=8.5Hz, 1H), 5.58 (s, 1H), 5.29-5.27 (m, 1H), 3.63 - 3.55 (m, 3H), 3.03-3.01 (br, 2H), 2.81-2.79 (br, 2H), 2.64 (s, 3H), 1.46-1.36 (m, 4H), 1.25 (m, 3H), 1.12 (s, 9H), 1.06 (s, 6H), 0.84 (s, 6H).

Example 157

To an ice-cold solution of cyclobutylmethanol (146 mg, 1.696 mmol) in DMF (2 mL) was added NaH (67.8mg, l .696mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-hydroxy-6-methyl-3,3'- bipyridin-5-yl)acetate (60 mg,0.127 mmol) in DMF (lml) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPLC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(6'-(cyclobutylmethoxy)-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (22.5 mg, 0.045 mmol, 26.8 % yield). LCMS [M + H] = 496. ¾ NMR (400 MHz, CD30D) d 8.31 (s, 1H), 8.17 (s, 1H), 7.73 (d, J = 7.3 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 5.68 (s, 1H), 4.43 - 4.28 (m, 2H), 3.13-3.11 (br, 2H), 2.96-2.94 (br, 2H), 2.90 - 2.80 (m, 1H), 2.80(s, 3H); 2.25 - 2.11 (m, 2H), 2.09 - 1.87 (m, 4H), 1.50-1.48 (br, 4H), 1.25 (s, 9H), 0.97 (s, 6H).

Example 158

To a solution of (l-methylcyclobutyl) methanol (38.2 mg, 0.382 mmol) in DMF (3mL) was added NaH (16.79 mg, 0.420 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fluoro-6- methyl-[3,3'-bipyridin]-5-yl)acetate (60 mg, 0.127 mmol) in DMF (lmL) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPLC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6-methyl-6'-((l-methylcyclobutyl)methoxy)-[3,3'-bipyridin]-5-yl)acetic acid (20.4 mg, 0.040mmol, 31.5 % yield). LCMS [M + H] = 510. Ή NMI1 (400 MHz, CD30D) d 8.12- 8.1 l(m,lH); 8.10 (d, J=2.3Hz, 1H), 7.66 (dd, J = 8.5, 2.3 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.78 (s, 1H), 5.33 - 5.14 (m, 2H), 3.15-3.13 (br, 2H), 2.78-2.76 (br, 2H), 2.66 (s, 3H), 2.06- 2.04 (m, 2H), 1.99-1.97 (m, 2H), 1.87-1.85 (br, 2H), 1.48-1.43 (br, 4H), 1.24 (s, 3H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 159

To an ice-cold solution of (S)-l-cyclobutylethanol (51.0 mg, 0.509 mmol) in DMF (3 mL) was added NaH (22.39 mg, 0.560 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fluoro-6- methyl-[3,3'-bipyridin]-5-yl)acetate (80 mg, 0.170 mmol) in DMF (lmL) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPLC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(6'-((S)-l-cyclobutylethoxy)- 4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (15.0 mg, 0.029 mmol, 17.35 % yield). LCMS [M + H] = 510. Tl NMR ^OO MHz, CD30D) d 8.12 (d, J=2.3Hz, lH),8 0(s, 1H); 7.66 (dd, J = 8.5, 2.3 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.78 (s, 1H), 5.32 - 5.11 (m, 1H), 3.16-3.14 (br, 2H), 2.78-2.76 (br, 2H), 2.65-2.63(m, 1H); 2.64 (s, 3H), 2.18 - 1.69 (m, 6H), 1.46-1.44 (br, 4H), 1.24 (d, 3H), 1.21 (s, 9H), 0.91 (s, 6H). Example 160

To an ice-cold solution of (S)-l-cyclopropylethanol (43.8 mg, 0.509 mmol) in DMF (2 mL) was added NaH (27.1 mg, 0.679 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fluoro-6- methyl-[3,3'-bipyridin]-5-yl)acetate (80 mg, 0.170 mmol) in DMF (lmF) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPFC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(6'-((S)-l- cyclopropylethoxy)-4-(4,4-dimethylpiperidin- 1 -yl)-6-methyl- [3 ,3 '-bipyridin] -5 -yl)acetic acid (21.5 mg, 0.042 mmol, 25.05 % yield). FCMS [M + H] = 496. ¾NMR (400 MHz, CD30D) d 8.09 (d, J=2.4Hz, lH),8.09(s, 1H); 7.66 (dd, J = 8.6, 2.4 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 5.77 (s, 1H), 4.84 - 4.73 (m, 1H), 3.16-3.13 (br, 2H), 2.79-2.78 (br, 2H), 2.65 (s, 3H), 1.43- 1.40 (m, 1H), 1.13-1.40 (m, 3H); 1.20 (s, 9H), 1.17-1.13 (m, lH); 0.92 (s, 6H), 0.62 - 0.43 (m, 3H), 0.37 - 0.30 (m, 1H).

Example 161

To an ice-cold solution of (3-methylcyclobutyl)methanol (51.0 mg, 0.509 mmol) in DMF (2 mF) was added NaH (27.1 mg, 0.679 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fluoro-6- methyl-[3,3'-bipyridin]-5-yl)acetate (80 mg, 0.170 mmol) in DMF (1 mF) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPFC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6-methyl-6'-((3-methylcyclobutyl)methoxy)-[3,3'-bipyridin]-5-yl)acetic acid (19.2 mg, 0.037 mmol, 22.01 % yield). FCMS [M + H] = 510. ¾NMR (400 MHz, CD30D) d 8.11 (d, J=l .5Hz, 1H); 8.10 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 6.94 (dd, J = 8.5, 1.5 Hz, 1H), 5.78 (s, 1H), 4.50 - 4.18 (m, 2H), 3.16-3.13 (br, 2H), 2.77-2.72 (m, 3H), 2.70 (s. 3H); 2.54 - 2.21 (m, 2H), 2.16 - 2.00 (m, 1H), 1.82-1.80 (m, 1H), 1.46-1.43 (m, 5H), 1.25 (s, 9H); 1.20-1.02 (m, 3H), 0.92 (s, 6H).

Example 162

Stepl: To a solution of 4-fluoro-2-methylphenol (2 g, 15.86 mmol) in water (22 mL) was added the 2-bromoethanol (2.97 g, 23.75 mmol) and NaOH (0.95 g, 23.79 mmol) and the mixture was stirred at 90 °C for 16 h. The solution was cooled to room temperature, the pH was adjusted to about 7 with acetic acid and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous NaiSOr and concentrated to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet.

etherEtOAc (6: l~5 : 1) to give 2-(4-fluoro-2-methylphenoxy)ethanol (1 g, 5.58 mmol, 35.2 % yield). LCMS [M + H] = 171.1.

Step 2: To an ice-cold solution of 2-(4-fluoro-2-methylphenoxy)ethanol (130 mg, 0.76 mmol) in DMF (3 mL) was added NaH (33.9 mg, 0.848 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'- fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (40 mg, 0.085 mmol) in DMF (1 ml) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPLC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-(2-(4-fluoro-2-methylphenoxy)ethoxy)-6-methyl-[3,3'-bipyridin]- 5-yl)acetic acid (12.2 mg, 0.021 mmol, 24.81 % yield). LCMS [M + H] = 580.0. ¾ NMR (400 MHz, CD30D) d 8.22 - 8.09 (m, 2H), 7.71 (dd, J = 8.5, 2.4 Hz, 1H), 7.17 - 6.76 (m, 4H), 5.77 (s, 1H), 4.81 - 4.68 (m, 2H), 4.41 - 4.31 (m, 2H), 3.16-3.13 (br, 2H), 2.79-2.75 (br, 2H), 2.66 (s, 3H), 2.20 (s, 3H), 1.48-1.43 (br, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 163

Step 1 : To an ice-cold solution of 2-isopropoxyethanol (77.0 mg, 0.742 mmol) in anhydrous THF (3 mL) was added sodium hydride (29.7 mg, 0.742 mmol) and stirred at rt for 20 min. Then, the (S)-isopropyl 2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fluoro-6- methyl-3, 3'-bipyridin-5-yl)acetate(70 mg, 0.148 mmol) was added and stirred at rt for additional 2 h. The mixture was poured into ice-water and extracted with EtOAc (25 ml x 3), dried over Na2S04 and concentrated. The crude was purified by TLC (Pet. ether: EtOAc/4: 1, Rf = 0.4) to give (S)-2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-(2- isopropoxyethoxy)-6-methyl-3,3'-bipyridin-5-yl)acetic acid (60 mg, 65%). LCMS [M + H] = 556.4.

Step 2: To a solution of (S)-isopropyl 2-tert-butoxy-2-(6'-butoxy-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-3,3'-bipyridin-5-yl)acetate (60 mg, 0.108 mmol) in methanol (3 mL) and water (0.5 ml) was added sodium hydroxide (43 mg, 1.08 mmol) and heated at 70 °C overnight. The solution was adjusted to acidic by acetate acid and purified by preparative HPLC (TFA as buffer) to give (S)-2-tert-butoxy-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-(2-isopropoxyethoxy)-6-methyl-3,3'-bipyridin-5-yl)acetic acid (30 mg, 54%). LCMS [M + H] = 514.3. ¾ NMR (400 MHz, CD30D) d 8.32 (s, 1H), 8.18 (s, 1H), 7.74 (d, J = 6.9 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 5.67 (s, 1H), 4.55 - 4.43 (m, 2H), 3.89 - 3.78 (m, 2H), 3.73-3.70 (m, 1H), 3.13-3.11 (br, 2H), 2.98-2.94 (br, 2H), 2.79 (s, 3H), 1.46-1.44 (br, 4H), 1.25 (s, 9H); 1.24-1.16 (m, 6H), 0.97 (s, 6H).

Example 164

To an ice-cold solution of 2-methylpropane-l -thiol (76.0 mg, 0.848 mmol) in anhydrous DMF (3 mL) was added sodium hydride (33.9 mg, 0.848 mmol) and stirred at rt for 20 min. Then, to this mixture was added (S)-isopropyl 2-tert-butoxy-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-fluoro-6-methyl-3,3'-bipyridin-5-yl)acetate (70 mg, 0.148 mmol) and stirred at 90 °C overnight. The mixture was poured into ice-water and adjusted pH to7 by acetate acid. The crude was purified by preparative HPLC (TFA as buffer) to give (S)-2-tert- butoxy-2-(6'-butoxy-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-3,3'-bipyridin-5-yl)acetic acid (35 mg, 41%). LCMS [M + H] = 500.3. ¾ NMR (400 MHz, CD30D) d 8.44 (s, 1H), 8.35 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.46 (dd, J = 8.3, 0.6 Hz, 1H), 5.67 (s, 1H), 3.23-3.21 (m, 1H), 3.4-3.10 (m, 3H), 2.98-2.95 (br, 2H), 2.79 (s, 3H), 1.97 (m, 1H), 1.50-1.46 (br, 4H), 1.25 (s, 9H), 1.12-1.03 (m, 6H), 0.97 (s, 6H). Example 165

Step 1; To a mixture of 2-chloro-4-methylphenol (1 g, 7.01 mmol) in water (11 mL) was added 2-bromoethanol (1.315 g, 10.52 mmol), NaOH (0.421 g, 10.52 mmol) and stirred at 90 °C for 16 hours. The solution was cooled to room temperature and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous NaiSOr and concentrated to give a yellow crude product. The crude product was purified by silica gel chromatography (using 12 g, eluting with 14% ethyl acetate to 17% ethyl acetate in petroleum ether) to give the desired product 2-(2-chloro-4-methylphenoxy)ethanol (1.02 g, 4.85 mmol, 69.2 % yield) as a colorless oil. LCMS [M + H] = 187.0.

Step 2: To an ice-cold solution of 2-(2-chloro-4-methylphenoxy)ethanol (142 mg, 0.763 mmol) in DMF (2 mL) was added NaH (33.9 mg, 0.848 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (40 mg, 0.085 mmol) in DMF (1 mL) and stirred at 25 °C for 16 hours. Then, the pH was adjusted to 7 by acetate acid, filtered and the filtrate was concentrated to give a crude product which was purified by preparative HPLC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(6'-(2-(2-chloro-4- methylphenoxy)ethoxy)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (22 mg, 0.037 mmol, 43.3 % yield) as a white solid. LCMS [M + H] = 596.1. ¾ NMR (400 MHz, CD30D-d4) d 8.15 (d, J = 2.2 Hz, 1H), 8.12 (s, 1H), 7.70 (dd, J = 8.5, 2.4 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 7.08 (dd, J = 8.3, 1.4 Hz, 1H), 7.04 - 6.98 (m, 2H), 5.78 (s,

1H), 4.78 - 4.70 (m, 2H), 4.45 - 4.36 (m, 2H), 3.17-3.15 (br, 2H), 2.79-2.75 (br, 2H), 2.66 (s, 3H), 2.29 (s, 3H), 1.48-1.42 (br, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 166

Step 1 : To a mixture of 2-chloro-4-fluorophenol (1 g, 6.82 mmol) in water (11 mL) was added 2-bromoethanol (1.279 g, 10.24 mmol), NaOH (0.409 g, 10.24 mmol) and stirred at 90 °C for 16 hours. The solution was cooled to room temperature and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous NaiSOr and concentrated to give a yellow crude product. The crude product was purified by silica gel chromatography (using 12 g, eluting with 15% ethyl acetate to 17% ethyl acetate in petroleum ether) to give the desired product 2-(2-chloro-4-fluorophenoxy)ethanol (1.12 g, 5.42 mmol, 80 % yield) as a colorless oil. LCMS [M + H] = 190.9.

Step 2: To an ice-cold solution of 2-(2-chloro-4-fluorophenoxy)ethanol (145 mg, 0.763 mmol) in DMF (2 mL) was added NaH (33.9 mg, 0.848 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (40 mg, 0.085 mmol) in DMF (1 mL) and stirred at 25 °C for 16 hours. Then, the pH was adjusted to 7 by acetate acid, filtered and the filtrate was concentrated to give a crude product which was purified by preparative HPLC (NH4HC03 as buffer) to give (S)-2-(tert-butoxy)-2-(6'-(2-(2-chloro-4- fluorophenoxy)ethoxy)-4-(4,4-dimethylpiperidin- 1 -yl)-6-methyl- [3 ,3 '-bipyridin] -5 -yl)acetic acid (21.7 mg, 0.036 mmol, 42.2 % yield) as a white solid. LCMS [M + H] = 600.0. ¾ NMR (400 MHz, CD30D-d4) d 8.15 (d, J = 2.1 Hz, 1H), 8.12 (s, 1H), 7.71 (dd, J = 8.5, 2.4 Hz,

1H), 7.20 (m, 2H), 7.10 - 6.96 (m, 2H), 5.78 (s, 1H), 4.79 - 4.72 (m, 2H), 4.47 - 4.41 (m, 2H), 3.06-3.03 (br, 2H), 2.79-2.75 (br, 2H), 2.66 (s, 3H), 1.48-1.42 (br, 4H), 1.21 (s, 9H),

0.91 (s, 6H).

Example 167

Step 1 : To a mixture of 4-f uorophenol (1 g, 8.92 mmol) in water (11 mL) was added 2-bromoethanol (1.672 g, 13.38 mmol), NaOH (0.535 g, 13.38 mmol) and stirred at 90 °C for 16 hours. The solution was cooled to room temperature and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous NaiSOr and concentrated to give a yellow crude product. The crude product was purified by silica gel chromatography (using 12 g, eluting with 10% ethyl acetate to 15% ethyl acetate in petroleum ether) to give the desired product 2-(4-fluorophenoxy)ethanol (1.13 g, 6.40 mmol, 71.8 % yield) as a colorless oil. LCMS [M + H] = 157.1 Step 2: To an ice-cold solution of 2-(4-fluorophenoxy)ethanol (119 mg, 0.763 mmol) in DMF (2 mL) was added NaH (33.9 mg, 0.848 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fluoro- 6-methyl-[3,3'-bipyridin]-5-yl)acetate (40 mg, 0.085 mmol) in DMF (1 mL) and stirred at 25 °C for 16 hours. Then, the pH was adjusted to 7 by acetate acid, filtered and the filtrate was concentrated to give a crude product which was purified by preparative HPLC (NH4HC03 as buffer) to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-(2-(4- fluorophenoxy)ethoxy)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (20.5 mg, 0.035 mmol, 40.8 % yield) as a white solid . LCMS [M + H] = 566.1. ¾ NMR (400 MHz, CD30D) d 8.15 (d, J=2.0Hz, 1H), 8.12 (s, 1H), 7.72-7.69 (dd, J=8.4Hz, 2.0Hz, 1H); 7.05 - 6.96 (m, 5H), 5.78 (s, 1H), 4.76 - 4.64 (m, 2H), 4.45 - 4.23 (m, 2H), 3.05-3.03 (br, 2H), 2.78-2.73 (br, 2H), 2.66 (s, 3H), 1.45-1.40 (br, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 168

Step 1: To a mixture of 3-fluoro-4-methylphenol (1 g, 7.93 mmol) in water (11 mL) was added 2-bromoethanol (1.486 g, 11.89 mmol), NaOH (0.476 g, 11.89 mmol) and stirred at 90 °C for 16 hours. The solution was cooled to room temperature and extracted with DCM

(3 x 20 mL). The combined organic layers were dried over anhydrous NaiSOr and concentrated to give a yellow crude product. The crude product was purified by silica gel chromatography (using 12 g, eluting with 14% ethyl acetate to 17% ethyl acetate in petroleum ether) to give the desired product 2-(3-fluoro-4-methylphenoxy)ethanol (1.12 g, 6.58 mmol, 83 % yield) as a colorless oil. LCMS [M + H] = 171.1.

Step 2: To an ice-cold solution of 2-(3-fluoro-4-methylphenoxy)ethanol (130 mg, 0.763 mmol) in DMF (2 mL) was added the NaH (33.9 mg, 0.848 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (40 mg, 0.085 mmol) in DMF (1 mL) and stirred at 25 °C for 16 hours. Then, the pH was adjusted 7 by acetic acid, filtered and the filtrate was concentrated to give a crude product which was purified by preparative HPLC (NH4HC03 as buffer) to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-(2-(3- fluoro-4-methylphenoxy)ethoxy)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (22 mg, 0.038 mmol, 44.7 % yield) as a white solid. LCMS [M + H] = 580.2. 'HNMR (400 MHz, CD30D) 5 8.19 - 8.09 (m, 2H), 7.71 (dd, J = 8.5, 2.4 Hz, 1H), 7.13 (t, J = 8.9 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.73-6.70 (m, 2H), 5.78 (s, 1H), 4.71-4.69 (m, 2H), 4.35 (t, J = 4.6 Hz, 2H), 3.16- 3.14 (br, 2H), 2.78-2.76 (br, 2H), 2.66 (s, 3H), 2.20 (d, J = 1.5 Hz, 3H), 1.46-1.44 (br, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 169

Step 1 : To a mixture of 2-chloro-6-fluorophenol (1 g, 6.82 mmol) in water (11 mL) was added 2-bromoethanol (1.279 g, 10.24 mmol), NaOH (0.409 g, 10.24 mmol) and stirred at 90 °C for 16 hours. The solution was cooled to room temperature and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous NaiSOr and concentrated to give a yellow crude product. The crude product was purified by silica gel chromatography (using 12 g, eluting with 14% ethyl acetate to 17% ethyl acetate in petroleum ether) to give the desired product 2-(2-chloro-6-fluorophenoxy)ethanol (0.9 g, 4.40 mmol, 64.5 % yield) as a colorless oil. LCMS [M + H] = 191.0.

Step 2: To an ice-cold solution of 2-(2-chloro-6-fluorophenoxy)ethanol (145 mg,

0.763 mmol) in DML (2 mL) was added the NaH (33.9 mg, 0.848 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (40 mg, 0.085 mmol) in DML (1 mL) and stirred at 25 °C for 16 hours. Then, the pH was adjusted to 7 by acetate acid, filtered and the filtrate was concentrated to give a crude product which was purified by preparative HPLC (NH4HC03 as buffer) to give (S)-2-(tert-butoxy)-2-(6'-(2-(2-chloro-6- fluorophenoxy)ethoxy)-4-(4,4-dimethylpiperidin- 1 -yl)-6-methyl- [3 ,3 '-bipyridin] -5 -yl)acetic acid (21.5 mg, 0.036 mmol, 42.0 % yield) as a white solid.. LCMS [M + H] = 600.0. ¾ NMR (400 MHz, CD30D) 5 8.13 (d, J=2.4Hz, 1H), 8T2(s, 1H); 7.69 (dd, J = 8.5, 2.4 Hz, 1H), 7.24-7.22 (m, 1H), 7.18 - 7.06 (m, 2H), 6.92 (d, J = 8.5 Hz, 1H), 5.77 (s, 1H), 4.77 - 4.64 (m, 2H), 4.50 (t, J = 4.4 Hz, 2H), 3.16-3.14 (br, 2H), 2.78-2.76 (br, 2H), 2.66 (s, 3H), 1.46-1.44 (br, 4H), 1.21 (s, 9H), 0.91 (s, 6H). Example 170

To a ice cold solution of (l-methylcyclopropyl)methanol (21.11 mg, 0.245 mmol) in DMF (4 mL) was added NaH (24.51 mg, 0.613 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'-difluoro-6- methyl-[3,3'-bipyridin]-5-yl)acetate (60 mg, 0.123 mmol) in DMF (1 mF) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPFC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-5'-fluoro-6-methyl-6'-((l-methylcyclopropyl)methoxy)-[3,3'-bipyridin]-5-yl)acetic acid (24 mg, 0.047 mmol, 38.1 % yield). FCMS (M + H) = 496.0.

¾ NMR (400 MHz, CD30D) 5 8.13 (s, 1H), 7.90 (d, J= 1.9 Hz, 1H), 7.58 (d, J= 8.8 Hz, 1H), 5.79 (s, 1H), 4.33-4.24 (m, 2H), 3.16-3.13 (brs, 2H), 2.80-2.75 (brs, 2H), 2.65 (s, 3H), 1.48- 1.40 (brs, 4H), 1.27 (s, 3H), 1.21 (s, 9H), 0.93 (s, 6H), 0.63 (t, J= 4.8 Hz, 2H), 0.47 (t, J= 4.9 Hz, 2H).

Example 171

To a ice cold solution of (l-methylcyclobutyl)methanol (24.55 mg, 0.245 mmol) in DMF (4 mF) was added NaH (19.61 mg, 0.490 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'-difluoro-6- methyl-[3,3'-bipyridin]-5-yl)acetate (60mg, 0.123 mmol) in DMF (1 mF) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPFC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-5'-fluoro-6-methyl-6'-((l-methylcyclobutyl)methoxy)-[3,3'-bipyridin]-5-yl)acetic acid (9.5 mg, 0.018 mmol, 14.49 % yield) was obtained. FCMS (M + H) = 528.0. ¾ NMR (400 MHz, CD30D) 5 8.13 (s, 1H), 7.92 (d, J= 1.8 Hz, 1H), 7.58 (d, J= 10.8 Hz, 1H), 5.79 (s, 1H), 4.38-4.30 (m, 2H), 3.20-3.13 (brs, 2H), 2.80-2.75 (brs, 2H), 2.65 (s, 3H), 2.15 - 2.02 (m, 2H), 2.00 - 1.91 (m, 2H), 1.89 - 1.72 (m, 2H), 1.48-1.42 (s, 4H), 1.30 (s, 3H), 1.21 (s, 9H), 0.93 (s, 6H).

Example 172

To a ice cold solution of (S)-l-cyclobutylethanol (24.55 mg, 0.245 mmol) in DMF (4 mL) was added NaH (19.61 mg, 0.490 mmol) in portions. To this mixture was added a solution(S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'-difluoro-6- methyl-[3,3'-bipyridin]-5-yl)acetate (60mg, 0.123 mmol) in DMF (1 mL) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPLC (NH4HCO3 as buffer) purification to give (S)-2-(tert-butoxy)-2-(6'-((S)-l- cyclobutylethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (16.1 mg, 0.030 mmol, 24.69 % yield) was obtained. LCMS (M + H) = 528.0. ¾ NMR (400 MHz, CD30D) d 8.14 (s, 1H), 7.91 (s, 1H), 7.58 (s, 1H), 5.80 (s, 1H), 5.50 - 5.32 (m, 1H), 3.20-3.12 (brs, 2H), 2.83-2.75 (brs, 2H), 2.65 (s, 3H), 1.98-1.95 (m, 6H), 1.48- 1.45 (m, 4H), 1.29 (d, J= 6.2 Hz, 3H), 1.24-1.18 (m, lH),l .2l(s, 9H), 0.92 (s, 6H).

Example 173

To a ice cold solution of (3-methylcyclobutyl)methanol (24.55 mg, 0.245 mmol) in DMF (4 mL) was added NaH (19.61 mg, 0.490 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'-difluoro-6- methyl-[3,3'-bipyridin]-5-yl)acetate (60 mg, 0.123 mmol) in DMF (1 mL) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPLC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-5'-fluoro-6-methyl-6'-((3-methylcyclobutyl)methoxy)-[3,3'-bipyridin]-5-yl)acetic acid (26.8 mg, 0.051 mmol, 41.3 % yield) was obtained. LCMS (M + H) = 528.0. ¾ NMR (400 MHz, CD30D) d 8.14 (s, 1H), 7.92 (s, 1H), 7.57 (d, J= 9.5 Hz, 1H), 5.79 (s, 1H), 4.60 - 4.26 (m, 2H), 3.18-2.12 (brs, 2H), 2.82-2.75 (brs, 2H), 2.65 (s, 3H), 2.55-2.50 (m, 1H), 2.41-2.21 (m, 1H), 2.18- 2.01 (m, 1H), 1.85-1.80 (m, 1H), 1.60-1.55 (brs, 2H), 1.45-1.39 (m, 3H), 1.21 (s, 9H), 1.18-1.16 (m, 2H), 1.10-1.08 (m, 2H), 0.93 (s, 6H).

Example 174

To a ice cold solution (S)-l-cyclopropylethanol (21.11 mg, 0.245 mmol) in DMF (4 mL) was added NaH (19.61 mg, 0.490 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'-difluoro-6- methyl-[3,3'-bipyridin]-5-yl)acetate (60 mg, 0.123 mmol) in DMF (1 mF) and stirred at rt for 16 h. Then, the pH was adjusted to 7 with acetic acid, filtered and the filtrate was purified by Prep-HPFC (NH4HCO3 as buffer) to give (S)-2-(tert-butoxy)-2-(6'-((S)-l- cyclopropylethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (28 mg, 0.053 mmol, 43.1 % yield) was obtained. FCMS (M + H) = 514.0. Ή NMR (400 MHz, CD30D) d 8.14 (s, 1H), 7.88 (d, J= 1.7 Hz, 1H), 7.56 (d, J= 10.9 Hz, 1H), 5.79 (s, 1H), 3.45-3.35 (brs, 1H), 3.18-3.10 (brs, 2H), 2.82-2.75 (brs, 2H), 2.65 (s, 3H), 1.50- l .45(m, 7H), l .25-l .20(m, 1H), 1.21 (s, 9H), 0.93 (s, 6H), 0.69 - 0.44 (m, 3H), 0.35 (dd, J= 9.0, 4.5 Hz, 1H).

Example 175

Step 1 : A stirred mixture of tris(dibenzylideneacetone)dipalladium(0) (30.4 mg, 0.033 mmol), (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5- (((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (200 mg, 0.332 mmol), butane- l-thiol (150 mg, 1.662 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (38.5 mg, 0.066 mmol) and Cs2C03 (325 mg, 0.997 mmol) in toluene (10 mF) was placed under N2 atm (vac/fill ^c 3). Then, the mixture was heated at 100 °C overnight under N2. Cooled, diluted with EtOAc (50 mL) and H2O (20 mL) were added. Organic layer separated and aqueous layer extracted with EtOAc (20 mL ^c 3). The combined organic layers were dried with NaiSOr. concentrated and purified by Prep TLC (EtOAc:pet. Ether/l : 1) to give (S)-isopropyl 2-(tert-butoxy)-2-(5-(butylthio)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (40 mg, 0.072 mmol, 21.77 % yield). LCMS (M + H) = 543.

Step 2: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(5-(butylthio)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (40 mg, 0.074 mmol in methanol (8 mL) was added sodium hydroxide (59.1 mg, 1.477 mmol) in H20 (3 mL). Then, the reaction mixture was stirred at 80° overnight, cooled and acidified with HC1 to pH = 7. The crude was purified by Prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(butylthio)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (11.4 mg, 0.023 mmol, 30.9 % yield) as a white solid. LCMS (M + H) = 502. ¾ NMR (400 MHz, CD30D) d 8.62 (d, J = 1.8 Hz, 1H), 8.21 (s, 1H), 7.95 (dd, J = 8.2, 2.4 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 5.86 (s, 1H), 3.15-3.08 (m, 4H), 2.85-2.80 (brs, 2H), 2.66 (s, 3H), 1.79-1.61 (m, 2H), 1.59-1.34 (m, 6H), 1.21 (s, 9H), 0.97 (t, J = 7.3 Hz, 3H), 0.91 (s, 6H).

Example 176

Step 1 : To a mixture of (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (330 mg, 0.703 mmol) and K2C03 (291 mg, 2.108 mmol) in DML (8 mL) was added l-bromobutan-2-one (318 mg, 2.108 mmol) and heated at 50 °C for 1 h. Then, diluted with 50 mL of EtOAc and washed with H20 (50 mL x 2). The organic layer was dried and concentrated. The residue was purified by silica gel chromatography (pet. ether: EtOAc/ 1 : 1) to afford (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(2-oxobutoxy)-[2,3'-bipyridin]-5'-yl)acetate (185 mg, 0.322 mmol, 45.9 % yield). LCMS (M + H) = 540. Step 2: A mixture of (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)- 6'-methyl-5-(2-oxobutoxy)-[2,3'-bipyridin]-5'-yl)acetate (80 mg, 0.148 mmol) and DAST (1 mL, 7.57 mmol) was stirred at rt overnight. The mixture was poured into ice water and the extracted with DCM (20 mL x 2). The combined organic layers were dried and concentrated. The residue was purified by silica gel chromatography (pet. ether:EtOAc/l : 1) to afford (S)- isopropyl 2-(tert-butoxy)-2-(5-(2,2-difluorobutoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetate (80 mg, 0.134 mmol, 90 % yield). LCMS (M + H) =

562.

Step 3: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(5-(2,2-difluorobutoxy)-4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (80 mg, 0.142 mmol) in methanol (8 mL) was added sodium hydroxide (114 mg, 2.85 mmol) in H20 (3 mL). Then, the reaction mixture was stirred at 80°C overnight, cooled and acidified with HC1 to pH = 7. The crude was purified by Prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(2,2- difluorobutoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (38.3 mg, 0.073 mmol, 51.3 % yield as a white solid. LCMS ( M + H) = 520.

1H NMR (400 MHz, CD30D) d 8.46 (d, J = 2.7 Hz, 1H), 8.18 (s, 1H), 7.65 (dd, J = 8.6, 2.9 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 5.84 (s, 1H), 4.41 (t, J = 12.0 Hz, 2H), 2.98-2.90(brs, 2H), 2.85-2.80 (brs, 2H), 2.66 (s, 3H), 2.15-2.05 (m, 2H), 1.46-1.44 (brs, 4H), 1.21 (s, 9H), 1.12 (t, J = 7.5 Hz, 3H), 0.92 (s, 6H).

Example 177

Step 1 : To a mixture of (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(2-oxobutoxy)-[2,3'-bipyridin]-5'-yl)acetate (80 mg, 0.148 mmol) in methanol (5 mL) was added NaBHr (16.82 mg, 0.445 mmol) and stirred at rt for 1 h. Then, the mixture was diluted with 10 mL of water and extracted with EtOAc (10 mL x 2). The organic layers dried over Na2S04, concentrated and the residue was purified by Pre-TLC (pet. ether: EtOAc/ 1 :3) to afford (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)- 5-(2-hydroxybutoxy) -6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (60 mg, 0.111 mmol, 74.7 % yield) LCMS (M + H) = 542.

Step 2: To a solution of (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin- l-yl)-5-(2-hydroxybutoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (80 mg, 0.148 mmol) in DCM (5 mL) was added DAST (71.4 mg, 0.443 mmol) at 0 °C and stirred at rt for 2 h. The mixture was diluted with ice water and extracted with DCM (20 mL x 2). The organic layers were dried and concentrated. The residue was purified by silica gel column (pet.

ether: EtOAc/ 1 : 1) to afford (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)- 5-(2-fluorobutoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (40 mg, 0.059 mmol, 39.9 % yield). LCMS (M + H) = 544.

Step 3: To a solution of (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-

1-yl)-5-(2-fluorobutoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (40 mg, 0.074 mmol) in methanol (8 mL) was added sodium hydroxide (58.9 mg, 1.471 mmol) in LhO (3 mL). Then the reaction mixture was stirred at 80°C overnight and cooled. The mixture was acidified with HC1 to pH = 7 and concentrated. The crude was purified by Prep-HPLC to afford (2S)-

2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-(2-fluorobutoxy)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (28 mg, 0.056 mmol, 76 % yield) as a white solid. LCMS (M + H) = 502. ¾ NMR (400 MHz, MeOD) d 8.42 (d, J = 2.7 Hz, 1H), 8.18 (s, 1H), 7.61 (dd, J = 8.6, 2.9 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 5.83 (s, 1H), 4.88-4.67 (m, 1H), 4.52-4.13 (m, 2H),

3.02 (brs, 4H), 2.66 (s, 3H), 1.85-1.75 (m, 2H), 1.46-1.44 (brs, 4H), 1.21 (s, 9H), 1.10-1.08 (m, 3H), 0.92 (s, 6H).

Example 178

Step 1 : A solution of chloromethylbenzene (1 g, 7.90 mmol) in pentane- l,2-diol (8.23 g, 79 mmol) was added diacetoxycopper (1.435 g, 7.90 mmol) and the mixture was stirred at 80 °C for 12 hr. Then, mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over NaiSOr. fdtered and concentrated to give residue. The residue was purified by prep-HPLC to give 1- (benzyloxy) pentan-2-ol (400 mg, 0.993 mmol, 12.58 % yield) as colorless oil. LCMS (M + H) = 192.

Step 2: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (200 mg, 0.426 mmol), 1- (benzyloxy)pentan-2-ol (165 mg, 0.852 mmol) and triphenylphosphine (223 mg, 0.852 mmol) THF (4 mL) was added DEAD (0.135 mL, 0.852 mmol) at 0 °C under N2 and stirred overnight at ambient temperature. The mixture diluted with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2S0₄, filtered and concentrated. The residue was purified by prep-TLC (pet.

ether:EtOAc/l : l) to (2S)-isopropyl 2-(5-((l-(benzyloxy)pentan-2-yl)oxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (260 mg, 0.370 mmol, 87 % yield) as yellow oil. LCMS (M + H) = 646.

Step 3: A solution of (2 S) -isopropyl 2-(5-((l-(benzyloxy)pentan-2-yl)oxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (400 mg, 0.619 mmol) in methanol (70 mL) was purged with N2 and added Pd/C. The mixture was stirred under balloon hydrogen for 24 h and filtered through diatomaceous earth. The filtrate was concentrated and the residue was purified by silica gel column (pet. ether/EtOAc/l : 1) to afford (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin- 1 -yl)-5 -(( 1 -hydroxypentan- 2-yl)oxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (100 mg, 0.175 mmol, 28.2 % yield) as oil. LCMS (M + H) = 556.

Step 4: To a solution of (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((l-hydroxypentan-2-yl)oxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (100 mg, 0.180 mmol) in DCM (10 mL) was added the DAST (0.048 mL, 0.360 mmol) and stirred at ambient temperaure for 16 h. The mixture was diluted with ice water and extracted with DCM (20 mL x 2). The organic layer was dried over NaiSOi. concentrated and the crude was purified by Prep-HPLC to give (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((l-fluoropentan-2-yl)oxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (30 mg, 0.051 mmol, 28.4 % yield) as white solid. LCMS (M + H) = 558.

Step 5: To a solution of (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((l-fluoropentan-2-yl)oxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (30 mg, 0.054 mmol) in MeOH (10 mL) was sodium hydroxide in H2O (0.5 ml) and stirred at 90 °C for 36 h. Then, cooled, acidified to pH of 7 and concentrated. The crude was purified by Prep-HPLC to give (2S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin- 1 -yl)-5-(( 1 -fluoropentan-2-yl)oxy)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetic acid (3.7 mg, 7.18 pmol) as a white solid. LCMS (M + H) = 516. ¾ NMR (400 MHz, MeOD) d 8.30 (s, 1H), 8.06 (s, 1H), 7.51 (dd, J = 8.9, 2.2 Hz,

1H), 7.36 (d, J = 8.5 Hz, 1H), 5.71 (s, 1H), 4.76 - 4.43 (m, 3H), 3.03 (s, 2H), 2.69 (s, 2H), 2.53 (s, 3H), 1.67-1.56 (m, 2H), 1.54-1.34 (m, 2H), 1.25-1.23 (brs, 4H), 1.09 (s, 9H), 0.91 (s, 6H), 0.78 - 0.70 (m, 3H).

Example 179

Step 1: To an ice-cold solution of butane- 1,3 -diol (8 g, 89 mmol) and

methanesulfonyl chloride (20.34 g, 178 mmol) in DCM (40 mL) was added triethylamine (11.68 g, 115 mmol) dropwise. The mixture was stirred for 2 h at 25 °C and concentrated.

The residue was taken up into EtOAc (300 mL)/H20 (150 mL)and the organic phase separated, dried over NaiSOr. concentrated to afford the desired product 3-hydroxybutyl methanesulfonate .

Step 2A: mixture of (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)- 5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (300 mg, 0.639 mmol), 3-hydroxybutyl methanesulfonate (1,075 mg, 6.39 mmol) and potassium carbonate (883 mg, 6.39 mmol) in DMF (10 mL) was stirred at 75 °C for 3 h. Then, cooled, diluted with LhO (100 mL) and EtOAc (150 mL). The organic layer was separated, washed with LhO (100 mL ^c 3), dried over Na2S0₄, concentrated to afford the desired product (2S)-isopropyl 2-(tert-butoxy)-2-(4'- (4,4-dimethylpiperidin- 1 -yl)-5 -(3-hydroxybutoxy)-6'-methyl- [2,3 '-bipyridin] -5 '-yl)acetate (120 mg, 34.6 % yield). LCMS (M + H) = 542.4.

Step 3: To a solution of (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-(3-hydroxybutoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (120 mg, 0.222 mmol) in DCM (8 mL) was added DAST (0.117 mL, 0.886 mmol) at 0 °C. The mixture was stirred overnight at 25 °C under the nitrogen and concetrated. The residue was diluted EtOAc (200 mL) and saturated solution ofNaHC03 (100 mL) were added. The organic phase was seperated and washed with saturated solution ofNaHC0₃ (100 mL ^c 3), dried over NaiSOi. and concentrated. The residue was purified by silica gel column (pet. ether/EtOAc/l : 1) to afford the desired product (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)- 5-(3-fluorobutoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (70 mg, 55.5 % yield). ESI-LCMS (M + H) = 544.2.

Step 4: To a solution of (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-(3-fluorobutoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (70 mg, 0.129 mmol) in methanol (20 mL) was added in a solution of sodium hydroxide (154 mg, 3.86 mmol) in water (5.00 mL). The reaction mixture was heated at 86 °C overnight, cooled and the pH of the mixture was adjusted to 8 with diluted hydrochloric acid. Then, concentrated and the residue was purified by Prep-HPLC to afford the desired product (2S)-2-(tert-butoxy)-2-(4'- (4,4-dimethylpiperidin-l-yl)-5-(3-fluorobutoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (28.7 mg, 44.3 % yield). LCMS (M + H) = 502.1. ¾ NMR (400 MHz, MeOD) d 8.27 (d, J = 2.7 Hz, 1H), 8.05 (s, 1H), 7.46 (dd, J = 8.6, 2.9 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 5.71 (s, 1H), 4.90 (dd, J = 12.3, 6.1 Hz, 1H), 4.19 - 4.12 (m, 2H), 2.70-2.68 (brs, 4H), 2.54 (s, 3H), 2.06-1.97 (m, 2H), 1.32-1.28 (m, 7H), 1.09 (s, 9H), 0.79 (s, 6H).

Example 180

Step 1 : To a ice-cold solution of 2-methylpropane-l,3-diol (1 g, 11.10 mmol) and methanesulfonyl chloride (2.54 g, 22.19 mmol) in DCM (35 mL) was added triethylamine (1.460 g, 14.43 mmol) dropwise. The mixture was stirred for 2 h at 25 °C and concentrated. The residue was diluted with EtOAc (150 mL)/H20 (100 mL) and the organic phase was separated, dried over NaiSOr. and concetrated to afford the desired product 2-methylpropane- l,3-diyl dimethane sulfonate.

Step 2: To mixture of 2-methylpropane-l,3-diyl dimethanesulfonate (157 mg, 0.639 mmol), (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl- [2,3'-bipyridin]-5'-yl)acetate (200 mg, 0.426 mmol) and potassium carbonate (294 mg, 2.129 mmol) in DMF (10 mL) was stirred at 90 °C for 1.5 h. Then, diluted with H2O (100 mL) and EtOAc (150 ml). The organic layer was separated, washed with H2O (100 ml ^c 3) and dried over Na2S0₄, concentrated to afford the desired product (2S)-isopropyl 2-(tert-butoxy)-2-(4'- (4, 4-dimethylpiperidin-l-yl)-6'-methyl-5 -(2 -methyl-3 -((methylsulfonyl)oxy)propoxy)- [2,3'- bipyridin]-5'-yl)acetate (135 mg, 17.90 % yield). LCMS (M + H) =620.1.

Step 3: To a solution of (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(2-methyl-3-((methylsulfonyl)oxy)propoxy)-[2,3'-bipyridin]-5'-yl)acetate (100 mg, 0.161 mmol) in THF (15 mL) was added tributylammonium fluoride (331 mg,

1.613 mmol). The reaction mixture was heated at 90 °C for 3 h. and concetrated. The residue was diluted with H2O (100 mL) and EtOAc (150 mL). The organic layer was separated, dried over Na2S0₄, concentrated and purified by silica gel column (pet. Ether:EtOAc/l : 1) to afford the desired product (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-(3- fluoro-2-methylpropoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (80 mg, 62.0 % yield). LCMS (M + H) =544.2. Step 4: To a solution of (2S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-(3-fhioro-2-methylpropoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (80 mg, 0.147 mmol) in methanol (20 mL) was added a solution of sodium hydroxide (5.89 mg, 0.147 mmol) in water (5.00 mL). The reaction mixture was heated at 85 °C overnight. The pH of the mixture was adjusted to 8 with diluted hydrochloric acid and concentrated. The residue was purified by Prep-HPLC to afford the desired product (2S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-(3-fluoro-2-methylpropoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (38.7 mg, 52.2 % yield). LCMS (M + H) = 502.0. ¾ NMR (400 MHz, MeOD) d 8.40

(d, J = 2.8 Hz, 1H), 8.17 (s, 1H), 7.59 (dd, J = 8.6, 2.9 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 5.83 (s, 1H), 4.59 - 4.47 (m, 2H), 4.14 - 4.12 (m, 2H), 3.10-3.2.80 (brs, 4H), 2.66 (s, 3H), 2.45- 2.42 (m, 1H), 1.46-1.43 (brs, 4H), 1.21 (s, 9H), 1.16 (d, J = 7.0 Hz, 3H), 0.91 (s, 6H).

Example 181

Step 1 : A mixture of (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)- 5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (750 mg, 0.639 mmol), l,2-dibromoethane (360 mg, 1.916 mmol) and K2CO3 (132 mg, 0.958 mmol) in acetonitrile (15 mL) was heated at 80 °C overnight. The mixture was cooled, filtered and concentrated. The residue was purified by silica gel chromatography (pet. ether:EtOAc/l : l) to give (S)-isopropyl 2-(5-(2- bromoethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert- butoxy)acetate (400 mg, 0.402 mmol, 63.0 % yield). LCMS (M + H) = 576.

Step 2: A mixture of (S)-isopropyl 2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (35 mg, 0.061 mmol), 3-fluoro-4- methylphenol (11.48 mg, 0.091 mmol) and CS2CO3 (39.6 mg) in DMF (3 mL) was heated at 80 °C overnight. Then, the reaction mixture was diluted with 30 mL of EtOAc and washed with water (20 mL x 2). The organic layer was concentrated and the residue was purified by Prep-TLC (pet. ether:EtOAc/l : 1) to give (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-(2-(3-fluoro-4-methylphenoxy)ethoxy)-6'-methyl-[2,3'-bipyridin]- 5'-yl)acetate (50 mg, 0.062 mmol, 102 % yield). LCMS (M + H) = 622.

Step 3: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-(2-(3-fluoro-4-methylphenoxy)ethoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.080 mmol) in methanol (8 mL) was added sodium hydroxide (64.3 mg, 1.608 mmol in ThO (3 mL) and stirred at 80 °C overnight. Then, cooled, acidified with HC1 to pH = 7 and concentrated. The crude was purified by Prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-(2-(3-fluoro-4-methylphenoxy)ethoxy)-6'-methyl-[2,3'-bipyridin]- 5'-yl)acetic acid (9.5 mg, 0.016 mmol, 20.38 % yield) as a white solid. LCMS (M + H) = 580. ¾ NMR (400 MHz, MeOD) d 8.44 (d, J = 2.8 Hz, 1H), 8.18 (s, 1H), 7.64 (dd, J = 8.6, 2.9 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.15 (t, J = 8.9 Hz, 1H), 6.74-6.70 (m, 2H), 5.83 (s, 1H), 4.63 - 4.20 (m, 4H), 2.86-2.80 (brs, 4H), 2.66 (s, 3H), 2.20 (d, J = 1.5 Hz, 3H), l .46-l.42(brs, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 182

Step 1 : A mixture of (S)-isopropyl 2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (35 mg, 0.061 mmol), 4-fluoro-2- methylphenol (11.48 mg, 0.091 mmol) and CS2CO3 (39.6 mg) in DML (3 mL) was heated at 80 °C overnight. Then, cooled, diluted with 30 mL of EtOAc and washed with water (20 mL x 2). The organic layer was concentrated and the residue was purified by Prep-TLC (pet. ether: EtOAc/ 1 : 1) to give (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5- (2-(4-fhioro-2-methylphenoxy)ethoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.025 mmol, 41.1 % yield. LCMS (M + H) = 622.

Step 2: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-(2-(4-fluoro-2-methylphenoxy)ethoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.040 mmol) in methanol (8 mL) was added sodium hydroxide (32.2 mg, 0.804 mmol) in H2O (3 mL). Then, the reaction mixture was stirred at 80°C overnight and cooled. The mixture was acidified with HC1 to pH = 7, concentrated and the crude was purified by Prep- HPLC to afford (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-(2-(4-fluoro-2- methylphenoxy)ethoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (7.9 mg, 0.014 mmol, 33.9 % yield) as a white solid. LCMS (M + H) = 580. ¾ NMR (400 MHz, MeOD) d 8.33 (d, J = 2.8 Hz, 1H), 8.06 (s, 1H), 7.53 (dd, J = 8.6, 2.9 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 6.96 - 6.63 (m, 3H), 5.71 (s, 1H), 4.56 - 4.10 (m, 4H), 2.74-2.70 (brs, 4H), 2.54 (s, 3H), 2.09 (s, 3H), 1.35-1.30 (m, 4H), 1.09 (s, 9H), 0.78 (s, 6H).

Example 183

Step 1 : A mixture of (S)-isopropyl 2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (35 mg, 0.061 mmol), 2-chloro-6- methylphenol (12.98 mg, 0.091 mmol) and CS2CO3 (39.6 mg) in DMF (3 mL) was heated at 80 °C overnight. Then, cooled, diluted with 30 mL of EtOAc and washed with water (20 mL x 2). The organic layer was concentrated and the residue was purified by Prep-TLC (pet. ether: EtOAc/ 1 : 1) to give (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-6- methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (40 mg, 0.060 mmol, 98 % yield) as oil. LCMS (M + H) = 638.

Step 2: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-6- methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (40 mg, 0.063 mmol) in methanol (8 mL) was added sodium hydroxide (50.1 mg, 1.253 mmol) in H2O (3 mL). Then, the reaction mixture was stirred at 80 °C overnight and cooled. The mixture was acidified with HC1 to pH = 7, concentrated and the crude was purified by Prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6- methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (8.4 mg, 0.014 mmol, 22.48 % yield) as a white solid. LCMS (M + H) = 596.

¾ NMR (400 MHz, MeOD) d 8.44 (d, J = 2.8 Hz, 1H), 8.20 (s, 1H), 7.65 (dd, J = 8.6, 2.9 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.32 - 7.13 (m, 2H), 7.03 (t, J = 7.8 Hz, 1H), 5.83 (s, 1H), 4.63 - 4.18 (m, 4H), 3.24 - 2.69 (m, 4H), 2.66 (s, 3H), 2.36 (s, 3H), 1.44 (m, 4H), 1.21 (s, 9H), 0.89 (s, 6H).

Example 184

Step 1 : To a solution of (S)-isopropyl 2-(5-(2-bromoethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (30 mg, 0.052 mmol), 4-chloro-2-methylphenol (7.42 mg, 0.052 mmol) in DMF (25 mL) was added potassium carbonate (71.9 mg, 0.520 mmol). The mixture was stirred overnight at 85 °C, cooled, filtered, and the filtrate was concentrated. The residue was purified by silica gel column (n-hexane:EtOAc/l : 1) to afford (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(4-chloro-2- methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (17 mg, 0.019 mmol, 35.8 % yield) as a oil. LCMS (M + H) = 638.

Step 2: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(4-chloro-2- methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (17 mg, 0.027 mmol) in methanol (10 mL) was added a solution of sodium hydroxide (21.31 mg, 0.533 mmol) in water (4.00 mL). Then, the reaction mixture was stirred at 80 °C overnight and cooled. The pH was adjusted to 8 with dilute hydrochloric acid, concentrated and the residue was purified by Prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5- (2-(4-chloro-2-methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (3 mg, 5.03 pmol, 18.89 % yield) as a white solid. LCMS (M + H) = 596. ¾ NMR (400 MHz, MeOD) d 8.45 (d, J = 2.8 Hz, 1H), 8.18 (s, 1H), 7.65 (dd, J = 8.6, 2.9 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.31 - 7.08 (m, 2H), 6.97 (d, J = 9.4 Hz, 1H), 5.83 (s, 1H), 4.65 - 4.26 (m, 4H), 2.92-2.85 (brs, 4H), 2.66 (s, 3H), 2.19 (s, 3H), 1.47-1.42 (brs, 4H), 1.21 (s, 9H), 0.90 (s, 6H).

Example 185

Step 1 : To a solution of (S)-isopropyl 2-(5-(2-bromoethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (30 mg, 0.052 mmol), 2-chloro-4-methylphenol (7.42 mg, 0.052 mmol) in DMF (25 mL) was added potassium carbonate (71.9 mg, 0.520 mmol). The mixture was stirred overnight at 85 °C and cooled. The mixture was filtered, the filtrate was concentrated and the residue was purified by silica gel column (n-hexane:EtOAc/l : l) to (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-4- methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (17 mg, 0.017 mmol, 33.3 % yield) as a oil. LCMS (M + H) = 638.

Step 2: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-4- methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (30 mg, 0.047 mmol) in methanol (10 mL) was added a solution of sodium hydroxide (37.6 mg, 0.940 mmol) in water (4.00 mL). Then, the reaction mixture was stirred at 80 °C overnight and cooled to rt. The pH was adjusted to 8 with dilute hydrochloric acid and concentrated. The residue was purified by Prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5- (2-(2-chloro-4-methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (10.5 mg, 0.017 mmol, 37.1 % yield). LCMS (M + H) = 596. Ή NMR (400 MHz, MeOD) d 8.45 (d, J = 2.8 Hz, 1H), 8.18 (s, 1H), 7.68 (dd, J = 8.6, 2.9 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 7.16 - 6.98 (m, 2H), 5.82 (s, 1H), 4.72 - 4.29 (m, 4H), 2.99-2.85 (brs, 4H), 2.66 (s, 3H), 2.29 (s, 3H), 1.46-1.42 (brs, 4H), 1.21 (s, 9H), 0.89 (s, 6H).

Example 186

Step 1 : A solution of (S)-isopropyl 2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (30 mg, 0.052 mmol) and 2-chloro- 6-fluorophenol (15.25 mg, 0.104 mmol) in DMF (2 mL) was added CS2CO3 (16.95 mg, 0.052 mmol). The mixture was stirred at 80 °C for 12 hr. Then, the reaction mixture was poured into water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2S04, filtered and concentrated. The residue was purified by prep-TLC (pet. ether :EtOAc/2: l) to give (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2- chloro-6-fluorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (30 mg, 0.022 mmol, 41.5 % yield) as a colorless oil. LCMS (M + H) = 642.

Step 2: A solution of (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-6- fluorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (30 mg, 0.047 mmol) in THF (2 mL) and water (2 mL) was added NaOH (1.868 mg, 0.047 mmol). The mixture was stirred at 80 °C for 12 hr. Then, cooled, pH adjusted to ~7 with HC1 (1 N), filtered and concentrated. The residue was purified by prep-HPLC to give the desired product (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-fluorophenoxy)ethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (17 mg, 0.028 mmol, 60.2 % yield) as a colorless solid. FCMS (M + H) = 600. ¾ NMR (400 MHz, MeOD) d 8.44 (s, 1H), 8.18 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 26.3 Hz, 1H), 6.90-6.70 (m, 3H), 5.83 (s, 1H), 4.56 - 4.23 (m, 4H), 2.70-7.65 (brs, 4H), 2.66 (s, 3H), 2.26 (s, 3H), 1.46-1.42 (brs, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 187

Stepl : To a solution of (S)-isopropyl 2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin- l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (40 mg, 0.069 mmol) in DMF (5 mL) was added CS2CO3 (45.2 mg, 0.139 mmol) and a solution of 2-chloro-4-fluorophenol (15.25 mg, 0.104 mmol) in DMF (1 mF). The mixture was stirred at 90 °C for 16 h, cooled and pH was adjusted to about 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPFC to give (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-4- fluorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (40 mg, 0.059 mmol, 85 % yield). FCMS (M + H) = 642.

Step 2: To a solution of NaOH (18.68 mg, 0.467 mmol) in methanol (5mF) and H2O (0.5 ml) was added the (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-4- fluorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (30 mg, 0.047 mmol). The mixture was stirred at 90 °C for 36 h, cooled, pH was adjusted to ~7 and concentrated. The crude was purified by Prep-HPFC to give (S)-2-(tert- butoxy)-2-(5-(2-(2-chloro-4-fluorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetic acid (19 mg, 0.030 mmol, 65.2 % yield) as a white solid. FCMS (M + H) = 600. ¾ NMR (400 MHz, MeOD) d 8.45 (d, J = 2.7 Hz, 1H), 8.18 (s, 1H), 7.67 (dd, J = 8.6, 2.9 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.24-7.21 (m, 2H), 7.11 - 6.99 (m, 1H), 5.82 (s, 1H), 4.65 - 4.33 (m, 4H), 2.76-2.72 (brs, 4H), 2.66 (s, 3H), 1.46-1.42 (brs, 4H), 1.21 (s, 9H), 0.90 (s, 6H).

Example 188

Step 1 : A solution of of (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-4- methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (60 mg, O. lOOmmol) and 4-fluoro-3-methylphenol (13.13 mg, 0.104 mmol) in DMF (2 mL) was added CS2CO3 (33.9 mg, 0.104 mmol) and was stirred at 80 °C for 12 hr. The mixture was poured into water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2S04, filtered and concentrated to give crude residue which was purified by Prep-TLC (pet. ether: EtOAc/2: 1) to give (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-(2-(4-fluoro-3- methylphenoxy)ethoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (27 mg, 0.013 mmol, 25.04 % yield) as a colorless oil. LCMS (M + H) = 622.

Step 2: A solution of (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)- 5-(2-(4-fhioro-3-methylphenoxy)ethoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (27 mg, 0.043 mmol) in THF (2 mL) and water (2 mL) was added NaOH (1.737 mg, 0.043 mmol) was stirred at 80 °C for 12 hr. Then, cooled, pH was adjusted to ~7 with HC1 (1 N), concentrated, and the residue was purified by Prep-HPLC to give the desired product (S)-2- (tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-(2-(4-fhioro-3-methylphenoxy)ethoxy)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetic acid (6.5 mg, 0.011 mmol, 25.7 % yield) as a colorless solid. LCMS (M + H) = 580. ¾ NMR (400 MHz, MeOD) d 8.36 (d, J = 2.7 Hz, 1H), 8.18 (s, 1H), 7.76-7.37 (m, 2H), 7.31-6.93 (m, 3H), 5.83 (s, 1H), 4.49-4.35 (m, 4H), 2.93-2.84 (brs, 3H), 2.66 (s, 3H), 2.25(s, 3H), 1.45-1.43 (brs, 4H), 1.21 (s, 9H), 0.90 (s, 6H).

Example 189

Step 1 : A solution of of (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-4- methylphenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (60 mg, 0.100 mmol) and 3,5-difluorophenol (13.54 mg, 0.104 mmol) in DMF (2 mL) was added CS2CO3 (33.9 mg, 0.104 mmol) was stirred at 80 °C for 12 hr. Then, the mixture was poured into water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2S04, filtered, concentrated and the residue was purified by Prep-TLC (pet. ether: EtOAc/2: 1) to give the desired product (S)- isopropyl 2-(tert-butoxy)-2-(5-(2-(3,5-difluorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (28 mg, 0.013 mmol, 25.8 % yield) as a colorless oil. LCMS (M + H) = 626.

Step 2: A solution of (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(3,5- difluorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (28 mg, 0.045 mmol) in THF (2 mL) and water (2 mL) was added NaOH (1.790 mg, 0.045 mmol). The mixture was stirred at 80 °C for 12 hr, cooled, pH was adjusted with HC1 ( 1 N) to pH=6~7, concentrated, and the residue was purified by Prep-HPLC to give the desired product (S)-2-(tert-butoxy)-2-(5-(2-(3,5-difluorophenoxy)ethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (11.3 mg, 0.019 mmol, 43.3 % yield) as a colorless solid. LCMS (M + H) = 584. ¾ NMR (400 MHz, MeOD) d 8.44 (d, J = 2.7 Hz, 1H), 8.18 (s, 1H), 7.64 (dd, J = 8.6, 2.9 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 6.61-6.50 (m, 3H), 5.83 (s, 1H), 4.67 - 4.19 (m, 4H), 2.83-2.80 (brs, 4H), 2.66 (s, 3H), 1.46- 1.43 (brs, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 190

Step 1 : To a ice cold solution of (S)-isopropyl 2-(5-(2-bromoethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (40 mg, 0.069 mmol) was added the CS2CO3 (45.2 mg, 0.139 mmol) and a solution of 4-chloro-2- fluorophenol (15.25 mg, 0.104 mmol) in DMF (1 ML). The mixture was stirred at 80 °C for 16 h, cooled, and the pH was adjusted to about 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC to give (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(4- chloro-2-fhiorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (30 mg, 0.044 mmol, 64.0 % yield). LCMS (M + H) = 642.

Step 2: To a solution ofNaOH (18.68 mg, 0.467 mmol) in methanol (5 mL) and H2O (0.5 ml) was added the (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(4-chloro-2- fluorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (30 mg, 0.047 mmol) and stirred at 90 °C for 36 h. Then, cooled, the pH was adjusted to ~7 and purified by Prep-HPLC to give (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-2- fluorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (13.8 mg, 0.023 mmol, 49.1 % yield) as a white solid. LCMS (M + H) = 600. ¾ NMR (400 MHz, MeOD) d 8.44 (d, J = 2.8 Hz, 1H), 8.18 (s, 1H), 7.65 (dd, J = 8.6, 2.9 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.20-7.10 (m, 3H), 5.82 (s, 1H), 4.76 - 4.32 (m, 4H), 2.99-2.97 (brs, 4H), 2.66 (s, 3H), 1.46-1.43 (brs, 4H), 1.21 (s, 9H), 0.90 (s, 6H).

Example 191

Step 1 : To a solution of 4-chloro-2-fluorophenol (1.2 g, 8.19 mmol) in water (22 mL) was added the l-bromopropan-2-ol (1.707 g, 12.28 mmol), NaOH (0.491 g, 12.28 mmol) and the mixture was stirred at 90 °C for 16 h. The solution was cooled to room temperature and the pH was adjusted to about 7 with acetic acid. The mixture was extracted with DCM (3 x 20 mL), the combined organic layers were dried over anhydrous NaiSOr then evaporated in vacuum to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. etherEtOAc (6: 1-5: 1) to give 2-(4-chloro-2- fluorophenoxy)ethanol (700 mg, 3.49 mmol, 42.6 % yield). LCMS (M + H) = 191.

Step 2: To the ice cold solution of 2-(4-chloro-2-fluorophenoxy)ethanol (29.2 mg, 0.153 mmol) in DMF (3 mL) was added NaH (12.25 mg, 0.306 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-5',6'-difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (30 mg, 0.061 mmol) in DMF (1 ML) at once. The mixture was stirred at 90°C for 16 h and the pH was adjusted to -7 with acetic acid. The mixture was purified by pre-HPLC to get the desired product S)-2-(tert-butoxy)-2- (6'-(2-(4-chloro-2-fluorophenoxy)ethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro-6-methyl- [3,3'-bipyridin]-5-yl)acetic acid (12 mg, 0.018 mmol, 30.1 % yield) was obtained as white solid. LCMS (M + H) = 6l8. ¾ NMR (400 MHz, MeOD) d 8.13 (s, 1H), 7.95 (d, J= 1.7 Hz, 1H), 7.60 (d, J= 10.6 Hz, 1H), 7.29 - 7.04 (m, 3H), 5.80 (s, 1H), 4.94 - 4.71 (m, 2H), 4.57 - 4.41 (m, 2H), 3.15-3.13 (brs, 2H), 2.78-2.76 (brs, 2H), 2.4 (s, 3H), 1.46-1.43 (brs, 4H),l .2l (s, 9H), 0.91 (s, 6H).

Example 192

Step 1 : To a solution of 3,5-difluorophenol (1.2 g, 9.22 mmol) in water (22 mL) was added the 2-bromoethanol (1.729 g, 13.84 mmol) and NaOH (0.553 g, 13.84 mmol). The mixture was stirred at 90 °C for 16 h and cooled to room temperature. Then, the pH was adjusted to about 7 with acetic acid and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous NaiSCL and evaporated in vacuum to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. etherEtOAc (6: 1-5: 1) to give 2-(3,5-difluorophenoxy)ethanol (700 mg, 3.82 mmol, 41.4 % yield). LCMS (M + H) = 175.

Step 2: To the ice cold solution of 2-(3,5-difluorophenoxy)ethanol (26.7 mg, 0.153 mmol) in DMF (3 mL) was added NaH (12.25 mg, 0.306 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'- difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (30 mg, 0.061 mmol) in DMF (1 ML) and stirred at rt for additional 16 h. Then, the pH was adjusted to -7 with acetic acid. The mixture was purified by pre-HPLC to get the desired product (S)-2-(tert-butoxy)-2-(6'-(2-(3,5- difluorophenoxy)ethoxy)-4-(4,4-dimethylpiperidin- 1 -yl)-5 '-fluoro-6-methyl- [3 ,3 '-bipyridin] - 5-yl)acetic acid (7.3 mg, 0.012 mmol, 19.58 % yield)was obtained as white solid. LCMS (M + H) = 602. ¾ NMR (400 MHz, MeOD) d 8.12 (s, 1H), 7.95 (s, 1H), 7.61 (d, J= 10.6 Hz, 1H), 6.80 - 6.53 (m, 3H), 5.80 (s, 1H), 4.86 - 4.77 (m, 2H), 4.51 - 4.35 (m, 2H), 3.18-3.15 (brs, 2H), 2.78-2.75 (brs, 2H), 2.65 (s, 3H), 1.46-1.44 (brs, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 193

Step 1 : To a solution of 2-chloro-6-fluorophenol (1 g, 6.82 mmol)in water (22 mL) was added 2-bromoethanol (1.729 g, 13.84 mmol), NaOH (0.553 g, 13.84 mmol) and the mixture was stirred at 90 °C for 16 h. Then, the reaction mixture was cooled to room temperature, the pH was adjusted to about 7 with acetic acid and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous NaiSOr and evaporated in vacuum to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. etherEtOAc (6: 1-5: 1) to give 2-(2-chloro-6- fluorophenoxy)ethanol (600 mg, 2.99 mmol, 43.8 % yield). LCMS (M + H) = 191.

Step 2: To the ice cold solution of 2-(2-chloro-6-fluorophenoxy)ethanol (20.24 mg, 0.106 mmol) in DMF (3 mL) was added NaH (13.07 mg, 0.327 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-5',6'-difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (40 mg, 0.082 mmol) in DMF (1 ML) at once. The mixture was stirred at 90°C for 16 h and the pH was adjusted to ~7 with acetic acid. The mixture was purified by pre-HPLC to get the desired product (S)-2-(tert-butoxy)-2- (6'-(2-(2-chloro-6-fluorophenoxy)ethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro-6-methyl- [3,3'-bipyridin]-5-yl)acetic acid (10.1 mg, 0.016 mmol, 19.50 % yield)was obtained as white solid. LCMS (M + H) = 6l8. ¾ NMR (400 MHz, MeOD) d 8.13 (s, 1H), 7.93 (d, J= 1.8 Hz, 1H), 7.58 (d, J= 10.6 Hz, 1H), 7.31 - 7.01 (m, 3H), 5.79 (s, 1H), 4.81 (dd, J= 16.5, 10.4, 4.2 Hz, 2H), 4.53 (t, J= 4.4 Hz, 2H), 3.17-3.14 (brs, 2H), 2.78-2.76 (brs, 2H), 2.68 (s, 3H), 1.46- 1.44 (brs, 4H), 1.19 (s, 9H), 0.90 (s, 6H).

Example 194

Step 1 : To a solution of 3-fluoro-4-methylphenol (1 g, 7.93 mmol) in water (22 mL) was added 2-bromoethanol (1.486 g, 11.89 mmol), NaOH (0.476 g, 11.89 mmol) and the mixture was stirred at 90 °C for 16 h. Then, the reaction solution was cooled to room temperature and the pH was adjusted to about 7 with acetic acid, extracted with DCM (3 x 20 mL), the organic combined layers were dried over anhydrous NaiSOr and evaporated in vacuum to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. etherEtOAc (6: 1-5: 1) to give 2-(3-fluoro-4- methylphenoxy)ethanol (600 mg, 3.35 mmol, 42.2 % yield). LCMS (M + H) = 171.

Step 2: To the ice cold solution of 2-(3-fluoro-4-methylphenoxy)ethanol (20.86 mg, 0.123 mmol) in DMF (3 mL) was added NaH (13.07 mg, 0.327 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-5',6'-difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (40 mg, 0.082 mmol)in DMF (1 ML) and stirred at 90°C for 16 h. The pH was adjusted to -7 with acetic acid. The mixture was purified by pre-HPLC to get the desired product (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-5'-fluoro-6'-(2-(3-fluoro-4-methylphenoxy)ethoxy)-6-methyl-[3,3'- bipyridin]-5-yl)acetic acid (13 mg, 0.021 mmol, 26.0 % yield) as white solid. LCMS (M + H) = 598. ¾ NMR (400 MHz, MeOD) d 8.13 (s, 1H), 7.95 (d, J= 1.8 Hz, 1H), 7.60 (d, J= 10.5 Hz, 1H), 7.13 (t, J= 8.8 Hz, 1H), 6.83 - 6.63 (m, 2H), 5.80 (s, 1H), 4.81 (d, J= 2.5 Hz, 2H), 4.38 (t , J= 4.6 Hz, 2H), 3.17-3.14 (brs, 2H), 2.75-2.72 (brs, 2H), 2.65 (s, 3H), 2.20 (d, J= 1.5 Hz, 3H), 1.46-1.43 (brs, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 195

Step 1 : To a solution of 2-chloro-4-fluorophenol (1.2 g, 8.19 mmol) in water (22 mL) was added 2-bromoethanol (1.535 g, 12.28 mmol), NaOH (0.491 g, 12.28 mmol) and the mixture was stirred at 90 °C for 16 h. Then, the reaction solution was cooled to room temperature and the pH was adjusted to about 7 with acetic acid, extracted with DCM (3 x 20 mL), the organic combined layers were dried over anhydrous NaiSOr and evaporated in vacuum to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. etherEtOAc (6: 1-5: 1) to give 2-(2-chloro-4- fluorophenoxy)ethanol (500 mg, 2.492 mmol, 30.4 % yield). LCMS (M + H) =191.

Step 2: To the ice cold solution of 2-(2-chloro-4-fluorophenoxy)ethanol (20.24 mg, 0.106 mmol) in DMF (3 mL) was added NaH (9.80 mg, 0.245 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-5',6'-difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (40 mg, 0.082 mmol) in DMF (1 ML) and stirred at rt for 16 h. The pH was adjusted to -7 with acetic acid. The mixture was purified by pre-HPLC to get the desired product (S)-2-(tert-butoxy)-2-(6'-(2-(2-chloro-4- fluorophenoxy)ethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (20 mg, 0.032 mmol, 38.9 % yield) was obtained as white solid. LCMS (M + H) = 618. ¾ NMR (400 MHz, MeOD) 5 8.12 (s, 1H), 7.95 (d, J= 1.9 Hz, 1H), 7.60 (d, J = 10.6 Hz, 1H), 7.25 - 7.15 (m, 2H), 7.13 - 6.99 (m, 1H), 5.80 (s, 1H), 4.92-4.53 (m, 2H), 4.52 - 4.43 (m, 2H), 3.17-3.13 (brs, 2H), 2.79-2.75 (brs, 2H), 2.65 (s, 3H), 1.42-1.40 (brs, 4H), 1.20 (s, 9H), 0.91 (s, 6H).

Example 196

Step 1 : To a solution of 4-fluoro-3-methylphenol (1.2 g, 9.51 mmol) in water (22 mL) was added 2-bromoethanol (1.783 g, 14.27 mmol), NaOH (0.571 g, 14.27 mmol) and the mixture was stirred at 90 °C for 16 h. Then, the reaction solution was cooled to room temperature and the pH was adjusted to about 7 with acetic acid, extracted with DCM (3 x 20 mF), the organic combined layers were dried over anhydrous Na2S04 and evaporated in vacuum to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. etherEtOAc (6: 1-5: 1) to give 2-(4-fluoro-3- methylphenoxy)ethanol (500 mg, 2.64 mmol, 27.8 % yield). FCMS (M + H) = 171.

Step 2: To the ice cold solution of 2-(4-fluoro-3-methylphenoxy)ethanol (15.82 mg, 0.093 mmol) in DMF (3 mF) was added NaH (8.58 mg, 0.214 mmol). To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'- difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (35 mg, 0.071 mmol) DMF (1 MF) and stirred at rt for 16 h. The pH was adjusted to -7 with acetic acid. The mixture was purified by pre- HPFC to get the desired product (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5'- fluoro-6'-(2-(4-fluoro-3-methylphenoxy)ethoxy)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (10 mg, 0.017 mmol, 23.14 % yield)was obtained as white solid. FCMS (M + H) = 598. ¾ NMR (400 MHz, MeOD) 5 8.12 (s, 1H), 7.95 (d, J= 1.9 Hz, 1H), 7.60 (d, J= 10.7 Hz, 1H), 7.05 - 6.76 (m, 3H), 5.79 (s, 1H), 4.80-4.78 (m, 2H), 4.37 (t, J= 4.7 Hz, 2H), 3.156-3.14 (brs, 2H), 2.73-2.71 (brs, 2H), 2.65 (s, 3H), 2.25 (d, J= 1.8 Hz, 3H), 1.46-1.44 (brs, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 197

To the ice cold solution of 2-(4-fluorophenoxy)ethanol (14.51 mg, 0.093 mmol) in DMF (3 mL) was added NaH (8.58 mg, 0.214 mmol). To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'-difluoro-6-methyl- [3,3'-bipyridin]-5-yl)acetate (35 mg, 0.071 mmol) in DMF (1 MF) and stirred at rt for 16 h. The pH was adjusted to ~7 with acetic acid. The mixture was purified by pre-HPFC to get the desired product (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro-6'-(2-(4- fluorophenoxy)ethoxy)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (10.8 mg, 0.018 mmol, 25.3 % yield) was obtained as white solid. FCMS (M + H) = 584. Ή NMR (400 MHz, MeOD) d 8.12 (s, 1H), 7.95 (d, J= 1.8 Hz, 1H), 7.60 (d, J= 10.6 Hz, 1H), 7.01 (dd, J= 9.4, 3.7 Hz, 4H), 5.79 (s, 1H), 4.82-4.80 (m, 2H), 4.47 - 4.34 (m, 2H), 3.16-3.14 (brs, 2H), 2.79-2.77 (brs, 2H), 2.65 (s, 3H), 1.46-1.44 (brs, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 198

Step 1 : To a solution of p 4-chloro-2-methylphenol (1.0 g, 7.01 mmol) in water (22 mL) was added 2-bromoethanol (1.315 g, 10.52 mmol), NaOH (0.421 g, 10.52 mmol) and the mixture was stirred at 90 °C for 16 h. Then, the reaction solution was cooled to room temperature and the pH was adjusted to about 7 with acetic acid, extracted with DCM (3 x 20 mL), the organic combined layers were dried over anhydrous NaiSOr and evaporated in vacuum to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. etherEtOAc (6: 1-5: 1) to give 2-(4-chloro-2- methylphenoxy)ethanol (500 mg, 2.55 mmol, 36.3 % yield). LCMS (M + H) = 187.

Step 2: To the ice cold solution of 2-(4-chloro-2-methylphenoxy)ethanol (17.34 mg, 0.093 mmol) in DMF (3 mL) was added NaH (8.58 mg, 0.214 mmol). To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'- difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (35 mg, 0.071 mmol) in DMF (1 ML) and stirred at rt for 16 h. The pH was adjusted to -7 with acetic acid. The mixture was purified by pre-HPLC to get the desired product (S)-2-(tert-butoxy)-2-(6'-(2-(4-chloro-2- methylphenoxy)ethoxy)-4-(4,4-dimethylpiperidin- 1 -yl)-5 '-fluoro-6-methyl- [3 ,3 '-bipyridin] -5 - yl)acetic acid (6.3 mg, 10.06 pmol, 14.08 % yield) was obtained as white solid. LCMS (M + H) = 614. ¾ NMR (400 MHz, MeOD) d 8.13 (s, 1H), 7.95 (d, J= 1.8 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.24-7.05 (m, 2H), 7.01-6.91 (m, 1H), 5.79 (s, 1H), 4.90 - 4.81 (m, 2H), 4.49 - 4.35 (m, 2H), 3.16-3.14 (brs, 2H), 2.78-2.76 (brs, 2H), 2.65 (s, 3H), 2.18 (s, 3H), 1.46-1.44 (brs, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 199

Step 1 : To a solution of p-cresol (1.0 g, 9.25 mmol) in water (22 mL) was added 2- bromoethanol (1.387 g, 11.10 mmol), NaOH (0.555 g, 13.87 mmol) and the mixture was stirred at 90 °C for 16 h. Then, the reaction solution was cooled to room temperature and the pH was adjusted to about 7 with acetic acid, extracted with DCM (3 x 20 mL), the organic combined layers were dried over anhydrous NaiSCL and evaporated in vacuum to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. ether: EtO Ac (6: 1-5: 1) to give 2-(p-tolyloxy)ethanol (900 mg, 5.62 mmol, 60.8 % yield). LCMS (M + H) = 153.

Step 2: To the ice cold solution of 2-(p-tolyloxy)ethanol (16.16 mg, 0.106 mmol) in DMF (3 mL) was added NaH (9.80 mg, 0.245 mmol). To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'-difluoro-6-methyl- [3,3'-bipyridin]-5-yl)acetate (40 mg, 0.082 mmol) in DMF (1 ML) and stirred at rt for 16 h. The pH was adjusted to -7 with acetic acid. The mixture was purified by pre-HPLC to get the desired product (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro-6-methyl-6'- (2-(p-tolyloxy)ethoxy)-[3,3'-bipyridin]-5-yl)acetic acid (20 mg, 0.035 mmol, 42.2 % yield) was obtained as white solid. LCMS (M + H) = 614. ¾ NMR (400 MHz, MeOD) d 8.08 (s, 1H), 7.94 (d, J= 1.9 Hz, 1H), 7.59 (d, J= 10.2 Hz, 1H), 7.10 (d, J= 8.3 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.76 (s, 1H), 4.81-4.79 (m, 2H), 4.37 (t, J= 4.7 Hz, 2H), 3.12-3.10 (brs, 2H), 2.79-2.77 (brs, 2H), 2.64 (s, 3H), 2.29 (s, 3H), 1.46-1.44 (brs, 4H), 1.20 (s, 9H), 0.91 (s, 6H).

Example 200

Step 1: To a solution of 2-chloro-6-methylphenol (1.0 g, 7.01 mmol) in water (22 mL) was added 2-bromoethanol (1.315 g, 10.52 mmol), NaOH (0.421 g, 10.52 mmol) and the mixture was stirred at 90 °C for 16 h. Then, the reaction solution was cooled to room temperature and the pH was adjusted to about 7 with acetic acid, extracted with DCM (3 x 20 mL), the organic combined layers were dried over anhydrous NaiSOr and evaporated in vacuum to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. etherEtOAc (6: 1-5: 1) to give 2-(2-chloro-6- methylphenoxy)ethanol (500 mg, 2.55 mmol, 36.3 % yield), LCMS (M + H) = 187.

Step 2: To the ice cold solution of 2-(2-chloro-6-methylphenoxy)ethanol (19.82 mg, 0.106 mmol) in DMF (3 mL) was added NaH (9.80 mg, 0.245 mmol). To the mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'- difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (40 mg, 0.082 mmol) in DMF (1 ML) and stirred at rt for 16 h. The pH was adjusted to ~7 with acetic acid. The mixture was purified by pre-HPLC to get the desired product (S)-2-(tert-butoxy)-2-(6'-(2-(2-chloro-6- methylphenoxy)ethoxy)-4-(4,4-dimethylpiperidin- 1 -yl)-5 '-fluoro-6-methyl- [3 ,3 '-bipyridin] -5 - yl)acetic acid (20 mg, 0.033 mmol, 39.8 % yield) was obtained as white solid. LCMS (M +

H) = 614. ¾ NMR (400 MHz, MeOD) d 8.14 (s, 1H), 7.95 (s, 1H), 7.62 (d, J= 11.8 Hz, 1H), 7.24 (d, J= 7.6 Hz, 1H), 7.16 (d, J= 7.7 Hz, 1H), 7.01 (t, J= 7.8 Hz, 1H), 5.79 (s, 1H), 4.86- 4.84 (m, 2H), 4.39-4.37 (brs, 2H), 3.16-3.14 (brs, 2H), 2.72 (s, 2H), 2.65 (s, 3H), 2.35 (s,

3H), 1.46-1.43 (brs, 4H), 1.21 (s, 9H), 0.89 (s, 6H).

Example 201

Step 1 : To the ice cold solution of 2-(4-chlorophenoxy)ethanol (25.2 mg, 0.146 mmol) in THF (3 mL) was added the (13.48 mg, 0.337 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5',6'- difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (55 mg, 0.112 mmol) in THF (1 ML) and stirred at rt for 16 h. Then, the pH was adjusted to about 7 with acetic acid, filtered and the filtrate was purified by Prep-HPLC to give the desired product (25mg, yield 35%), LCMS (M + H) = 642.

Step 2: To a solution of sodium hydroxide (15.57 mg, 0.389 mmol) in MeOH (10 mL) and H20 (0.5 ml) was added (S)-isopropyl 2-(tert-butoxy)-2-(6'-(2-(4- chlorophenoxy)ethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro-6-methyl-[3,3'-bipyridin]-5- yl)acetate (25 mg, 0.039 mmol) and stirred at 90 °C for 36 h. The pH was adjusted to ~7 with acetic acid. The mixture was purified by pre-HPLC to get the desired product (S)-2-(tert- butoxy)-2-(6'-(2-(4-chlorophenoxy)ethoxy)-4-(4,4-dimethylpiperidin-l-yl)-5'-fluoro-6- methyl-[3,3'-bipyridin]-5-yl)acetic acid (2.5 mg, 4.13 pmol, 10.60 % yield)) as white solid. LCMS (M + H) = 600. ¾ NMR (400 MHz, MeOD) 5 8.12 (s, 1H), 7.95 (d, J= 1.9 Hz, 1H), 7.59 (d, J= 10.2 Hz, 1H), 7.28 (d, J= 8.3 Hz, 2H), 7.00 (d, J= 8.6 Hz, 2H), 5.79 (s, 1H), 4.91-4.80 (m, 2H), 4.41-4.39 (m, 2H), 3.12-3.10 (brs, 2H), 2.79-2.77 (brs, 2H), 2.64 (s, 3H), 1.46-1.44 (brs, 4H), 1.20 (s, 9H), 0.91 (s, 6H).

Example 202

Step 1 : To a solution of 2-chloro-4-methylphenol (1.2 g, 8.42 mmol) in water (22 mL) was added 2-bromoethanol (1.578 g, 12.62 mmol), NaOH (0.505 g, 12.62 mmol)and the mixture was stirred at 90 °C for 16 h. Then, the reaction solution was cooled to room temperature and the pH was adjusted to about 7 with acetic acid, extracted with DCM (3 x 20 mL), the organic combined layers were dried over anhydrous Na2S04 and evaporated in vacuum to give a yellow crude product. The crude product was purified by silica gel chromatography eluting with pet. etherEtOAc (6: 1-5: 1) to give 2-(2-chloro-4- methylphenoxy)ethanol (600 mg, 3.05 mmol, 36.3 % yield). LCMS (M + H) = 187.

Step 2: To the ice cold solution of 2-(2-chloro-4-methylphenoxy)ethanol (20.97 mg, 0.112 mmol) in THF (3 mL) was added NaH (13.48 mg, 0.337 mmol) in portions. To this mixture was added a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-5',6'-difluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (55 mg, 0.112 mmol) in THF (1 ML) and stirred at rt for 16 h. Then, the pH was adjusted to about 7 with acetic acid, filtered and the filtrate was purified by Prep-HPLC to give the desired product (25mg, yield 36.3%). LCMS (M + H) = 656.

Step 3: To a solution of NaOH (18.68 mg, 0.467 mmol) in methanol (5 mL) and H20 (0.5 ml) was added (S)-isopropyl 2-(tert-butoxy)-2-(6'-(2-(2-chloro-4- methylphenoxy)ethoxy)-4-(4,4-dimethylpiperidin- 1 -yl)-5 '-fluoro-6-methyl- [3 ,3 '-bipyridin] -5 - yl)acetate (25 mg, 0.038 mmol). The mixture was stirred at 90 °C for 36 h. The pH was adjusted to -7 with acetic acid. The mixture was purified by pre-HPLC to get the desired product (S)-2-(tert-butoxy)-2-(6'-(2-(2-chloro-4-methylphenoxy)ethoxy)-4-(4,4- dimethylpiperidin-l-yl)-5'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (8.5 mg, 0.014 mmol, 36.3 % yield) as white solid. FCMS (M + H) = 614. ¾ NMR (400 MHz, MeOD) d 8.45 (d, J= 2.7 Hz, 1H), 8.18 (s, 1H), 7.67 (dd, J= 8.6, 2.9 Hz, 1H), 7.50 (d, J= 8.6 Hz, 1H), 7.21 - 7.03 (m, 2H), 5.82 (s, 1H), 4.57-4.55 (m, 2H), 4.49 - 4.36 (m, 2H), 3.28-3.25 (brs,2H), 3.16-3.14 (brs, 2H), 2.82 (s, 3H), 2.66 (s, 3H), 1.45-1.43 (brs, 4H), 1.21 (s, 9H), 0.90 (s, 6H).

(S)-2-phenoxypropan-1-ol ( )-2-phenoxypropan-1 -ol

Peak 1 Peak 2

1 g of 2-phenoxypropan-l-ol was separated by chiral-HPLC [Co-Solvent : EtOH (1% ammonia in Methanol) Column: OD-H (4.6* 100*5 pm), Column Temperature: 40 °C, C02 Flow Rate : 3.6, Co-Solvent Flow Rate: 0.4, Co-Solvent %: l0, Total Flow: 4, Front Pressure: 150, Back Pressure: 120, Pressure Drop: 30, PDA Start Wavelength: 214, PDA Stop

Wavelength: 359] to give (S)-2-phenoxypropan-l-ol (0.35 g) and (R)-2-phenoxypropan-l-ol (0.30 g).

Example 203

To an ice-cooled solution of (S)-2-phenoxypropan-l-ol (1 1.29 mg, 0.074 mmol) in DMF (3 mF) was added the NaH (8.90 mg, 0.223 mmol) in one portion. Isopropyl (S)-2- (tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5- yl)acetate (35 mg, 0.074 mmol) in DMF (1 mF) was added and the mixture was stirred at rt for addtional 16 h. Then, pH was adjusted to ~7 with 1N HC1. The mixture was filtered and subjected to prep-HPFC purification {Instrument Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 2l .2x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient: 55-63%B in 8.0 min, stop at 13.0 min;Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6-methyl-6'-((S)-2- phenoxypropoxy)-[3,3'-bipyridin]-5-yl)acetic acid (10.8 mg, 0.019 mmol, 25.2 % yield). FC- MS: 562.3 [M+H], Retention time (0.0l% NH₄HCC>3) = 1.62 min. Ή NMR (400 MHz, MeOD) d 8.27-8.04 (m, 2H), 7.69-7.68 (m, 1H), 7.28 (t, J= 8.0 Hz, 2H), 7.11-6.79 (m, 4H), 5.77 (s, 1H), 4.90-4.86 (m, 1H), 4.57 (dd, J= 11.2, 6.2 Hz, 1H), 4.46 (dd, = 11.2, 6.2 Hz, 1H), 3.15-3.14 (m, 2H), 2.74-2.73 (m, 2H), 2.66 (s, 3H), 1.45-1.43 (m, 7H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 204

To an ice-cooled solution (R)-2-phenoxypropan-l-ol (11.29 mg, 0.074 mmol) in DMF (3 mL) was added the NaH (8.90 mg, 0.223 mmol) in one portion. Isopropyl (S)-2-(tert- butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (35 mg, 0.074 mmol) was added and the mixture was stirred at rt for addtional 16 h. Then pH was adjusted to ~7 with 1N HC1. The mixture was filtered and purified by prep-HPLC

{InstrumentGilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 2l .2x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient: 55-63%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)- 2-(4-(4,4-dimethylpiperidin-l-yl)-6-methyl-6'-((R)-2-phenoxypropoxy)-[3,3'-bipyridin]-5- yl)acetic acid (7.5 mg, 0.013 mmol, 17.38 % yield). FC-MS: 562.3 [M+H], Retention time (0.01% NH4HCO3) = 1.62 min. ¾ NMR (400 MHz, MeOD) d 8.20-7.98 (m, 2H), 7.69 (dd, J = 8.5, 2.3 Hz, 1H), 7.41-7.11 (m, 2H), 7.11-6.75 (m, 4H), 5.77 (s, 1H), 4.90-4.86 (m,lH), 4.54-4.45 (m, 2H), 3.15-3.14 (m, 2H), 2.75-2.74 (m, 2H), 2.66 (s, 3H), 1.44-1.42 (m, 7H),

1.21 (s, 9H), 0.91 (s, 6H).

Example 205

Step 1 : To a stiired solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (60 mg, 0.128 mmol), (S)-2-phenoxypropan-l-ol (38.9 mg, 0.256 mmol) and triphenylphosphine (67.0 mg, 0.256 mmol) in THF (5 mF) was added diisopropyl diazene-l,2-dicarboxylate (51.7 mg, 0.256 mmol) at 0 °C. Then, the reaction mixture was stirred at rt overnight and solvent was removed under reduced pressure. H2O (100 ml) and ethyl acetate (150 mF) were added. The organic layer was separated, dried over Na2SC>4, and concentrated. The residue was purified by prep-TLC (pet. ether/EtOAc; 2: 1) to afford isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-((S)-2-phenoxypropoxy)-[2,3'-bipyridin]-5'-yl)acetate (10 mg, 0.016 mmol, 12.99 % yield) as a yellow oil. LC-MS: 604.2 [M+H], Retention time (0.01% NH4HCO3) = 2.66 min.

Step 2: To a solution of sodium hydroxide (2.65 mg, 0.066 mmol) in MeOH (3 mL) and H2O (0.5 ml) was added isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)- 6'-methyl-5-((S)-2-phenoxypropoxy)-[2,3'-bipyridin]-5'-yl)acetate (10 mg, 0.016 mmol). The mixture was stirred at 90 °C for 16 h, cooled and the pH of the mixture was adjusted to ~7 with 1N HC1. The crude was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient: 55-63%B in 8.0 min, stop at 13.0 min;Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-((S)-2- phenoxypropoxy)-[2,3'-bipyridin]-5'-yl)acetic acid (5.3 mg, 9.44 pmol, 14.24 % yield) as white solid. LC-MS: 562.2[M+H], Retention time (0.0l% NH₄HCO3) =1.66 min. Ή NMR (400 MHz, MeOD) d 8.40 (d, J= 2.8 Hz, 1H), 8.16 (s, 1H), 7.61 - 7.60 (m, 1H), 7.59-7.58 (m, 1H), 7.31-7.27 (m, 2H), 7.00-6.90 (m, 3H), 5.82 (s, 1H), 4.88-4.85 (m, 1H), 4.32-4.30 (m, 2H), 3.15-3.14 (m, 2H), 2.76-2.75 (m, 2H), 2.65 (s, 3H), 1.48-1.45 (m, 7H), 1.20 (s, 9H), 0.91 (s, 6H).

Example 206

Step 1 : A solution of triethylamine (0.220 mL, 1.577 mmol), (R)-2-phenoxypropan-l- ol (60 mg, 0.394 mmol) in DCM (5 mL) was stirred at 0 °C for 5 min. Then, MsCl (0.061 mL, 0.788 mmol) was added at 0 °C. Then the reaction mixture was stirred at rt overnight and solvent was removed under reduced pressure. H2O (100 mL) and ethyl acetate (150 mL) were added. The organic layer was separated, dried over NarSCL, and concentrated. The residue was purified by prep-TLC (pet. ether/EtOAc; 1 : 1) to afford (R)-2-phenoxypropyl methanesulfonate (70 mg, 0.304 mmol, 77 % yield) as yellow oil. Step 2: A mixture of K2CO3 (23.41 mg, 0.169 mmol), (R)-2-phenoxypropyl methanesulfonate (30 mg, 0.130 mmol) and isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (73.4 mg, 0.156 mmol) in DMF (1 mL) was stirred at 0 °C for 5 min. Then reaction mixture was stirred at 75 °C for 16 hr. The solvent was removed under reduced pressure. H2O (100 mL) and ethyl acetate (150 mL) were added. The organic layer was separated, dried over NaiSCL. and concentrated. The residue was purified by prep-TLC (pet. ether/EtOAc; 2: 1) to afford isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-((R)-2- phenoxypropoxy)-[2,3'-bipyridin]-5'-yl)acetate ( 25 mg, 0.041 mmol, 31.8 % yield) as a yellow oil. LC-MS: 604.2[M+H], Retention time (0.01% NH4HCO3) = 2.63 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-((R)-2-phenoxypropoxy)-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.041 mmol) in a mixed solvent (2 mL EtOH/0.400 mL H20) was added NaOH (33.1 mg, 0.828 mmol). The resulting mixture was stirred at 90 °C for 10 hours. The pH was adjusted to about 7 with acetic acid. The crude product was purified by prep-HPLC {Instrument: Gilson 281 (PHG- 009; Column: Xtimate Prep C18 OBD, 2l .2x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient: 55-63%B in 8.0 min, stop at l3.0min;Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5- ((R)-2-phenoxypropoxy)-[2,3'-bipyridin]-5'-yl)acetic acid (15 mg, 0.027 mmol, 64.5 % yield) as white solid. LC-MS: 562.2 [M+H], Retention time (0.0l% NH4HCO3) = 1.64 min. Ή NMR: (400 MHz, MeOD) d 8.40 (d, J= 2.8 Hz, 1H), 8.16 (s, 1H), 7.61-7.58 (m, 1H), 7.48- 7.46 (m, 1H), 7.31-7.27 (m, 2H), 7.00-6.94 (m, 3H), 5.82 (s, 1H), 4.88-4.85 (m, 1H), 4.3 l(d, J= 5.2 Hz, 2H), 3.33-3.32 (m, 2H), 3.13-3.09 (m, 1H), 3.89-3.65 (m, 1H), 2.65 (s, 3H), 1.46- 1.40 (m, 7H), 1.20 (s, 9H), 0.91 (s, 6H).

(R)-1-phenoxypropan-2-ol (S)-1-phenoxypropan-2-ol

Peak 1 Peak 2

1 g of l-phenoxypropan-2-ol was separated by chiral-HPLC [Co-Solvent : EtOH (1% ammonia in Methanol) Column: OD-H (4.6* 100*5 pm), Column Temperature: 40 °C, C02 Flow Rate: 3.6, Co-Solvent Flow Rate: 0.4, Co-Solvent %: l0, Total Flow: 4, Front Pressure: 150, Back Pressure: 120, Pressure Drop: 30, PDA Start Wavelength: 214, PDA Stop Wavelength: 359] to give (R)-2-phenoxypropan-l-ol (0.30 g) and (S)-2-phenoxypropan-l-ol (0.25 g).

Example 207

To an ice-cooled solution (R)-l-phenoxypropan-2-ol (22.59 mg, 0.148 mmol) in DMF (3 mL) was added NaH (8.90 mg, 0.223 mmol) in one portion. Isopropyl (S)-2-(tert-butoxy)- 2-(4-(4,4-dimethylpiperidin- 1 -yl)-6'-fluoro-6-methyl-[3 ,3 '-bipyridin] -5 -yl)acetate (35 mg, 0.074 mmol) in DMF (1 mF) was added and the mixture was stirred at rt for addtional 16 h. Then pH was adjusted to ~7 with 1N HC1. The mixture was filtered and directly subjected to Prep-HPFC purification {Instrument Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient: 55-63%B in 8.0 min, stop at 13.0 min;Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6-methyl-6'-(((R)-l- phenoxypropan-2-yl)oxy)-[3,3'-bipyridin]-5-yl)acetic acid (19.7 mg, 0.033 mmol, 44.1 % yield). FC-MS: 562 [M+H], Retention time (0.0l% NH₄HCC>3) = 1.71 min. Ή NMR (400 MHz, MeOD) d 8.20-8.02 (m, 2H), 7.68 (dd, J= 8.5, 2.5 Hz, 1H), 7.37-7.20 (m, 2H), 6.95 (dd, J= 8.5, 5.7 Hz, 4H), 5.78 (s, 1H), 5.63 (dd, J= 10.6, 6.2 Hz, 1H), 4.25-4.14 (m, 2H), 3.15-3.14 (m, 2H), 2.76-2.75 (m, 2H), 2.66 (s, 3H), 1.48-1.45 (m, 7H), 1.17 (s, 9H), 0.91 (s, 6H).

Example 208

To an ice-cooled solution (S)-l-phenoxypropan-2-ol (11.29 mg, 0.074 mmol) in DMF (3 mF) was added NaH (8.90 mg, 0.223 mmol) in one portion. Isopropyl (S)-2-(tert-butoxy)- 2-(4-(4,4-dimethylpiperidin- 1 -yl)-6'-fhioro-6-methyl-[3 ,3 '-bipyridin] -5 -yl)acetate (35 mg, 0.074 mmol) was added and the mixture was stirred at rt for addtional 16 h. Then pH was adjusted to ~7 with 1N HC1. The mixture was filtered and directly subjected to Prep-HPFC purification {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 2l .2x 250 mm, 10 pm; Mobile Phase A: Water (lOmmol NH4HCO3); B: MeCN; Gradient: 55- 63%B in 8.0 min, stop at 13.0 min;Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6-methyl-6'-(((S)-l-phenoxypropan-2- yl)oxy)-[3,3'-bipyridin]-5-yl)acetic acid (16.3 mg, 0.029 mmol, 39.1 % yield). LC-MS: 562 [M+H], Retention time (0.01% NH4HCO3) = 1.71 min. Ή NMR (400 MHz, MeOD) d 8.20 - 8.02 (m, 2H), 7.68 (dd, J= 8.5, 2.5 Hz, 1H), 7.37 - 7.20 (m, 2H), 6.95 (dd, J= 8.5, 5.7 Hz, 4H), 5.78 (s, 1H), 5.63 (dd, J= 10.6, 6.2 Hz, 1H), 4.25-4.14 (m, 2H), 3.15-3.14 (m, 2H), 2.76-2.75 (m, 2H), 2.66 (s, 3H), 1.48-1.45 (m, 7H), 1.17 (s, 9H), 0.91 (s, 6H).

Example 209

Step 1 : To a stirred solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (60 mg, 0.128 mmol), (R)-l-phenoxypropan-2-ol (38.9 mg, 0.256 mmol) and triphenylphosphine (67.0 mg, 0.256 mmol) in THF (3 mL) was added diisopropyl diazene-l,2-dicarboxylate (51.7 mg, 0.256 mmol) at 0 °C. Then the reaction mixture was stirred at rt overnight and the solvent was removed under reduced pressure. H2O (100 ml) and ethyl acetate (150 mL) were added. The organic layer was separated, dried over Na2SC>4, and concentrated. The residue was purified by prep-TLC (pet. ether/EtOAc; 2: 1) to afford isopropyl (S)-2-(tert-butoxy)-2-(4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(((S)-l-phenoxypropan-2-yl)oxy)-[2,3'-bipyridin]- 5'-yl)acetate (22 mg, 0.036 mmol, 28.5 % yield) as a yellow oil. LCMS: 604.2 [M+H], Retention time (0.01% NH4HCO3) = 2.65 min.

Step 2: To a solution ofNaOH (21.86 mg, 0.547 mmol) in ethanol (3 mL) and H2O (0.500 mL) was added the isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(((S)-l-phenoxypropan-2-yl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (33 mg, 0.055 mmol). The mixture was stirred at 90 °C for 20 h. The pH was adjusted to about 7 with acetic acid. The mixture was filtered and the filtrate was directly subjected to prep-HPLC purification {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 2l .2x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient: 55- 63%B in 8.0 min, stop at 13.0 min;Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2- (4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(((S)-l-phenoxypropan-2-yl)oxy)-[2,3'- bipyridin]-5'-yl)acetic acid (23 mg, 0.041 mmol, 74.9 % yield) as white solid. LC-MS: 562.2 [M+H], Retention time (0.01% NH4HCO3) = 1.64 min. Ή NMR (400 MHz, MeOD) d 8.42 (d, = 2.8 Hz, 1H), 8.19 (s, 1H), 7.66 (dd, J= 8.6, 2.9 Hz, 1H), 7.48 (d, = 8.6 Hz, 1H), 7.32-7.22 (m, 2H), 6.98-6.90 (m, 3H), 5.84 (s, 1H), 5.08-4.98 (m, 1H), 4.21 (d, J= 5.0 Hz, 2H), 3.34 (d, J= 1.5 Hz, 2H), 2.79-2.76 (m, 2H), 2.66 (s, 3H), 1.49 (d, J= 8.8 Hz, 3H), 1.46- 1.26 (m, 4H), 1.21 (s, 9H), 0.89 (s, 6H).

Example 210

Step 1 : To a stirred solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (60 mg, 0.128 mmol), (S)-l-phenoxypropan-2-ol (38.9 mg, 0.256 mmol) and triphenylphosphane (67.0 mg, 0.256 mmol) in THF (5 mL) was added diisopropyl diazene-l,2-dicarboxylate (51.7 mg, 0.256 mmol) at 0 °C. Then the reaction mixture was stirred at rt overnight and the solvent was removed under reduced pressure. H2O (100 mL) and ethyl acetate (150 mL) were added. The organic layer was separated, dried over NaiSOr. and concentrated. The residue was purified by prep-TLC (pet. ether/EtOAc; 2: 1) to afford isopropyl (S)-2-(tert-butoxy)-2-(4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(((R)-l-phenoxypropan-2-yl)oxy)-[2,3'-bipyridin]- 5'-yl)acetate (7 mg, 0.012 mmol, 9.07 % yield) as a yellow oil. LCMS: 604.2 [M+H], Retention time (0.01% NH4HCO3) = 2.64 min.

Step 2: To a solution of NaOH (4.64 mg, 0.116 mmol) in ethanol (3 mL) and H2O (0.500 mL) was added the isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(((R)-l-phenoxypropan-2-yl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (7 mg, 0.012 mmol). The mixture was stirred at 90 °C for 20 h. The pH was adjusted to about 7 with acetic acid. The mixture was filtered and the filtrate was directly subjected to prep-HPLC purification {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 2l .2x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient: 55-63%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert- butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(((R)-l-phenoxypropan-2-yl)oxy)- [2,3'-bipyridin]-5'-yl)acetic acid (3.3 mg, 5.87 pmol, 50.7 % yield) as white solid. LC-MS: 562.7 [M+H], Retention time (0.01% NH4HCO3) = 1.63 min. Ή NMR (400 MHz, MeOD) d 8.42 (d, J= 2.8 Hz, 1H), 8.19 (s, 1H), 7.66 (dd, J= 8.6, 2.9 Hz, 1H), 7.48 (d, J= 8.6 Hz, 1H), 7.32-7.22 (m, 2H), 6.98-6.90 (m, 3H), 5.84 (s, 1H), 5.08-4.98 (m, 1H), 4.21 (d, J= 5.0 Hz, 2H), 3.34 (d, J= 1.5 Hz, 2H), 2.79-2.76 (m, 2H), 2.66 (s, 3H), 1.49 (d, J= 8.8 Hz, 3H), 1.46- 1.26 (m, 4H), 1.21 (s, 9H), 0.89 (s, 6H).

Example 211

To a solution of lH-pyrazole (4.72 mg, 0.069 mmol) in DMF (1.5 mL) was added isopropyl (S)-2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)-2-(tert-butoxy)acetate (20 mg, 0.035 mmol) and CS2CO3 (22.60 mg, 0.069 mmol). The mixture was stirred at 65 °C for 2 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SC>4, filtered and concentrated. The residue was dissolved in MeOH (1.5 mL) and water (1.5 mL), then NaOH (27.7 mg, 0.694 mmol) was added and the mixture was stirred at 70 °C for 12 hrs. LCMS showed the starting material was consumed completely. The pH of mixture was adjusted with HC1 (1 N) to 5~6, and concentrated. The residue was dissolved in DMF (2 mL) and filtered. The filtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG- 009; Column: Xtimate Prep C18 OBD, 2l .2x 250 mm, 10 pm; Mobile Phase A: water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min;Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(5-(2-(lH-pyrazol-l-yl)ethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetic acid (5 mg, 9.58 pmol, 27.6 % yield) as white solid. LCMS (M +H) = 522.2; Retention time (10 mM NH4HC03) = 1.38 min. ¾ NMR (400 MHz, MeOD): d 8.32 (d, J = 2.8 Hz, 1H), 8.12 (s, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.51 (dd, J = 2.8, 8.8 Hz, 1H) 7.44 (d, J = 8.4 Hz, 1H), 6.32 (t, J = 2 Hz, 1H), 5.79 (s, 1H), 4.62-4.59 (m, 2H), 4.50-4.48 (m, 2H), 3.18-2.67 (m, 4H), 2.63 (s, 3H), 1.54-1.31 (m, 4H), 1.10 (s, 9H), 0.88 (s, 6H).

Example 212

To a solution of 3,5-dimethyl-lH-pyrazole (6.67 mg, 0.069 mmol) in DMF (1.5 mL) was added isopropyl (S)-2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl- [2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (20 mg, 0.035 mmol) and CS2CO3 (22.60 mg, 0.069 mmol). The mixture was stirred at 65 °C for 2 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL x 2), dried over NaiSCL, filtered and concentrated. The residue was dissolved in MeOH (1.5 mL) and water (1.5 mL).Then NaOH (27.7 mg, 0.694 mmol) was added and the mixture was stirred at 70 °C for another 12 hrs. LCMS showed the starting material was consumed completely. The pH of mixture was adjusted with HC1 (1 N) to 5~6, and concentrated. The residue was dissolved in DMF (2 mL), and filtered. The filtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 2l .2x 250 mm, 10 pm; Mobile Phase A: water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-(2-(3,5- dimethyl- lH-pyrazol- 1 -yl)ethoxy)-4'-(4,4-dimethylpiperidin- 1 -yl)-6'-methyl-[2,3 '-bipyridin] - 5'-yl)acetic acid (9.4 mg, 0.017 mmol, 49.3 % yield) as white solid. LCMS (M +H) = 550.2; Retention time (10 mM NH4HC03) =1.46 min. Ή NMR (400 MHz, MeOD): d 8.28 (d, J = 2.8 Hz, 1H), 8.10 (s, 1H), 7.48 (dd, J = 2.8, 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 5.84 (s, 1H), 5.79 (s, 1H), 4.46-4.42 (m, 4H), 3.20-2.68 (m, 4H), 2.62(s, 3H), 2.33 (s, 3H), 2.18 (s, 3H), 1.46-1.30 (m, 4H), 1.18 (s, 9H), 0.88 (s, 6H).

Example 213

Step 1 : To a solution of methyl 3-hydroxybenzoate (100 mg, 0.657 mmol) and 1,2- dibromoethane (247 mg, 1.315 mmol) in DMF (2 mL) was added CS2CO3 (428 mg, 1.315 mmol) portion-wise. The mixture was stirred at RT for 30 min and at 65 °C for 1.5 hrs.

LCMS showed the starting material was consumed completely and product was detected. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine (10 mL *3), dried over NarSCL, filtered and concentrated to residue. The residue was purified by prep-TLC (pet. etherethyl acetate; 2: 1) to give the desired product methyl 3-(2-bromoethoxy)benzoate (60 mg, 0.232 mmol, 35.2 % yield) as white solid. LCMS (M +H) = 259; Retention time (10 mM NH4HC03) = 1.82 min.

Step 2: To a mixture of methyl 3-(2-bromoethoxy)benzoate (227 mg, 0.085 mmol) in DMF (1.5 mL) was added isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5- hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.043 mmol) and CS2CO3 (27.8 mg, 0.085 mmol). The mixture was stirred at 65 °C for 2 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL x 2), dried over NaiSCL, filtered and concentrated. The residue was dissolved in MeOH (1.5 mL), water (1.5 mL) and NaOH (34.1 mg, 0.852 mmol) added and the mixture was stirred at 70 °C for 12 hrs. LCMS showed the starting material was consumed completely. The pH of mixture was adjusted with HC1 (1 N) to 5~6, and concentrated. The residue was dissolved in DMF (2 mL), and filtered. The filtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2x 250 mm, 10 pm; Mobile Phase A: water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-3-(2-((5'-(tert-butoxy(carboxy)methyl)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5-yl)oxy)ethoxy)benzoic acid (18.7 mg, 0.032 mmol, 74.2 % yield) as white solid. LCMS (M +H) = 592; Retention time (10 mM NH4HC03) = 1.22 min. ¾ NMR (400 MHz, MeOD): d 8.43 (d, J = 2.8 Hz, 1H), 8.14 (s,

1H), 7.64-7.61 (m, 3H), 7.48 (d, J = 8.8 H_z, IH), 7.39 (t, J = 8.0 Hz, 1H), 7.20-7.17 (m, 1H), 5.78 (s, 1H), 4.53-4.51 (m, 2H), 4.45-4.43 (m, 2H), 3.13-2.71 (m, 4H), 2.64 (s, 3H), 1.48- 1.32 (m, 4H), 1.18 (s, 9H), 0.88 (s, 6H).

Example 214

To a solution of isopropyl (S)-2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin-l-yl)- 6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (20 mg, 0.035 mmol) and 4-chloro- lH-pyrazole (7.11 mg, 0.069 mmol) in DMF (1.5 mL) was added CS2CO3 (22.60 mg, 0.069 mmol). The mixture was stirred at 65 °C for 2 hrs. LCMS showed the starting material was consumed completely and product was detected. The mixture was poured into water (5. mL), extracted with ethyl acetate (5 mL * 2) and washed with brine (5 mL), dried over NaiSOi. filtered and concentrated. The residue was dissolved in MeOH (1.5 mL) and NaOH (27.7 mg, 0.694 mmol) in water (1.5 mL) was added and the mixture was stirred at 65 °C for 12 hrs. TLC showed the product was detected. The pH of mixture was adjusted with HC1 (1 N) to 5~6, and concentrated. The residue was dissolved in DMF (2 mL), and filtered. The filtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2x 250 mm, 10 pm; Mobile Phase A: water (10 mmol NH4HCO3); B: MeCN;

Gradient 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-lH-pyrazol-l-yl)ethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (11.7 mg, 0.021 mmol, 60.7 % yield) as white solid. LCMS (M +H) = 556.0; Retention time (10 mM NH4HC03) = 1.49 min. ¾ NMR (400 MHz, MeOD): d 8.33 (d, J = 2.4 Hz, 1H), 8.11 (s, 1H), 7.53-7.49 (m,3H), 7.44 (d, J = 8.8 Hz, 1H), 5.78 (s, 1H), 4.58-4.55 (m, 2H), 4.50-4.48 (m, 2H), 3.13- 2.70 (m, 4H), 2.62 (s, 3H), 1.48-1.31 (m, 4H), 1.18 (s, 9H), 0.88 (s, 6H).

Example 215

To a solution of 4-methyl- lH-pyrazole (5.70 mg, 0.069 mmol) in DMF (1.5 mL) was added isopropyl (S)-2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)-2-(tert-butoxy)acetate (20 mg, 0.035 mmol) and CS2CO3 (22.60 mg, 0.069 mmol). The mixture was stirred at 65 °C for 2 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SC>4, filtered and concentrated. The residue was dissolved in MeOH (1.5 mL), water (1.5 mL) and NaOH (27.7 mg, 0.694 mmol) were added. The mixture was stirred at 70 °C for 12 hrs. LCMS showed the starting material was consumed completely. The pH of mixture was adjusted with HC1 (1 N) to 5~6, and concentrated. The residue was dissolved in DMF (2 mL), and filtered. The filtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2x 250 mm, 10 pm; Mobile Phase A: water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(2-(4-methyl-lH-pyrazol-l-yl)ethoxy)-[2,3'-bipyridin]-5'-yl)acetic acid (8.5 mg, 0.016 mmol, 45.7 % yield) as white solid. LCMS (M +H) = 536.2; Retention time (10 mM NH4HC03) = 1.45 min. ¾ NMR (400 MHz, MeOD): d 8.31 (d, J = 2.8 Hz, 1H), 8.08 (s, 1H), 7.52-7.51 (brs, 1H), 7.51 (dd, J = 2.8, 8.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.33-7.32 (brs, 1H), 5.76 (s, 1H), 4.53 (t, J = 4.8 Hz, 2H), 4.46 (t, J = 4.8 Hz, 2H), 3.06-2.70 (m, 4H), 2.62 (s, 3H), 27 (s, 3H), 1.47-1.20 (m, 4H), 1.17 (s, 9H), 0.87 (s, 6H).

Example 216

Step 1 : To a solution of methyl 4-hydroxybenzoate (100 mg, 0.657 mmol) and 1,2- dibromoethane (247 mg, 1.315 mmol) in DMF (2 mL) was added CS2CO3 (428 mg, 1.315 mmol) portion-wise. The mixture was stirred at RT for 30 min and at 65 °C for 1.5 hrs.

LCMS showed the starting material was consumed completely and product was detected. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine (10 mL *3), dried over Na2SC>4, filtered and concentrated. The residue was purified by prep-TLC (pet. ether: ethyl acetate; 2: 1 to give the desired product methyl 4-(2-bromoethoxy)benzoate (80 mg, 0.309 mmol, 47.0 % yield) as white solid. LCMS (M +H) = 259.0; Retention time (10 mM NH4HC03) = 1.82 min.

Step 2: To a mixture of methyl 4-(2-bromoethoxy)benzoate (33.1 mg, 0.128 mmol) in DMF (1.5 mL) was added isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5- hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (30 mg, 0.064 mmol) and CS2CO3 (22.60 mg, 0.069 mmol). The mixture was stirred at 65 °C for 2 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with ethyl acetate (5 mL *3). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SC>4, filtered and concentrated. The residue was dissolved in MeOH (1.5 mL), water (1.5 mL) and NaOH (51.1 mg, 1.278 mmol) were added. The mixture was stirred at 70 °C for 12 hrs. LCMS showed the starting material was consumed completely. The pH of mixture was adjusted with HC1 (1 N) to 5~6, and concentrated. The residue was dissolved in DMF (2 mL), and filtered. The filtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 2l .2x 250 mm, 10 pm; Mobile Phase A: water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-4-(2-((5'-(tert-butoxy(carboxy)methyl)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5-yl)oxy)ethoxy)benzoic acid (28 mg, 0.047 mmol, 74.1 % yield) as white solid. LCMS (M +H) = 592; Retention time (10 mM NH4HC03) = 1.22 min. Ή NMR (400 MHz, MeOD): d 8.40 (d, J = 2.8 Hz, 1H), 8.04 (s, 1H), 7.9- 7.92 (m, 2H), 7.62 (dd, J = 2.8, 8.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 6.98-6.97 (m, 2H); 5.68 (s, 1H), 4.51-4.49 (m, 2H), 4.43-4.41 (m, 2H), 3.30-3.20 (m, 4H), 2.62 (s, 3H), 2.41-1.29 (m, 4H), 1.15 (s, 9H), 0.87 (s, 6H).

Example 217

To a mixture of methyl 2-hydroxybenzoate (10.56 mg, 0.069 mmol) and CS2CO3 (33.9 mg, 0.104 mmol) in DMF (1.5 mL) was added isopropyl (S)-2-(5-(2-bromoethoxy)-4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (20 mg, 0.035 mmol). The mixture was stirred at 65 °C for 2 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SC>4, filtered and concentrated. The residue was dissolved in MeOH (1.5 mL), water (1.5 mL) and NaOH (27.7 mg, 0.694 mmol) was added and the mixture was stirred at 70 °C for another 12 hrs. LCMS showed the starting material was consumed completely. The pH of mixture was adjusted with HC1 (1 N) to 5~6, and concentrated. The residue was dissolved in DMF (2 mL), and filtered. The filtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2x 250 mm, 10 pm; Mobile Phase A: water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(2-((5'-(tert-butoxy(carboxy)methyl)- 4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5-yl)oxy)ethoxy)benzoic acid (8 mg, 0.014 mmol, 39.0 % yield) as white solid. LCMS (M +H) = 592.1; Retention time (10 mM NH4HC03) = l .23min. ¾ NMR (400 MHz, MeOD): d 8.42 (d, J = 3.2 Hz, 1H), 8.15 (s, 1H), 7.75 (dd, J = 1.6, 7.6 Hz, 1H), 7.68 (dd, J = 3.2, 8.8 H_z, IH), 7.50-7.46 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 5.79 (s, 1H), 4.57-4.54(m, 2H), 4.51-4.49 (m, 2H), 3.20-2.70 (m, 4H), 2.64 (s, 3H), 1.51-1.34 (m, 4H), 1.19 (s, 9H), 0.87 (s, 6H).

Example 218

Step 1 : To a solution of l,2-dibromoethane (130 mg, 0.694 mmol) and 4-phenyl-lH- pyrazole (100 mg, 0.694 mmol) in DMF (2 mL) was added CS2CO3 (226 mg, 0.694 mmol) portion-wise. The mixture was stirred at RT for 30 min and at 65 °C for 1.5 hrs. LCMS showed the starting material was consumed completely and product was detected. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over NaiSOr. filtered and concentrated to residue. The residue was purified by prep-TLC (pet. etherethyl acetate; 2: 1) to give the desired product l-(2-bromoethyl)-4-phenyl-lH-pyrazole (60 mg, 0.239 mmol,

34.4 % yield) as yellow oil. LCMS (M +H) = 251.0; Retention time (10 mM NH4HC03) = 1.40 min.

Step 2: To a mixture of l-(2-bromoethyl)-4-phenyl-lH-pyrazole (21.39 mg, 0.085 mmol) in DMF (1.5 mL) was added isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.043 mmol) and CS2CO3 (27.8 mg, 0.085 mmol). The mixture was stirred at 65 °C for 2 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over NaiSOi. filtered and concentrated. The residue was dissolved in MeOH (1.5 mL) and water (1.5 mL), NaOH (34.1 mg, 0.852 mmol) was added and the mixture was stirred at 70 °C for 12 hrs. LCMS showed the starting material was consumed completely. The pH of mixture was adjusted with HC1 (1 N) to 5~6 and concentrated. The residue was dissolved in DMF (2 mL), and filtered. The filtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2x 250 mm, 10 pm; Mobile Phase A: water (10 mmol NH4HC03); B: MeCN; Gradient 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(2-(4- phenyl-lH-pyrazol-l-yl)ethoxy)-[2,3'-bipyridin]-5'-yl)acetic acid (8.4 mg, 0.014 mmol, 33 % yield) as white solid. LCMS (M +H) = 598.0; Retention time (10 mM NH4HC03) = 1.55 min. ¾ NMR (400 MHz, MeOD): d 8.35 (d, J = 2.8 Hz, 1H), 8.10-8.09 (brs, 1H), 8.08-8.07 (brs, 1H), 7.87-7.86 (brs, 1H), 7.55-7.50 (m,3H), 7.43 (d, J = 8.8 Hz, 1H), 7.36 (t, J = 8.4 Hz, 2H) 7.22 (t, J = 7.6 Hz, 1H), 5.78 (s, 1H), 4.64-4.62 (m, 2H), 4.56-4.54 (m, 2H), 3.17-2.68 (m, 4H), 2.62 (s, 3H), 1.45-1.28 (m, 4H), 1.17 (s, 9H), 0.84 (s, 6H).

Example 219

To a mixture of 5-methyl- lH-pyrazole (2.85 mg, 0.035 mmol) in DMF (2 mL) was added isopropyl (S)-2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)-2-(tert-butoxy)acetate (20 mg, 0.035 mmol) and CS2CO3 (22.6 mg, 0.069 mmol). The mixture was stirred at 65 °C for2 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over NaiSOr. filtered and concentrated. The residue was dissolved in MeOH (1.5 mL) and water (1.5 mL).Then NaOH (27.7 mg, 0.694 mmol) was added and the mixture was stirred at 70 °C for 12 hrs. LCMS showed the starting material was consumed completely. The pH of mixture was adjusted with HC1 (1 N) to 5~6, and concentrated. The residue was dissolved in DMF (2 mL), and filtered. The filtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG- 009; Column: Xtimate Prep C18 OBD, 21.2x 250 mm, lOum; Mobile Phase A: water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin- l-yl)-6'-methyl-5-(2-(5-methyl-lH-pyrazol-l-yl)ethoxy)-[2,3'-bipyridin]-5'-yl)acetic acid (8.5 mg, 0.016 mmol, 45.7 % yield) as white solid. LCMS (M +H) = 536.1; Retention time (10 mM NH4HC03) = 1.43 min. ¹H NMR (400 MHz, MeOD): d 8.30 (dd, J = 2.4, 13.6 H_z, 1H), 8.07 (d, J = 2.8 Hz, 1H), 7.61-7.40 (m, 3H), 6.08 -6.06 (m, 1H), 5.74 (s, 1H), 4.52-4.45 (m, 4H), 3.30-2.69 (m, 4H), 2.62 (s, 3H), 2.40-2.25 (m, 4H), 1.49-1.30 (m, 4H), 1.17 (s, 9H), 0.87 (s, 6H). Example 220

Step 1 : To a solution of Pd(Ph3P)4 (0.254 g, 0.220 mmol), 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenol (0.966 g, 4.39 mmol) and isopropyl (S)-2-(5-bromo-4-(4,4- dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate (1 g, 2.196 mmol) in l,4-dioxane (10 mL) was added K2CO₃ (0.607 g, 4.39 mmol). The mixture was stirred at 100 °C for 5.0 hrs under N2. LCMS showed the starting material was consumed completely and product was detected. The mixture was filtered, poured into water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated. The residue was purified by flash silica column (pet. ether: ethyl acetate; 20: 1 to 3: 1) to give the desired product isopropyl (S)-2-(tert-butoxy)-2-(4- (4,4-dimethylpiperidin-l-yl)-5-(4-hydroxyphenyl)-2-methylpyridin-3-yl)acetate (1.0g, 1.882 mmol, 86 % yield) as yellow oil. LCMS (M +H) = 469; Retention time (10 mM NH4HC03)

= 1.58 min.

Step 2; To a mixture of 2-(2-chlorophenoxy)ethyl methanesulfonate (10.70 mg, 0.043 mmol) and CS2CO3 (27.8 mg, 0.085 mmol) in DML (1.5 mL) was added isopropyl (S)-2-(tert- butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5-(4-hydroxyphenyl)-2-methylpyridin-3-yl)acetate (20 mg, 0.043 mmol). The mixture was stirred at 65 °C for 2 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SC>4, filtered and concentrated. The residue was dissolved in MeOH (1.5 mL) and water (1.5 mL), NaOH (34.1 mg, 0.854 mmol) was added and the mixture was stirred at 70 °C for 12 hrs. LCMS showed the starting material was consumed completely.

The pH of mixture was adjusted with HC1 (1 N) to 5~6, and concentrated. The residue was dissolved in DML (2 mL), and filtered. The filtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 2l .2x 250 mm, 10 pm; Mobile Phase A: water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Plow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-(4-(2-(2- chlorophenoxy)ethoxy)phenyl)-4-(4,4-dimethylpiperidin-l-yl)-2-methylpyridin-3-yl)acetic acid (7.2 mg, 0.012 mmol, 29.0 % yield) as white solid. LCMS (M +H) = 581.1; Retention time (10 mM NH4HC03) = 1.74 min. ¹H NMR (400 MHz, MeOD): 5 8.08 (s, 1H), 7.38 (dd, J = 1.6, 7.6 Hz, 1H), 7.30-7.25 (m, 3H), 7.16-7.14 (m, 3H), 6.97 (dt, J = 1.2, 7.6 Hz, 1H), 5.68 (s, 1H), 4.46-4.42 (m, 4H), 3.30- 2.69 (m, 4H), 2.65 (s, 3H), 1.48 -1.32 (m, 4H), 1.19 (s, 9H), 0.88 (s, 6H).

Example 221

Step 1 : A mixture of 2-((3bR,4aS)-3-(difhioromethyl)-5,5-difluoro-3b,4,4a,5- tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetic acid (50 mg, 0.189 mmol) and BH3.THF (5 mL, 0.189 mmol) was stirred at 75 °C for 4.0 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL *3). The combined organic layers were washed with brine (10 mL), dried over NaiSOr. filtered and concentrated. The residue was purified by prep-TLC (pet. etherethyl acetate; 1 : 1) to give the desired product 2-((3bR,4aS)-3- (difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2- c]pyrazol-l-yl)ethan-l-ol (35 mg, 0.140 mmol, 73.9 % yield) as colorless oil. LCMS (M +H) = 251.2; Retention time (10 mM NH4HC03) = 1.57 min.

Step 2: To a mixture of 2-((3bR,4aS)-3-(difluoromethyl)-5,5-difhioro-3b,4,4a,5- tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)ethan-l-ol (35 mg, 0.140 mmol) and Et3N (0.058 mL, 0.420 mmol) in DCM (3 mL) was added MsCl (0.016 mL, 0.210 mmol). The mixture was stirred at rt for 4.0 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL *3). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and concentrated to give the desired crude product 2-((3bR,4aS)-3- (difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2- c]pyrazol-l-yl)ethyl methanesulfonate (40 mg, 0.088 mmol, 63.0 % yield) as yellow oil. LCMS (M +H) = 329; Retention time (10 mM NH4HC03) = 1.44 min. Step 3: To a mixture of 2-((3bR,4aS)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5- tetrahydro- lH-cyclopropa[3,4]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)ethyl methanesulfonate (20.97 mg, 0.064 mmol) and CS2CO3 (41.6 mg, 0.128 mmol) in DMF (1.5 mL) was added isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]- 5'-yl)acetate (30 mg, 0.064 mmol). The mixture was stirred at 65 °C for 2 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over NaiSOr. fdtered and concentrated. The residue was dissolved in MeOH (1.5 mL) and water (1.5 mL), NaOH (51.1 mg, 1.278 mmol) was added and the mixture was stirred at 70 °C for another 12 hrs. LCMS showed the starting material was consumed completely. The pH of mixture was adjusted with HC1 (1 N) to 5~6, and concentrated. The residue was dissolved in DMF (2 mL), and fdtered. The fdtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2x 250 mm, 10 pm; Mobile Phase A: water (10 mmol NHdTCCh); B: MeCN; Gradient 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product S)-2-(tert-butoxy)-2-(5-(2-((3bR,4aS)-3-(difluoromethyl)-5,5-difluoro- 3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)ethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (4 mg, 6.06 pmol, 9.49 % yield) as white solid. LCMS (M +H) = 660; Retention time (10 mM NH4HC03) = 1.58 min. ¾ NMR (400 MHz, MeOD): d 8.24 (d, J = 2.8 Hz, 1H), 8.00 (s, 1H), 7.47 (dd, J = 3.2, 8.8 Hz, 1H), 7.39 (d, J = 8.8 H_z, IH), 6.72 (t, J = 14.8 Hz, 1H), 5.66 (s, 1H), 4.55-4.52 (m, 4H), 2.62 (s, 3H), 2.54- 2.45 (m, 2H), 2.40-1.29 (m, 8H), 1.14 (s, 9H), 1.00-0.67 (m, 8H).

Example 222

Step 1 : A mixture of 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5- tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetic acid (50 mg, 0.189 mmol) and BH3.THF (5 mL, 0.189 mmol) was stirred at 75 °C for 4.0 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL *3). The combined organic layers were washed with brine (10 mL), dried over NaiSOr. filtered and concentrated. The residue was purified by prep-TLC to get the desired product 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5- tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)ethan-l-ol (40 mg, 0.160 mmol, 84 % yield) as colorless oil. LCMS (M +H) = 251.2; Retention time (10 mM NH4HC03) = 1.57 min.

Step 2: To a mixture of 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5- tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)ethan-l-ol (40 mg, 0.160 mmol) and Et3N (0.067 mL, 0.480 mmol) in DCM (3 mL) was added MsCl (0.019 mL, 0.240 mmol). The mixture was stirred at rt for 4.0 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL *3). The combined organic layers were washed with brine (10 mL), dried over NaiSCL, filtered and concentrated to the desired crude product 2-((3bS,4aR)-3- (difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2- c]pyrazol-l-yl)ethyl methanesulfonate (50 mg, 0.117 mmol, 73.4 % yield) as yellow oil. LCMS (M +H) = 328.7; Retention time (10 mM NH4HC03) = 1.44 min.

Step 3: To a mixture of 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5- tetrahydro- lH-cyclopropa[3,4]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)ethyl methanesulfonate (20.97 mg, 0.064 mmol) and CS2CO3 (41.6 mg, 0.128 mmol) in DMF (1.5 mL) was added isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]- 5'-yl)acetate (30 mg, 0.064 mmol). The mixture was stirred at 65 °C for 2 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over NarSOi. filtered and concentrated. The residue was dissolved in MeOH (1.5 mL) and water (1.5 mL), NaOH (51.1 mg, 1.278 mmol) was added and the mixture was stirred at 70 °C for 12 hrs. LCMS showed the starting material was consumed completely. The pH of mixture was adjusted with HC1 (1 N) to 5~6, and concentrated. The residue was dissolved in DMF (2 mL), and filtered. The filtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 2l .2x 250 mm, 10 pm; Mobile Phase A: water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)- 2-(5-(2-((3bS,4aR)-3-(difhioromethyl)-5,5-difhioro-3b,4,4a,5-tetrahydro-lH- cyclopropa[3 ,4]cyclopenta[ 1 ,2-c]pyrazol- 1 -yl)ethoxy)-4'-(4,4-dimethylpiperidin- 1 -yl)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetic acid (2.9 mg, 4.40 pmol, 6.88 % yield) as white solid. LCMS (M +H) = 660.2; Retention time (10 mM NH4HC03) = 1.59 min. Ή NMR (400 MHz, MeOD): d 8.24 (d, J = 2.4 Hz, 1H), 8.00 (s, 1H), 7.47 (dd, J = 3.2, 8.8 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 6.75 (t, J = 14.8 Hz, 1H), 5.66 (s, 1H), 4.81- 4.52 (m, 4H), 2.61 (s, 3H), 2.56- 2.41 (m, 2H), 2.21- 1.29 (m, 8H), 1.14 (s, 9H), 1.00-0.67 (m, 8H).

Example 223

To a l-dram vial equipped with a stir bar was added cyclopropylmethanol (23.74 mg, 0.329 mmol), triphenylphosphine (86 mg, 0.329 mmol), isopropyl (S)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-propoxyacetate (50 mg, 0.110 mmol) and THF (1097 pl). To the stirring solution was added diisopropyl (E)-diazene- l,2-dicarboxylate (64.0 mΐ, 0.329 mmol). The solution was stirred at r.t. for 1 hr. LCMS showed a major peak with the M+H of the expected product. The reaction was concentrated and taken up in Ethanol (1.5 mL) and then was treated with naoh (5M) (110 mΐ, 0.549 mmol) at rt. The reaction was stirred at 70 °C for 5 hrs. The reaction was cooled to rt and filtered and purified by prep-LCMS: Purification Conditions: Step 1 : Column: Waters Xterra C18, 19 x 100 mm, 10 pm particles; Solvent A = 0.1% NH40H in 100% Water. Solvent B =

Acetonitrile. Flow Rate = 40 mL/min. Start % B = 17.7 Final % B = 37.7. Gradient Time = 6 min, then a 2 min hold at 98% B. Wavelength = 215 and 254 nm. ESI + Range: 150 to 1500 dalton. Sample was loaded at 10% B. Step 2: Column: Zorbax Eclipse Plus C18, 21.2 x 100 mm, 5 pm particles; Solvent A = 0.1% Formic Acid in 100% Water. Solvent B =

Acetonitrile. Flow Rate = 40 mL/min. Start % B = 28.8 Final % B = 48.8. Gradient Time = 7 min, then a 2 min hold at 98% B. Wavelength = 215 and 254 nm. ESI + Range: 150 to 1500 dalton. Sample was loaded at 15% B. (S)-2-(5-(cyclopropylmethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-propoxyacetic acid (12.8 mg,

25%) was isolated consistent by LCMS and NMR. FinalQC: Column: Acquity UPLC BEH C18, 2.1 x 30 mm, 1.7 pm particles; Solvent A = 0.1% Formic acid in l00% Water. Solvent B = 0.1% Formic Acid in 100% Acetonitrile. Flow Rate = 0.8 mL/min. Start % B = 5. Final % B = 95. Gradient Time = 1.6 min, then a 0.25 min hold at 95% B. Wavelength = 215 nm. rt: 1.00 min, M+H = 467.2 'H NMR (METHAN OL-d₄, 500 MHz) d 8.37 (d, 1H, J=2.7 Hz), 8.17 (s, 1H), 7.54 (dd, 1H, J=2.7, 8.9 Hz), 7.47 (d, 1H, J=8.5 Hz), 5.58 (s, 1H), 4.00 (d, 2H, J=7.0 Hz), 3.6-3.7 (m, 1H), 3.4-3.4 (m, 1H), 3.2-3.3 (m, 1H), 2.95 (br s, 1H), 2.83 (br s, 2H), 2.64 (s, 3H), 1.62 (sxt, 2H, J=7. l Hz), 1.3-1.5 (m, 5H), 0.9-0.9 (m, 9H), 0.7-0.7 (m, 2H), 0.43 (q, 2H, J=5.0 Hz)

Example 224

To a l-dram vial equipped with a stir bar was added cyclobutylmethanol (28.4 mg, 0.329 mmol), triphenylphosphine (86 mg, 0.329 mmol), isopropyl (S)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-propoxyacetate (50 mg, 0.110 mmol) and THF (1097 pl). To the stirring solution was added diisopropyl (E)-diazene- l,2-dicarboxylate (64.0 mΐ, 0.329 mmol). The solution was stirred at r.t. for 1 hr. LCMS showed a major peak with the M+H of the expected ester intermediate. The reaction was concentrated and taken up in ethanol (1.5 mL) and then was treated with naoh (5M) ( 110 mΐ, 0.549 mmol) at rt. The reaction was stirred at 70 °C for 5 hrs. The reaction was cooled to rt and filtered and purified by prep-LCMS: Purification Conditions: Column: Waters Xterra C18, 19 x 100 mm, 10 pm particles; Solvent A = 0.1% NH40H in 100% Water. Solvent B = Acetonitrile. Flow Rate = 40 mL/min. Start % B = 21.5 Final % B = 41.5. Gradient Time = 6 min, then a 2 min hold at 98% B. Wavelength = 215 and 254 nm. ESI⁺ Range: 150 to 1500 dalton. Sample was loaded at 10% B. (S)-2-(5-(cyclobutylmethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-propoxyacetic acid (16.1 mg,

31%) was isolated consistent by FCMS and NMR. FinalQC: Column: Acquity UPFC BEH C18, 2.1 x 30 mm, 1.7 pm particles; Solvent A = 0.1% Formic acid in l00% Water. Solvent B = 0.1% Formic Acid in 100% Acetonitrile. Flow Rate = 0.8 mF/min. Start % B = 5. Final % B = 95. Gradient Time = 1.6 min, then a 0.25 min hold at 95% B. Wavelength = 215 nm. rt: 1.10, M+H = 481.2. ¾ NMR (METHANOF-d4, 500 MHz) d 8.36 (d, 1H, J=2.7 Hz), 8.16 (s, 1H), 7.55 (dd, 1H, J=3. l, 8.5 Hz), 7.46 (d, 1H, J=8.9 Hz), 5.57 (s, 1H), 4.12 (d, 2H, J=6.4 Hz), 3.6-3.7 (m, 1H), 3.4-3.4 (m, 1H), 3.2-3.3 (m, 1H), 2.94 (br s, 1H), 2.8-2.9 (m, 3H), 2.64 (s, 3H), 2.2-2.2 (m, 2H), 1.9-2.1 (m, 4H), 1.61 (sxt, 2H, J=7.0 Hz), 1.42 (br s, 2H), 1.37 (br d, 2H, J=7.6 Hz), 0.9-0.9 (m, 9H)

Example 225

To a l-dram vial equipped with a stir bar was added 2-(2-chlorophenoxy)ethan-l-ol (56.8 mg, 0.329 mmol), triphenylphosphine (86 mg, 0.329 mmol), isopropyl (S)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-propoxyacetate (50 mg, 0.110 mmol) and THF (1097 pl). To the stirring solution was added diisopropyl (E)-diazene- l,2-dicarboxylate (64.0 mΐ, 0.329 mmol). The solution was stirred at r.t. for 1 hr. LCMS showed a major peak with the M+H of the expected ester intermediate. The reaction was concentrated and taken up in ethanol (1.5 mL) and then was treated with NaOH (5M) ( 110 mΐ, 0.549 mmol) at rt. The reaction was stirred at 70 °C for 5 hrs. The reaction was cooled to rt and filtered and purified by prep-LCMS: Column: Waters XTerra C18, 19 x 100 mm, 10 pm particles; Solvent A = 0.1% NH40H in 100% Water. Solvent B = Acetonitrile. Flow Rate = 40 mL/min. Start % B = 18.4 Final % B = 38.4. Gradient Time = 6 min, then a 2 min hold at 98% B. Wavelength = 215 and 254 nm. ESI⁺ Range: 150 to 1500 dalton. Sample was loaded at 10% B. (S)-2-(5-(2-(2-chlorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl- [2,3'-bipyridin]-5'-yl)-2-propoxyacetic acid (17.6 mg, 0.031 mmol, 28.2 % yield) was isolated consistent by FCMS and NMR. Basic Final QC method: Column: Waters XTerra C18, 4.6 x 50 mm, 5 pm particles; Solvent A = 0.1% NH40H in 100% Water. Solvent B = Acetonitrile. Flow Rate = 2.5 mF/min. Start % B = 5. Final % B = 95. Gradient Time = 4 min, then a 1 min hold at 95% B. Wavelength = 215 nm and 254 nm Mass Spectra data was collected by Agilent G6125B. Mass range: 150 to 1500 Dalton. rt: 2.16, M+H = 568.3. ¾ NMR

(METHANOF-d₄, 500 MHz) d 8.45 (d, 1H, J=2.7 Hz), 8.16 (s, 1H), 7.67 (dd, 1H, J=2.7, 8.5 Hz), 7.49 (d, 1H, J=8.2 Hz), 7.38 (d, 1H, J=7.6 Hz), 7.29 (br t, 1H, J=7.5 Hz), 7.17 (d, 1H, J=7.9 Hz), 6.97 (t, 1H, J=7.8 Hz), 5.57 (s, 1H), 4.5-4.6 (m, 2H), 4.5-4.5 (m, 2H), 3.6-3.7 (m, 1H), 3.1-3.3 (m, 2H), 2.9-3.0 (m, 1H), 2.Ί-2.9 (m, 2H), 2.64 (s, 3H), 1.6-1.6 (m, 2H), 1.3-1.5 (m, 4H), 0.8-0.9 (m, 9H). Example 226

Step 1 : To a solution oftert-butyl (2-hydroxyethyl)carbamate (10 g, 62.0 mmol) and DIEA (13.00 mL, 74.4 mmol) in DCM (30 mL) was added methane sulfonyl chloride (5.32 mL, 68.2 mmol) dropwise with ice-water cooling. The mixture was stirred at 20 °C for 2 h. Then saturated ammonium chloride solution was added to the mixture until the solution was about pH 7, and the mixture was extracted with DCM (3 x 40 mL). The combined organic layers were dried over NaiSCri, and the solvent was removed in vacuo to give 2-((tert- butoxycarbonyl)amino)ethyl methane sulfonate (14.8 g, 61.8 mmol, 100 % yield) as a yellow oil. LCMS (M + H) = 240.1; Retention time (0.0l%TFA, MSD 1) =1.771 min.

Step 2: To a stirred solution of 2-chloro-4-fluorophenol (1 g, 6.82 mmoL) in DMF (15 mL) was added CS2CO3 (4.45 g, 13.65 mmoL) in one-portion at 20 °C. The reaction mixture was stirred at 20 °C for 0.5 h. Then 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.633 g, 6.82 mmoL) was added and heated up to 100 °C for 16 h. LCMS showed most of the starting material was consumed. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (10 ml x 2), the filtrate was diluted with water (200 ml) and ethyl acetate (100 ml), separated and the organic phase was washed by with brine (200 ml x 3), dried over anhydrous NaiSCri, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(2-chloro-4-fluorophenoxy)ethyl)carbamate (800 mg, 2.76 mmoL,

40.5 % yield). LCMS (M + H) = 312 & 314, Retention time (0.1% TFA): 1.639 min.

Step 3: To tert-butyl (2-(2-chloro-4-fluorophenoxy)ethyl)carbamate (0.4 g, 1.381 mmoL) in dioxane (5.00 ml, 20 mmoL) was added 4M HC1 at once. The reaction mixture was stirred at 15 °C for 12 h. LCMS showed reaction was completed. The solvent was removed in vacuo, the resulting solid was tritirated with ether (10 ml), filtered and washed with ether (10 ml) and dried to give 2-(2-chloro-4-fluorophenoxy)ethan-l-amine (250 mg, 1.318 mmoL, 96 % yield) as a white solid which was used in next step without further purification. LCMS (M+H) = 190&192, Retention time(0. l% TFA): 1.158 min.

Step 4: To a stirred mixture of 2-(2-chloro-4-fluorophenoxy)ethan-l -amine (31.5 mg, 0.166 mmoL), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5- (((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmoL), CS2CO3 (81 mg, 0.249 mmoL), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenyl-phosphine) (9.62 mg, 0.017 mmoL) and Pd2(dba)₃ (7.61 mg, 8.31 pmol) in toluene (3 mL) was placed under N2 atm (wac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. LCMS showed the reaction was completed. The reaction mixture was diluted with ethyl acetate (50 ml) and H2O (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 ml ^c 3). The combined organic layers were dried with NaiSOi and concentrated. The residue was purified by Prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00)) to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-4-fluorophenoxy)ethyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (40 mg, 0.062 mmoL, 75 % yield). LCMS: Retention time (10 M NH4HCO3) = 2.402 min, m/z (M+H) = 641 & 643.

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-4- fluorophenoxy)ethyl) amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (20 mg, 0.031 mmoL) in ethanol (5 mL) and ater (1 mL) was added NaOH (31.4 mg, 0.785 mmoL) at once. The resulting mixture was stirred at 90 °C for 16 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid, then concentrated under vacuum and purified by Prep-HPLC. (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-4- fhiorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (5.3 mg, 8.85 pmol, 28.4 % yield) as white solid. LCMS (M+H) = 598 & 600, Retention time (10 M NH4HCO3): 1.542 min. ¹H NMR (400 MHz, CDCb) d 8.28 (s, 1H), 8.24-8.23 (m, 1H), 7.22-7.12 (m, 2H), 7.12-7.06 (m, 1H), 7.01-6.88 (m, 2H), 6.00 (s, 1H), 4.42-4.41 (brs, 1H), 4.25-4.23 (m, 2H), 3.65-3.40 (m, 4H), 2.60 (s, 3H), 2.27-2.25 (brs, 2H), 1.60-1.59 (brs, 2H), 1.38-1.37 (brs, 2H), 1.22 (s, 9H), 0.85 (s, 6H).

Example 227

Step 1 : To a stirred solution of 2-chloro-4-fluorophenol (1 g, 6.82 mmoL) in DMF (15 mL) was added CS2CO3 (4.45 g, 13.65 mmoL) in one-portion at 20 °C. The reaction mixture was stirred at 20 °C for 0.5 h. Then 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.633 g, 6.82 mmoL) was added and heated at 100 °C for 16 h. LCMS showed most of the starting material was consumed. The reaction mixture was filtered and the filter cake was washed with ethyl acetate (10 ml x 2). The filtrate was diluted with water (200 ml) and ethyl acetate (100 ml), organic phase separated and washed by and brine (200 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert- butyl (2-(2-chloro-4-fluorophenoxy)ethyl)carbamate (800 mg, 2.76 mmoL, 40.5 % yield). LCMS (M + H) = 312 & 314, Retention time (0.1% TFA): 1.639 min.

Step 2: To a stirred solution of tert-butyl (2-(2-chloro-4- fluorophenoxy)ethyl)carbamate (400 mg, 1.381 mmoL) in DMF (5 mL) was added NaH (66.3 mg, 2.76 mmoL) in one-portion at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Then Mel (0.086 mL, 1.381 mmoL) was added and warmed to 25 °C and stirred for 0.5 h. LCMS showed reaction was completed. The reaction mixture was diluted with water (100 ml) and ethyl acetate (200 ml), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous NarSOi. filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(2-chloro-4-fluorophenoxy)ethyl)(methyl)carbamate (260 mg, 0.616 mmoL, 44.6 % yield) as a colorless oil. LCMS: Retention time (0.1% TFA): 1.725 min, m/z: (M+Na) = 326 & 328

Step 3: To a tert-butyl (2-(2-chloro-4-fhiorophenoxy)ethyl)(methyl)carbamate (0.26 g, 0.856 mmoL) in dioxane (5.0 ml, 20 mmoL) was added 4M HC1 at once. The reaction mixture was stirred at 15 °C for 12 h. LCMS showed reaction was completed. The solvent was removed in vaccuo, the resulting solid was triturated with ether (10 ml), filtered and the filter cake was washed with ether (10 ml), dried to give 2-(2-chloro-4-fluorophenoxy)-N- methylethan-l -amine (150 mg, 0.737 mmoL, 86 % yield) as a white solid. LCMS: Retention time (0.1% TFA): 1.180 min, m/z: (M+H) = 204 & 206.

Step 4: To a stirred mixture of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (50 mg, 0.083 mmoL) , 2-(2-chloro-4-fhiorophenoxy)-N-methylethan-l -amine (33.8 mg, 0.166 mmoL), cesium carbonate (81 mg, 0.249 mmoL), (9,9-dimethyl-9H- xanthene-4,5-diyl) bis(diphenylphosphine) (9.62 mg, 0.017 mmoL) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. LCMS showed the reaction was completed. The reaction mixture was diluted with ethyl acetate (50 ml) and H2O (20 ml). The organic layer separated and aqueous layer extracted with ethyl acetate (50 ml ^c 3). The combined organic layers were dried with Na2S04 and concentrated to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro- 4-fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (50 mg, 0.076 mmoL, 92 % yield) which was used in the next step without further purification.

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-4- fluorophenoxy)ethyl) (methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (50 mg, 0.076 mmoL) in ethanol (5 mL) and water (1 mL) was added NaOH (61 mg, 1.526 mmoL) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and concentrated. The crude product was purified by prep-HPLC (Instrument: Gilson 281 (PHG- 009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-4- fluorophenoxy)ethyl)(methyl) amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (12.9 mg, 0.020 mmoL, 26.3 % yield) as white solid. LCMS: Retention time (10 M NH4HCO3): 1.355 min, (M+H) = 613 & 615. Ή NMR (400 MHz, MeOD) d 8.28-8.27 (m, 1H), 8.14 (s, 1H), 7.43 (dd, J = 8.8, 3.1 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.20 (dd, J = 8.2, 2.9 Hz, 1H), 7.12-6.98 (m, 2H), 5.76 (s, 1H), 4.28 (t, J = 4.9 Hz, 2H), 3.96 (t, J = 4.9 Hz, 2H), 3.21-3.20 (m, 5H), 2.86-2.85 (brs, 2H), 2.66 (s, 3H), 1.42-1.41 (brs, 4H), 1.20 (s, 9H), 0.86 (s, 6H). Example 228

Step 1: To a stirred solution of 4-chloro-2-methylphenol (1 g, 7.01 mmoL) in DMF (15 mL) was added CS2CO3 (4.57 g, 14.02 mmoL) in one-portion . The reaction mixture was stirred at 20 °C for 0.5 h. Then2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.677 g, 7.01 mmoL) was added and heated up to 120 °C for 16 h. LCMS showed most of the starting material was consumed. The reaction mixture was diluted with water (100 ml) and ethyl acetate (200 ml), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to obtain tert- butyl (2-(4-chloro-2-methylphenoxy)ethyl)carbamate (0.6 g, 2.034 mmoL, 29.0 % yield) as a white solid. LCMS: Retention time (0.1% TFA): 1.716 min, m/z: (M+Na) = 308.

Step 2: To a stirred solution of tert-butyl (2-(4-chloro-2- methylphenoxy)ethyl)carbamate (300 mg, 1.050 mmoL) in DMF (10 mL) was added NaH (50.4 mg, 2.100 mmoL) in one-portion at 0 °C and stirred for 0.5 h. Then, Mel (0.066 mL, 1.050 mmoL) was added and warmed up to 25 °C and stirred for 0.5 h. LCMS showed reaction was completed . The reaction mixture was diluted with water (100 ml) and ethyl acetate (200 ml), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to give an yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert- butyl (2-(4-chloro-2-methylphenoxy)ethyl)(methyl)carbamate (180 mg, 0.481 mmoL, 45.8 % yield) as a colorless oil. LCMS: Retention time (0.1% TFA): l.745min, m/z: (M+H) = 300.

Step 3 : To a solution of tert-butyl (2-(4-chloro-2- methylphenoxy)ethyl)(methyl)carbamate (0.18 g, 0.600 mmoL) in DCM (6 mL) was added 2,2,2-trifluoroacetic acid (1 mL, 13.46 mmoL) at once. The reaction mixture was stirred at 15 °C for 12 h. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with DCM (50 ml), washed with water (50 ml x3), then organic layer was dried over Na2S04 and concentrated to afford a brown oil. The brown oil was purified by chromatography on silica gel eluting with pet. ether :EtOAc (10: 1) to afford the desired product 2-(4-chloro-2-methylphenoxy)-N-methylethanamine (110 mg, 0.551 mmoL, 92 % yield) as yellow solid. LCMS: Retention time (0.1% TFA) = 1.287 min, (M+H) = 200 & 202.

Step 4: To a stirred mixture of 2-(4-chloro-2-methylphenoxy)ethan-l -amine (30.9 mg, 0.166 mmoL), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5- (((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmoL), (9,9- dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmoL), Pd2(dba)3 (7.61 mg, 8.31 pmol) and CS2CO3 (81 mg, 0.249 mmoL) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. LCMS showed the reaction was completed. The reaction mixture was diluted with ethyl acetate (50 ml) and H2O (20 ml), organic layer separated and aqueous extracted with ethyl acetate (50 ml ^c 3). The combined organic layers were dried with Na2S04 and concentrated to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2-methylphenoxy)ethyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (48 mg, 0.075 mmoL, 91 % yield). The crude residue was used in the next step without further purification.

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2- methylphenoxy)ethyl) (methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (48 mg, 0.074 mmoL) in ethanol (5 mL) and water (1 mL) was added NaOH (59.0 mg, 1.474 mmoL) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2-methylphenoxy)ethyl)(methyl) amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (4.7 mg, 7.37 pmol, 9.99 % yield) as a light yellow solid. LCMS: Retention time (10 M NH4HCO3): 1.66 min, (M+H) = 609 & 611. ¾ NMR (400 MHz, CDC13) d 8.28-8.27 (m, 2H), 7.20 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 2.7 Hz, 1H), 7.09 (d, J = 9.0 Hz, 2H), 6.69 (d, J = 8.3 Hz, 1H),

6.00 (s, 1H), 4.16 (t, J = 5.2 Hz, 2H), 4.09- 3.92 (m, 1H), 3.88-3.87 (brs, 2H), 3.65-3.64 (brs, 1H), 3.49-3.25 (m, 1H), 3.16 (s, 3H), 2.60 (s, 3H), 2.27-2.26 (brs, 1H), 2.14 (s, 3H), 1.61- 1.60 (brs, 2H), 1.33-1.32 (brs, 2H), 1.24 (s, 9H), 0.84 (s, 6H). Example 229

Step 1: To a stirred solution of 2-chloro-4-methylphenol (1 g, 7.01 mmoL) in DMF (15 mL) was added CS2CO3 (4.57 g, 14.02 mmoL) in one-portion at 20 °C and stirred for 0.5 h. Then, 2-((tert-butoxycarbonyl)amino)ethyl methane sulfonate (1.677 g, 7.01 mmoL) was added and heated up to 100 °C for 16 h. LCMS showed most of the starting material was consumed. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (10 ml x 2), the filtrate was diluted with water (200 ml) and ethyl acetate (100). The organic layer separated, washed with brine (200 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel

chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(2-chloro-4- methylphenoxy)ethyl)carbamate (1.2 g, 3.55 mmoL, 50.6 % yield). LCMS: Retention time (0.1% TFA): l.682min, m/z: (M+H) = 308 & 310.

Step 2: To tert-butyl (2-(2-chloro-4-methylphenoxy)ethyl)carbamate (0.6 g, 2.100 mmoL) in dioxane (5.00 ml, 20 mmoL) was added 4M HC1 in dioxane at once. The reaction mixture was stirred at 15 °C for 12 h. LCMS showed reaction was completed. The solvent was removed in vacuo and the resulting solid was triturated with ether (10 ml) and filtered. The yellow solid was washed with ether (10 ml), dried and was used in the step, 2-(2-chloro- 4-methylphenoxy)ethan-l -amine (280 mg, 1.508 mmoL, 71.8 % yield), without LCMS (M+H) = 186 & 188, Retention time (0.1% TFA): 1.211 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmoL) in toluene (3 mL) was added 2-(2-chloro-4-methylphenoxy)ethan-l -amine (30.9 mg, 0.166 mmoL), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmoL), Pd₂(dba)₃ (7.61 mg, 8.31 pmol) and cesium carbonate (81 mg, 0.249 mmoL) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed reaction was completed. Then, the reaction mixture was diluted with ethyl acetate (50 ml) and H2O (20 ml) were added. The organic layer separated and aqueous layer was extracted with ethyl acetate (50 ml ^c 3). The combined organic layers were dried with NaiSOr and concentrated. The residue was purified by Prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00)) to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-4- methylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (20 mg, 0.028 mmoL, 33.3 % yield). LCMS: Retention time (10 M NH4HCO3) =l .98min, m/z (M+H) = 637 & 639.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-4- methylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (50 mg, 0.078 mmoL) in methanol (5 mL) and water (1.0 mL) was added NaOH (62.8 mg, 1.569 mmoL) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid, then concentrated under vacuum and purified by Prep-HPLC. (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-4- fluorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (5.3 mg, 8.85 pmol, 28.4 % yield) as white solid. LCMS (M+H) = 598 & 600, Retention time (10 M NH4HC03): 1.542 min. Ή NMR (400 MHz, CDC13) d 8.28 (s, 1H), 8.22-8.21 (m, 1H), 7.23-7.15 (m, 2H), 7.08 (dd, J = 8.3, 2.8 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.01 (s, 1H), 4.46-4.45 (brs, 1H), 4.25-4.24 (m, 2H), 3.63-3.62 (m, 3H), 3.37-3.36 (brs, 1H), 2.60 (s, 3H), 2.29-2.28 (m, 5H), 1.60-1.59 (brs, 2H), 1.35-1.34 (brs, 2H), 1.24 (s, 9H), 0.85 (s, 6H).

Example 230

Step 1 : To a stirred solution of 2-chloro-4-methylphenol (1 g, 7.01 mmoL) in DMF (15 mL) was added CS2CO3 (4.57 g, 14.02 mmoL) in one-portion at 20 °C and stirred for 0.5 h. Then, 2-((tert-butoxycarbonyl)amino)ethyl methane sulfonate (1.677 g, 7.01 mmoL) was added and heated at 100 °C for 16 h. LCMS showed most of the starting material was consumed. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (10 ml x 2), the filtrate was diluted with water (200 ml) and ethyl acetate (100). The organic layer separated and was washed with brine (200 ml x 3), dried over anhydrous NaiSOi. filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(2-chloro-4- methylphenoxy)ethyl)carbamate (1.2 g, 3.55 mmoL, 50.6 % yield). LCMS: Retention time (0.1% TFA): l .682min, m/z: (M+H) = 308 & 310.

Step 2: To a stirred solution of tert-butyl (2-(2-chloro-4- methylphenoxy)ethyl)carbamate (600 mg, 2.100 mmoL) in DMF (5 mL) was added NaH (101 mg, 4.20 mmoL) in one-portion at 0 °C and stirred for 0.5 h. Then, Mel (0.263 mL, 4.20 mmoL) was added and warmed up to 25 °C and stirred for 0.5 h. LCMS showed reaction was completed . The reaction mixture was diluted with water (100 ml) and ethyl acetate (200 ml), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous NaiSOi. filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(2-chloro-4- methylphenoxy)ethyl)(methyl)carbamate (300 mg, 0.635 mmoL, 30.2 % yield) as a colorless oil. LCMS: Retention time (0.1% TFA): l .77lmin, m/z: (M+H) = 322 & 324.

Step 3: To tert-butyl (2-(2-chloro-4-methylphenoxy)ethyl)(methyl)carbamate (0.3 g, 1.001 mmoL) in dioxane (5.00 ml, 20 mmoL) was added 4M HC1 in dioxane at once. The reaction mixture was stirred at 15 °C for 12 h. LCMS showed reaction was completed. The solvent was removed in vacuo and the resulting solid was triturated with ether (10 ml) and filtered. The filter cake was washed with ether (10 ml) and dried to obtain the desired product 2-(2-chloro-4-methylphenoxy)-N-methylethan-l -amine (190 mg, 0.952 mmoL, 95 % yield) as yellow solid. LCMS: Retention time (0.1% TFA) = 1.229 min, (M+H) = 200 & 202.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmoL) in toluene (3 mL) was added 2-(2-chloro-4-methylphenoxy)-N-methylethan-l-amine (33.2 mg, 0.166 mmoL), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmoL), Pd₂(dba)3 (7.61 mg, 8.31 pmol) and cesium carbonate (81 mg, 0.249 mmoL) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed reaction was completed. The reaction mixture was diluted with ethyl acetate (50 ml) and H2O (20 ml), organic layer separated and aqueous layer was extracted with ethyl acetate (50 ml ^c 3). The combined organic layers were dried with NaiSOr and concentrated. The residue was purified by Prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL

NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00)) to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-4- methylphenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (20 mg, 0.031 mmoL, 37.0 % yield) as a white solid. LCMS:

Retention time: 2.191 min (10 M NH4HC03), m/z [M+H] = 651 & 653.

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-4- methylphenoxy)ethyl) (methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (20 mg, 0.031 mmoL) in a methanol (5 mL) and water (1.0 mL) was added NaOH (24.56 mg, 0.614 mmoL) at once. The resulting mixture was stirred at 90 °C for 10 h. The pH was adjusted to about 7 with acetic acid and purified by prep-HPLC

(Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give the desired product (S)-2-(tert- butoxy)-2-(5-((2-(2-chloro-4-methylphenoxy)ethyl)(methyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (16.5 mg, 0.027 mmoL,

87 % yield) (4.7 mg, 7.37 pmol, 9.99 % yield) as a white solid. LCMS: Retention time (10 M NH4HCO3): 1.65 min, (M+H) = 609 & 611. ¾ NMR (400 MHz, CDC13) d 8.29 (s, 1H), 8.27-8.26 (m, 1H), 7.22- 7.13 (m, 3H), 6.98 (d, J = 6.6 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.98 (s, 1H), 4.20 (t, J = 5.2 Hz, 2H), 3.94-3.85 (m, 2H), 3.63-3.62 (brs, 2H), 3.20 (s, 3H), 2.60 (s, 3H), 2.27-2.26 (m, 5H), 1.61-1.60 (brs, 4H), 1.22 (s, 9H), 0.84 (s, 6H).

Example 231

Step 1 : To a stirred solution of 4-fluoro-2-methylphenol (1 g, 7.93 mmoL) in DMF (15 mL) was added CS2CO3 (5.17 g, 15.86 mmoL) in one-portion and stirred at 20 °C for 0.5 h. Then, 2-((tert-butoxycarbonyl)amino)ethyl methane sulfonate (1.898 g, 7.93 mmoL) was added and heated at 120 °C for 16 h. LCMS showed the reaction was completed . The reaction mixture was filtered and the filter cake was washed with ethyl acetate (10 ml x 2). The filtrate was diluted with water (200 ml) and ethyl acetate (100), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous NaiSOi. filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(4-fluoro-2- methylphenoxy)ethyl)carbamate (1.2 g, 3.60 mmoL, 45.4 % yield) as a white solid. LCMS: Retention time (0.1% TFA): 1.646 min, m/z: (M+H) = 292.

Step 2: To a stirred solution of tert-butyl (2-(4-fluoro-2-methylphenoxy)ethyl) carbamate (600 mg, 2.228 mmoL) in DMF (5 mL) was added NaH (107 mg, 4.46 mmoL) in one-portion at 0 °C and stirred for 0.5 h. Then, Mel (0.279 mL, 4.46 mmoL) was added and warmed to 25 °C and stirred for 0.5 h. LCMS showed reaction was completed . The reaction mixture was diluted with water (100 ml) and ethyl acetate (200 ml), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous NaiSOi. filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(4-fluoro-2- methylphenoxy)ethyl)(methyl)carbamate (430 mg, 0.817 mmoL, 36.7 % yield)as a colorless oil. LCMS: Retention time (0.1% TFA): 1.51 min, m/z: (M+H) = 306.

Step 3 : To a solution of tert-butyl (2-(4-fluoro-2- methylphenoxy)ethyl)(methyl)carbamate (0.43 g, 1.518 mmoL) in dioxane (5.00 ml, 20 mmoL) was added 4M HC1 in dioxane at once. The reaction mixture was stirred at 15 °C for 12 h. LCMS showed reaction was completed. The solvent was removed in vacuo, the resulting solid was triturated with ether (10 ml) and filtered. The filter cake was washed with ether (10 ml) and dried to obtain the desired product 2-(4-fluoro-2-methylphenoxy)-N- methylethan-l -amine (255 mg, 1.392 mmoL, 92 % yield) as a white solid. LCMS: Retention time (0.1% TFA) = 0.903 min, (M+H) = 184.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmoL) in toluene (3 mL) was added 2-(4-fluoro-2-methylphenoxy)-N-methylethan-l -amine (30.5 mg, 0.166 mmoL), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis (diphenylphosphane) (9.62 mg, 0.017 mmoL),Pd2(dba)3 (7.61 mg, 8.31 pmol) and cesium carbonate (81 mg, 0.249 mmoL) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed reaction was completed. The reaction mixture was diluted with (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 ml ^c 3). The combined organic layers were dried with NaiSOr and concentrated. The residue was purified by Prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00)) to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4-fluoro-2- methylphenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.032 mmoL, 37.9 % yield) as a yellow solid. LCMS: Retention time: 2.04 min (10 M NH4HC03), m/z [M+H] = 635.

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((2-(4-fluoro-2-methylphenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (20 mg, 0.032 mmoL) in methanol (5 mL) and water (1.0 mL) was added NaOH (25.2 mg, 0.630 mmoL) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40- 68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give the desired product (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4-fluoro-2- methylphenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (5.4 mg,

9.11 pmol, 28.9 % yield) as a white solid. LCMS: Retention time (10 M NH4HCO3): 1.35 min, (M+H) = 593. ¾ NMR (400 MHz, MeOD) d 8.27 (d, J = 2.9 Hz, 1H), 8.14 (s, 1H), 7.41 (dd, J = 8.8, 3.0 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H), 6.86 (dd, J = 11.9, 7.0 Hz, 3H), 5.76 (s, 1H), 4.21 (t, J = 4.9 Hz, 2H), 3.96 (d, J = 2.2 Hz, 2H), 3.19-3.18 (m, 5H), 2.82-2.81 (brs, 2H), 2.66 (s, 3H), 2.12 (s, 3H), 1.42-1.41 (brs, 4H), 1.20 (s, 9H), 0.87 (s, 6H).

Example 232

Step 1 : To a stirred solution of 4-fluoro-2-methylphenol (1 g, 7.93 mmoL) in DMF (15 mL) was added Cs2C03 (5.17 g, 15.86 mmoL) in one-portion. The reaction mixture was stirred at 20 °C for 0.5 h. Then 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.898 g, 7.93 mmoL) was added and heated at l20°C for 16 h. LCMS showed the reaction was completed . The reaction mixture was filtered and the filter cake was washed with ethyl acetate (10 ml x 2). The filtrate was diluted with water (200 ml) and ethyl acetate (100), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous NaiSOi. filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(4-fluoro-2- methylphenoxy)ethyl)carbamate (1.2 g, 3.60 mmoL, 45.4 % yield) as a white solid. LCMS: Retention time (0.1% TFA): 1.646 min, m/z: (M+H) = 292.

Step 2: To tert-butyl (2-(4-fluoro-2-methylphenoxy)ethyl)carbamate (0.6 g, 2.228 mmoL) in dioxane (5.00 ml, 20 mmoL) was added 4M HC1 at once. The reaction mixture was stirred at 15 °C for 12 h. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was triturated with ether (10 ml), filtered and washed with ether (10 ml) and dried to afford 2-(4-fluoro-2-methylphenoxy)ethan-l -amine (330 mg, 1.950 mmoL, 88 % yield, light yellow solid) which was used in the next step without further purification. LCMS (M+H) = 170, Retention time (0.1% TFA): 0.882 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmoL) in toluene (3 mL) was added 2-(4-fluoro-2-methylphenoxy)ethan-l -amine (28.1 mg, 0.166 mmoL), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmoL), Pd2(dba)3 (7.61 mg, 8.31 pmol) and cesium carbonate (81 mg, 0.249 mmoL) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed reaction was completed. The reaction mixture was diluted with ethyl acetate (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 ml ^c 3). The combined organic layers were dried with NaiSOi and concentrated. The residue was purified by Prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00)) to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4-fluoro-2- methylphenoxy)ethyl)amino) -6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.032 mmoL, 38.8 % yield) as a yellow solid. LCMS: Retention time (10 M NH4HCO3) = 1.89 min, m/z (M+H) = 621.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((2-(4-fluoro-2-methylphenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (40 mg, 0.064 mmoL) in methanol (5 mL) and water (1.0 mL) was added NaOH (51.5 mg, 1.289 mmoL) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid, then concentrated under vacuum and purified by Prep-HPLC. (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL

NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give the desired product (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5- ((2-(4-fluoro-2-methylphenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (13.5 mg, 0.023 mmoL, 36.1 % yield) as white solid. LCMS (M+H) = 579, Retention time (10 M NH4HC03): 1.55 min. Ή NMR (400 MHz, CDC13) d 8.27 (s, 1H), 8.22-8.21 (m, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.4, 2.7 Hz, 1H), 6.85 (ddd, J = 11.3, 8.6, 4.5 Hz, 2H), 6.77 (dd, J = 8.8, 4.6 Hz, 1H), 5.99 (s, 1H), 4.28-4.27 (brs, 1H), 4.18 (t, J = 5.0 Hz, 2H), 3.64-3.63 (m, 3H), 3.32-3.31 (brs, 1H), 2.59 (s, 3H), 2.27-2.26 (brs, 1H), 2.24 (s, 3H), 1.49 (d, J = 92.6 Hz, 4H), 1.22 (s, 9H), 0.86 (s, 6H).

Example 233

Step 1 : To a stirred solution of 3,5-difluorophenol (1 g, 7.69 mmoL) in DMF (30 ml) was added Cs2C03 (4.57 g, 14.02 mmoL) in one-portion . The reaction mixture was stirred at 20 °C for 0.5 h. Then 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.677 g, 7.01 mmoL) was added and heated at 100 °C for 16 h. LCMS showed most of the starting material was consumed. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (10 ml x 2). The filtrate was diluted with water (200 ml) and ethyl acetate (100), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous NaiSCL, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(3, 5- difluorophenoxy)ethyl)carbamate (1.4 g, 2.88 mmoL, 41.0 % yield) as a yellow oil. LCMS: Retention time (0.1% TFA): 1.945 min, m/z: (M+Na) = 296. Step 2: To tert-butyl (2-(3, 5-difluorophenoxy)ethyl)carbamate (0.6 g, 2.196 mmoL) added 4M HC1 in dioxane (5.00 ml, 20 mmoL) at once. The reaction mixture was stirred at 15 °C for 12 h. LCMS showed reaction was completed. The solvent was removed in vacuo and the resulting solid was triturated with ether (10 ml), filtered and washed with ether (10 ml) and dried to afford 2-(3, 5-difluorophenoxy)ethan-l-amine (300 mg, 1.373 mmoL,

62.5 % yield) as a white solid which was used in the next step without further purification. LCMS (M+H) = 174, Retention time (0.1% TFA): 0.763 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmoL) in toluene (3 mL) was added 2-(3,5-difluorophenoxy)ethan-l-amine (28.8 mg, 0.166 mmoL), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmoL), Pd₂(dba)3 (7.61 mg, 8.31 pmol) and cesium carbonate (81 mg, 0.249 mmoL) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed reaction was completed. The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 ml 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by Prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40- 68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00)) to give isopropyl (S)-2-(tert- butoxy)-2-(5-((2-(3,5-difhiorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetate (30 mg, 0.041 mmoL, 49.9 % yield) as a white solid. LCMS: Retention time (10 M NH4HCO3) = 2.353 min, m/z (M+H) = 625.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(3,5- difluorophenoxy)ethyl) amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (30 mg, 0.048 mmoL) in methanol (5 mL) and water (1.0 mL) was added NaOH (38.4 mg, 0.960 mmoL) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid, then concentrated under vacuum and purified by Prep-HPLC. (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(3,5- difluorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (16.4 mg, 0.028 mmoL, 58.6 % yield) as white solid. LCMS (M+H) = 583, Retention time (10 M NH4HC03): 1.547 min. Tf NMR ^OO MHz, MeOD) d 8.18- 8.11 (m, 2H), 7.33- 7.22 (m, 2H), 6.61 (dt, J = 6.2, 3.1 Hz, 2H), 6.54 (tt, J = 9.2, 2.2 Hz, 1H), 5.77 (s, 1H), 4.22 (t, J = 5.1 Hz, 2H), 3.64 (t, J = 5.2 Hz, 2H), 3.15-3.14 (brs, 2H), 2.82-2.81 (brs, 2H), 2.66 (s, 3H), 1.44-1.42 (brs, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 234

Step 1 : To a stirred solution oftert-butyl (2-(3,5-difluorophenoxy)ethyl)carbamate (600 mg, 2.196 mmoL) in DMF (5 mL) was added NaH (105 mg, 4.39 mmoL) in one-portion at 0 °C and stirred for 0.5 h. Then Mel (0.275 mL, 4.39 mmoL) was added and warm up to 25 °C and stirred for 0.5 h. TLC (pet. etherEtOAc = 2: 1) showed reaction was completed . The reaction mixture was diluted with water (100 ml) and ethyl acetate (200 ml), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(3,5- difluorophenoxy)ethyl) (methyl)carbamate (540 mg, 1.709 mmoL, 78 % yield) as yellow oil. LCMS: Retention time (0.1% TFA): 1.47 min, m/z: (M+Na) = 310.

Step 2: To tert-butyl (2-(3, 5-difluorophenoxy)ethyl)(methyl)carbamate (0.54 g, 1.880 mmoL) was added HC1 (5.00 ml, 20 mmoL) at once. The reaction mixture was stirred at 15 °C for 12 h. LCMS showed reaction was completed. The solvent was removed in vacuo and the resulting solid was triturated with ether (10 ml), filtered and the filter cake was washed with ether (10 ml) and dried to give the desired 2-(3, 5-difluorophenoxy)-N- methylethan-l -amine (310 mg, 1.568 mmoL, 83 % yield) as a white solid. LCMS: Retention time (0.1% TFA) = 0.886 min, (M+H) = 188.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmoL) in toluene (3 mL) was added 2-(3,5-difhiorophenoxy)-N-methylethan-l-amine (31.1 mg, 0.166 mmoL), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmoL), Pd₂(dba)3 (7.61 mg, 8.31 pmol) and cesium carbonate (81 mg, 0.249 mmoL) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed reaction was completed. The reaction mixture was diluted with (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 ml 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by Prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40- 68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00)) to give isopropyl (S)-2-(tert- butoxy)-2-(5-((2-(3,5-difluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)- 6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (37 mg, 0.058 mmoL, 69.7 % yield) as a white solid. LCMS: Retention time: 2.516 min (10 M NH4HC03), m/z [M+H] = 639.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(3,5- difluorophenoxy)ethyl) (methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (37 mg, 0.058 mmoL) in methanol (5 mL) and water (1.0 mL) was added NaOH (46.3 mg, 1.158 mmoL) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B:

MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(3,5-difluorophenoxy)ethyl)(methyl) amino)- 4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (28.4 mg, 0.048 mmoL, 82 % yield) as a white solid. LCMS: Retention time (10 M NH4HCO3): 1.578 min, (M+H) = 597. ¾ NMR (400 MHz, MeOD) d 8.24 (d, J = 2.8 Hz, 1H), 8.16 (s, 1H), 7.40 (dd, J = 8.8, 3.0 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 6.58-6.48 (m, 3H), 5.78 (s, 1H), 4.25 (t, J = 5.1 Hz, 2H), 3.92 (t, J = 5.1 Hz, 2H), 3.16-3.15 (brs, 5H), 2.82-2.81 (brs, 2H), 2.66 (s, 3H), 1.40- 1.39 (brs, 4H), 1.21 (s, 9H), 0.89 (s, 6H).

Example 235

Step 1 : To a stirred solution of 4-chloro-2-methylphenol (1 g, 7.01 mmoL) in DMF (30 ml) was added Cs2C03 (4.57 g, 14.02 mmoL) in one-portion. The reaction mixture was stirred at 20 °C for 0.5 h. Then 2-((tert-butoxycarbonyl) amino)ethyl methane sulfonate (1.677 g, 7.01 mmoL) was added and heated at 100 °C for 16 h. TLC showed most of the starting material was consumed. The reaction mixture was filtered and the filter cake was washed with ethyl acetate (10 ml x 2). The filtrate was diluted with water (200 ml) and ethyl acetate (100), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous NaiSCL, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(4- chloro-2-methylphenoxy)ethyl)carbamate (1.1 g, 2.88 mmoL, 41.1 % yield) as a white solid. LCMS: Retention time (0.1% TFA): 1.39 min, m/z: (M+H) = 286 & 288.

Step 2: To tert-butyl (2-(4-chloro-2-methylphenoxy)ethyl)carbamate (0.48 g, 1.680 mmoL) was added 4M HC1 in dioxane (5.00 ml, 20 mmoL) at once. The reaction mixture was stirred at 15 °C for 12 h. TLC showed most of the starting material was consumed. The solvent was removed in vacuo and the resulting solid was triturated with ether (10 ml) and filtered. The solid was washed with ether (10 ml) and dried to give. 2-(2-chloro-4- methylphenoxy)ethan-l -amine (280 mg, 1.508 mmoL, 71.8 % yield) as a white solid which used in the next step without further purification. LCMS (M+H) = 186 & 188, Retention time (0.1% TFA): 1.022 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmoL) in toluene (3 mL) was added 2-(4-chloro-2-methylphenoxy)ethan-l -amine (30.9 mg, 0.166 mmoL), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmoL), Pd₂(dba)3 (7.61 mg, 8.31 pmol) and cesium carbonate (81 mg, 0.249 mmoL) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed reaction was completed. The reaction mixture was diluted with ethyl acetate (50 ml) and H20 (20 ml). Organic layer separated and aqueous layer extracted with ethyl acetate (50 ml ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by Prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00)) to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2-methylphenoxy)ethyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.039 mmoL, 47.2 % yield) as a white solid. LCMS: Retention time (10 M NH4HCO3) =2.639 min, m/z (M+H) = 638.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2- methylphenoxy)ethyl) amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (25 mg, 0.039 mmoL) in methanol (5 mL) and water (1.0 mL) was added NaOH (31.4 mg, 0.785 mmoL) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid, then concentrated under vacuum and purified by Prep-HPLC. (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2- methylphenoxy)ethyl)amino) -4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (14.7 mg, 0.025 mmoL, 62.9 % yield) as white solid. LCMS (M+H) = 595 & 597, Retention time (10 M NH4HC03): 1.708 min. Ή NMR (400 MHz, MeOD) d 8.15 (t, J = 1.7 Hz, 1H), 8.14 (s, 1H), 7.27 (d, J = 1.7 Hz, 2H), 7.15-7.10 (m, 2H), 6.93-6.88 (m, 1H), 5.76 (s, 1H), 4.20 (t, J = 5.2 Hz, 2H), 3.67 (dd, J = 5.4, 3.8 Hz, 2H), 3.15-3.14 (brs, 2H), 2.83- 2.82 (brs, 2H), 2.66 (s, 3H), 2.19 (s, 3H), 1.44-1.42 (brs, 4H), 1.20 (s, 9H), 0.89 (s, 6H).

Example 236

Step 1 : To a solution of 3-fluoro-4-methylphenol (l .Og, 7.93 mmol) in DMF (15 mL) was added Cs2C03 (5.17 g, 15.86 mmol) at 20 °C. The mixture was stirred for 15 minutes and 2-((tert-butoxycarbonyl)amino)ethyl methane sulfonate (1.897 g, 7.93 mmol) was added at once. The mixture was stirred at 100 °C for 16 h, cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over Na2SC>4, and the solvent was removed in vacuo to give the crude product as an oil which was purified by reversed phase column chromatography (Cl 8 ODS, using 80 g; Mobile Phase A: Water (10 mmoL NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(3-fluoro-4- methylphenoxy)ethyl)carbamate (1.0 g, 3.51 mmol, 44.3 % yield) as a yellow oil. LCMS (M + Na) = 292.1; Retention time (0.0l%TFA) =1.655 min.

Step 2: To a solution oftert-butyl (2-(3-fluoro-4-methylphenoxy)ethyl)carbamate (0.5 g, 1.857 mmol) in DMF (10 mL) was added NaH (0.089 g, 3.71 mmol) at 0 °C and stirred for 30 minutes. Then iodomethane (0.232 mL, 3.71 mmol) was added at once and stirred at 20 °C for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over NaiSCL, and the solvent was removed in vacuo to give tert-butyl (2-(3-fluoro-4- methylphenoxy)ethyl)(methyl)carbamate (0.5 g, 1.706 mmol, 92 % yield) as a pale yellow oil. LCMS (M + H) = 306.1; Retention time (0.0l%TFA) =1.733 min.

Step 3: To a 4M HC1 dioxan (8 mL,) was added tert-butyl (2-(3-fluoro-4- methylphenoxy)ethyl)(methyl)carbamate (0.6 g, 2.118 mmol) at once. The reaction mixture was stirred at 20 °C for 12 h. Then the mixture was filtered to give 2-(3-fluoro-4- methylphenoxy)-N-methylethanamine hydrochloride (0.369 g, 1.388 mmol, 65.6 % yield) as a white solid. LCMS (M + H) = 184.2; Retention time (10 mmoL NH4HCO3) = 1.379 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), 2-(3-fluoro-4-methylphenoxy)-N-methylethan-l- amine hydrochloride (36.5 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)₃ (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over NarSCL, and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 70-75%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-((2-(3-fluoro-4-methylphenoxy)ethyl)(methyl)amino)-6'-methyl- [2,3'-bipyridin]-5'-yl)acetate (30 mg, 0.047 mmol, 56.1 % yield) as yellow oil. LCMS (M +

H) = 635.2; Retention time (10 mmoL NH4HCO3) =2.061 min.

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((2-(3-fluoro-4-methylphenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (30 mg, 0.047 mmol) in ethanol (5 mL) was added sodium hydroxide (37.8 mg, 0.945 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 52-55% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(3-fluoro-4- methylphenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (25.6 mg, 0.043 mmol, 91 % yield) as white solid. LCMS (M + H) = 593.1; Retention time (10 mmoL NH4HCO3) =1.612 min. Ή NMR (400 MHz, MeOD): d 8.24 (d, J= 2.9 Hz, 1H), 8.16 (s, 1H), 7.41-7.38 (m, 1H), 7.34 (d, J= 8.7 Hz, 1H), 7.10 (t, J= 8.5 Hz, 1H), 6.65-6.59 (m, 2H), 5.77 (s, 1H), 4.21 (t, J= 5.1 Hz, 2H), 3.90 (t, J= 5.0 Hz, 2H), 3.52-3.47 (m, 1H), 3.16-3.15 (m, 4H), 2.83-2.68 (m, 2H), 2.66 (s, 3H), 2.18 (s, 3H), 1.49-1.36 (m, 4H), 1.20 (s, 9H), 0.88 (s, 6H).

Example 237

Step 1 : To a solution of 3-fluoro-4-methylphenol (l .Og, 7.93 mmol) in DMF (15 mL) was added Cs2C03 (5.17 g, 15.86 mmol) and the mixture was stirred at 20 °C for 15 minutes. Then 2-((tert-butoxycarbonyl)amino)ethyl methane sulfonate (1.897 g, 7.93 mmol) was added at once and stirred at 100 °C for 16 h. Then the mixture was cooled and diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over NaiSCL, and the solvent was removed in vacuo to give crude product as an oil which was purified by reversed phase column chromatography (C18 ODS, using 80 g; Mobile Phase A: Water (10 mmoL NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(3- fluoro-4-methylphenoxy)ethyl)carbamate (1.0 g, 3.51 mmol, 44.3 % yield) as a yellow oil. LCMS (M +Na) = 292.1; Retention time (0.0l%TFA) =1.655 min.

Step 2: To a 4M HC1 in dioxane (8 mL) was added tert-butyl (2-(3-fluoro-4- methylphenoxy)ethyl)carbamate (0.5 g, 1.857 mmol) at once. The reaction mixture was stirred at 20 °C for 12 h and filtered to give 2-(3-fluoro-4-methylphenoxy)ethanamine hydrochloride (0.419 g, 1.428 mmol, 77 % yield) as a white solid. LCMS (M + H) = 170.1; Retention time (10 mmoL NH4HCO3) =1.358 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), 2-(3-fluoro-4-methylphenoxy)ethan-l -amine hydrochloride (34.2 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over NarSCL, and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 62-65%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-((2-(3-fluoro-4-methylphenoxy)ethyl)amino)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (30 mg, 0.015 mmol, 18.35 % yield) as yellow oil. LCMS (M + H) = 621.3; Retention time (10 mmoL NH4HCO3) =1.919 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((2-(3-fhioro-4-methylphenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (30 mg, 0.048 mmol) in ethanol (5 mL) was added sodium hydroxide (38.7 mg, 0.966 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep- HPLC {Instrument Gilson 281 (PHG-009) ; Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 40-44% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2- (tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(3-fluoro-4- methylphenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (6 mg, 10.30 pmol, 21.32 % yield) as white solid. LCMS (M + H) = 579.3; Retention time (10 mmoL NH4HCO3) =1.313 min. ¾ NMR (400 MHz, MeOD): d 8.15-8.13 (m, 2H), 7.28-7.22 (m, 2H), 7.12 (t, J = 8.9 Hz, 1H), 6.74-6.66 (m, 2H), 5.76 (s, 1H), 4.18 (t, J= 5.2 Hz, 2H), 3.61 (t, J= 5.2 Hz, 2H), 3.24-2.92 (m, 2H), 2.84-2.73 (m, 2H), 2.66 (s, 3H), 2.19 (s, 3H), 1.54-1.38 (m, 4H), 1.20 (s, 9H), 0.90 (s, 6H). Example 238

Step 1 : To a solution of 2,4-difluorophenol (1.0 g, 7.69 mmol) in DMF (15 mL) was added Cs2C03 (5.01 g, 15.37 mmol) at 20 °C and stirred for 15 minutes. Then 2-((tert- butoxycarbonyl)amino)ethyl methanesulfonate (1.839 g, 7.69 mmol) was added at once and stirred at 100 °C for 16 h. Then the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over Na2SC>4, and the solvent was removed in vacuo to give crude product as an oil which was purified by reversed phase column chromatography (Cl 8 ODS, using 80 g; Mobile Phase A: Water (10 mmoL NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(2,4- difluorophenoxy)ethyl)carbamate (0.25 g, 0.915 mmol, 11.90 % yield) as a yellow oil. LCMS (M + Na) = 296.1; Retention time (0.0l%TFA) =1.600 min.

Step 2: To a 4M HC1 in dioxane (8 mL) was added tert-butyl (2-(2,4- difluorophenoxy)ethyl)carbamate (0.25 g, 0.915 mmol) at once. The reaction mixture was stirred at 20 °C for 12 h and filtered to give 2-(2,4-difluorophenoxy)ethan-l -amine hydrochloride (0.15 g, 0.716 mmol, 55.9 % yield) as a white solid. LCMS (M + H) = 174.1; Retention time (0.0l%TFA) =0.726 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), 2-(2,4-difluorophenoxy)ethan- 1 -amine hydrochloride (34.8 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over NarSOi. and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL

NH4HCO3); B: MeCN; Gradient 58-65% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,4-difluorophenoxy)ethyl)amino)-4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (30 mg, 0.048 mmol, 57.8 % yield) as a yellow oil. LCMS (M + H) = 625.1; Retention time (10 mmoL NH4HCO3) =1.810 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,4- difluorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (30 mg, 0.048 mmol) in ethanol (5 mL) was added sodium hydroxide (38.4 mg, 0.960 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument Gilson 281 (PHG-009) ; Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 40-60% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2,4-difluorophenoxy)ethyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (5.6 mg, 9.61 pmol,

20.01 % yield) as a white solid. LCMS (M + H) = 583.2; Retention time (10 mmoL

NH4HCO3) =1.506 min. Ή NMR (400 MHz, MeOD): d 8.14-8.13 (m, 2H), 7.28 (d, J= 1.3 Hz, 2H), 7.17-7.12 (m, 1H), 7.02-6.97 (m, 1H), 6.91-6.86 (m, 1H), 5.76 (s, 1H), 4.25 (t, J = 5.2 Hz, 2H), 3.65 (t, J= 5.2 Hz, 2H), 3.22-3.09 (m, 2H), 2.83-2.74 (m, 2H), 2.66 (s, 3H), 1.48-1.32 (m, 4H), 1.20 (s, 9H), 0.90 (s, 6H).

Example 239

Step 1 : To a solution of 2,4-difluorophenol (1.0 g, 7.69 mmol) in DMF (15 mL) was added Cs2C03 (5.01 g, 15.37 mmol) at 20 °C and stirred at 20 °C for 15 minutes. Then 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.839 g, 7.69 mmol) was added at once and stirred at 100 °C for 16 h. Then the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give crude product as an oil which was purified by reversed phase column chromatography (Cl 8 ODS, using 80 g; Mobile Phase A: Water (10 mmoL NLLHCCh), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(2,4- difluorophenoxy)ethyl)carbamate (0.25 g, 0.915 mmol, 11.90 % yield) as a yellow oil. LCMS (M +Na) = 296.1; Retention time (10 mmoL NLLHCCb) = 1.511 min.

Step 2: To a solution of tert-butyl (2-(2,4-difluorophenoxy)ethyl)carbamate (0.25 g, 0.915 mmol) in DMF (10 mL) was added NaH (0.044 g, 1.830 mmol) at 0 °C and stirred for 30 minutes. Then iodomethane (0.114 mL, 1.830 mmol) was added at once and stirred at 20 °C for 3 h. The reation mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over NaiSCL, and the solvent was removed in vacuo to give tert-butyl (2-(2,4- difluorophenoxy)ethyl)(methyl)carbamate (0.296 g, 0.844 mmol, 92 % yield) as a brown oil. LCMS (M +Na) = 310.2; Retention time (0.1% TFA) = 1.679 min.

Step 3 : To a 4M HC1 in dioxane (8 mL) was added tert-butyl (2-(2,4- difluorophenoxy)ethyl)(methyl)carbamate (0.296 g, 1.030 mmol) at once. The reaction mixture was stirred at 20 °C for 12 h and filtered to give 2-(2,4-difluorophenoxy)-N- methylethan-l -amine hydrochloride (0.15 g, 0.671 mmol, 65.1 % yield) as a white solid. LCMS (M +H) = 188.1; Retention time (10 mmoL NFLHCCh) = 1.271 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), CS2CO3 (81 mg, 0.249 mmol), 2-(2,4-difluorophenoxy)-N-methylethan-l -amine hydrochloride (37.2 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over Na2S0₄, and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 60-70% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,4- difluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (30 mg, 0.033 mmol, 39.5 % yield) as a yellow oil. LCMS (M + H) = 639.1; Retention time (10 mmoL NH4HCO3) =1.925 min.

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,4- difluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (30 mg, 0.047 mmol) in ethanol (5 mL) was added sodium hydroxide (37.6 mg, 0.939 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B:

MeCN; Gradient 40-55% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2,4-difhiorophenoxy)ethyl)(methyl)amino)- 4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (10.8 mg, 0.018 mmol, 38.5 % yield) as a white solid. LCMS (M + H) = 598.3; Retention time (10 mmoL NH4HCO3) = 1.311 min. ¾ NMR (400 MHz, MeOD): d 8.24 (d, J= 2.8 Hz, 1H), 8.15 (s, 1H), 7.41 (dd, J= 8.8, 3.0 Hz, 1H), 7.33 (d, J= 8.8 Hz, 1H), 7.09 (td, J= 9.3, 5.3 Hz, 1H), 7.00-6.94 (m, 1H), 6.89-6.84 (m, 1H), 5.76 (s, 1H), 4.28 (t, J= 5.0 Hz, 2H), 3.95-3.91 (m, 2H), 3.18 (s, 3H), 3.15-3.05 (m, 2H), 2.88-2.74 (m, 2H), 2.66 (s, 3H), 1.48-1.36 (m, 4H), 1.20 (s, 9H), 0.87 (s, 6H).

Example 240

Step 1 : To a solution of p-cresol (1.0 g, 9.25 mmol) in DMF (15 mL) was added Cs2C03 (6.03 g, 18.49 mmol) and the mixture was stirred at 20 °C for 15 minutes. Then 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (2.213 g, 9.25 mmol) was added at once and the mixture was stirred at 100 °C for 16 h. Then the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over NaiSCL, and the solvent was removed in vacuo to give crude product as an oil which was purified by reversed phase column chromatography (C18 ODS, using 80 g; Mobile Phase A: Water (10 mmoL NH₄HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(p- tolyloxy)ethyl)carbamate (0.97 g, 3.86 mmol, 41.7 % yield) as a yellow oil. LCMS (M + Na) = 274.1; Retention time (10 mmoL NH4HCO3) = 1.831 min.

Step 2: To a solution of tert-butyl (2-(p-tolyloxy)ethyl)carbamate (0.47 g, 1.870 mmol) in DCM (6 mL) was added 2,2,2-trifluoroacetic acid (2 mL, 1.870 mmol) at once and stirred at 20 °C for 12 h. The solvent was removed in vacuo, the solid was diluted with DCM (50 ml), washed with saturated NaiCCb (50 ml x2) and water (50 ml x2). The organic layer was dried over Na2SC>4 and concentrated to afford the desired product 2-(p- tolyloxy)ethanamine (0.2 g, 1.079 mmol, 57.7 % yield) as a yellow oil. LCMS (M + H) = 152.1; Retention time (10 mmoL NTLHCCh) = 1.137 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), CS2CO3 (81 mg, 0.249 mmol), 2-(p-tolyloxy)ethan- 1 -amine hydrochloride (31.2 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4, and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument Gilson 28 (PHG-009) ; Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 65-68% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-((2-(p- tolyloxy)ethyl)amino)-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.033 mmol, 39.3 % yield) as a yellow oil. LCMS (M + H) = 603.1; Retention time (10 mmoL NH4HCO3) = 1.911 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-((2-(p-tolyloxy)ethyl)amino)-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.033 mmol) in ethanol (5 mL) was added sodium hydroxide (26.5 mg, 0.664 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument Gilson 281 (PHG-009) ; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 50-60% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert- butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-((2-(p-tolyloxy)ethyl)amino)-[2,3'- bipyridin]-5'-yl)acetic acid (16.7 mg, 0.030 mmol, 90 % yield) as a white solid. LCMS (M + H) = 561.2; Retention time (10 mmoL NH4HCO3) = 1.548 min. Ή NMR (400 MHz, MeOD): d 8.14 (s, 2H), 7.27 (s, 2H), 7.09 (d, J= 8.4 Hz, 2H), 6.85 (d, J= 8.5 Hz, 2H), 5.76 (s, 1H), 4.17 (t, J= 5.3 Hz, 2H), 3.61 (t, J= 5.2 Hz, 2H), 3.20-3.12-3.10 (m, 2H), 2.85-2.73 (m, 2H), 2.66 (s, 3H), 2.28 (s, 3H), 1.48-1.40 (m, 4H), 1.20 (s, 9H), 0.90 (s, 6H).

Example 241

Step 1 : To a solution oftert-butyl (2-(p-tolyloxy)ethyl)carbamate (0.47 g, 1.870 mmol) in DMF (10 mL) was added NaH (0.090 g, 3.74 mmol) and the mixture was stirred at 0 °C for 30 minutes. Then iodomethane (0.140 mL, 2.244 mmol) was added at once and the mixture was stirred at 20 °C for 3 h. Then diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over NaiSCh, and the solvent was removed in vacuo to give tert-butyl methyl(2-(p- tolyloxy)ethyl)carbamate (0.42 g, 1.583 mmol, 85 % yield) as a pale yellow oil. LCMS (M - 55) = 210.1; Retention time (10 mmoL NH4HCO3) = 1.651 min.

Step 2: To a 4M HC1 in dioxane (8 mL) was added tert-butyl methyl(2-(p- tolyloxy)ethyl)carbamate (0.42 g, 1.583 mmol) at once. The reaction mixture was stirred at 20 °C for 12 h and filtered to give N-methyl-2-(p-tolyloxy)ethanamine hydrochloride (0.309 g, 1.087 mmol, 68.7 % yield) as a white solid. LCMS (M + H) = 166.2; Retention time (10 mmoL NHiHCCh) = 1.315 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), N-methyl-2-(p-tolyloxy)ethan-l-amine hydrochloride (33.5 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL

NH4HCO3); B: MeCN; Gradient 70-75% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5- (methyl(2-(p-tolyloxy)ethyl)amino)-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.032 mmol,

39.0 % yield) as a yellow oil. LCMS (M + H) = 617.1; Retention time (10 mmoL NH4HCO3) = 2.080 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(methyl(2-(p-tolyloxy)ethyl)amino)-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.032 mmol) in ethanol (5 mL) was added sodium hydroxide (25.9 mg, 0.648 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 55-60% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert- butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(methyl(2-(p-tolyloxy)ethyl)amino)- [2,3'-bipyridin]-5'-yl)acetic acid (16.2 mg, 0.028 mmol, 87 % yield) as a white solid. LCMS (M + H) = 575.2; Retention time (10 mmoL NH4HCO3) =1.602 min. Ή NMR (400 MHz, MeOD): d 8.24 (d, J= 2.8 Hz, 1H), 8.16 (s, 1H), 7.39 (dd, J= 8.8, 3.0 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H), 7.06 (d, J= 8.3 Hz, 2H), 6.78 (d, J= 8.6 Hz, 2H), 5.77 (s, 1H), 4.20 (t, J= 5.2 Hz, 2H), 3.90-3.87 (m, 2H), 3.16 (s, 3H), 3.11-2.99 (m, 2H), 2.87-2.76 (m, 2H), 2.66 (s, 3H), 2.26 (s, 3H), 1.46-1.40 (m, 4H), 1.21 (s, 9H), 0.88 (s, 6H).

Example 242

Step 1 : To a solution of 2,6-dimethylphenol (1.0 g, 8.19 mmol) in DMF (15 mL) was added Cs2C03 (5.33 g, 16.37 mmol) and the mixture was stirred at 20 °C for 15 minutes. Then 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.959 g, 8.19 mmol) was added at once and the mixture was stirred at 100 °C for 16 h. Then the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over NaiSCL, and the solvent was removed in vacuo to give crude product as an oil which was purified by reversed phase column chromatography (C18 ODS, using 80 g; Mobile Phase A: Water (10 mmoL NH₄HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2- (2,6-dimethylphenoxy)ethyl)carbamate (1.06 g, 3.62 mmol, 44.2 % yield) as a yellow oil. LCMS (M + Na) = 288.1; Retention time (10 mmoL NH4HCO3) = 1.897 min.

Step 2: To a solution of tert-butyl (2-(2,6-dimethylphenoxy)ethyl)carbamate (0.5 g, 1.884 mmol) in DCM (6 mL) was added 2,2,2-trifluoroacetic acid (2 mL, 1.870 mmol) at once and stirred at 20 °C for 12 h. Then, the solvent was removed in vacuo and the solid was dissolved DCM (50 ml), washed with saturated NarCCb a.q. (50 ml x2) and water (50 ml x2). The organic layer was dried over NarSCL and concentrated to afford the desired product 2- (2,6-dimethylphenoxy)ethanamine (0.26 g, 1.370 mmol, 72.7 % yield) as a yellow oil. LCMS (M + H) = 166.2; Retention time (0.0l%TFA) = 1.178 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), 2-(2,6-dimethylphenoxy)ethan-l -amine hydrochloride (33.5 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over NarSCL, and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL

NH4HCO3); B: MeCN; Gradient 70-75% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,6-dimethylphenoxy)ethyl)amino)-4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.032 mmol,

39.0 % yield) as a yellow oil. LCMS (M + H) = 617.1; Retention time (10 mmoL NH4HCO3) = 1.988 min. Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,6- dimethylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (20 mg, 0.032 mmol) in ethanol (5 mL) was added sodium hydroxide (25.9 mg, 0.648 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument Gilson 281 (PHG-009) ; Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 55-60% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2,6-dimethylphenoxy)ethyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (14.7 mg, 0.025 mmol,

77 % yield) as a white solid. LCMS (M + H) = 575.2; Retention time (10 mmoL NH4HCO3)

= 1.569 min. ¾ NMR (400 MHz, MeOD): d 8.18-8.15 (m, 2H), 7.32-7.29 (m, 2H), 6.99 (d, J = 7.5 Hz, 2H), 6.93-6.88 (m, 1H), 5.76 (s, 1H), 3.99 (t, J= 5.2 Hz, 2H), 3.73-3.60 (m, 3H), 3.17-3.15-3.13 (m, 1H), 2.84-2.75 (m, 2H), 2.66 (s, 3H), 2.25-2.24 (m, 6H), 1.47-1.40 (m, 4H), 1.20 (s, 9H), 0.87 (s, 6H).

Example 243

Step 1 : To a solution oftert-butyl (2-(2,6-dimethylphenoxy)ethyl)carbamate (0.5 g, 1.884 mmol) in DMF (10 mL) was added NaH (0.090 g, 3.77 mmol) at 0 °C and the mixture was stirred for 30 minutes. Then iodomethane (0.177 mL, 2.83 mmol) was added at once and stirred at 20 °C for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4, and the solvent was removed in vacuo to give tert-butyl (2-(2,6- dimethylphenoxy)ethyl)(methyl)carbamate (0.66 g, 1.740 mmol, 92 % yield) as a pale yellow oil. LCMS (M + Na) = 302.2; Retention time (0.0l%TFA) = 1.772 min.

Step 2: To a 4M HC1 in dioxane (8 mL) was added tert-butyl (2-(2,6- dimethylphenoxy)ethyl)(methyl)carbamate (0.66 g, 2.362 mmol) at once. The reaction mixture was stirred at 20 °C for 12 h and filtered to give 2-(2,6-dimethylphenoxy)-N- methylethanamine hydrochloride (0.377 g, 1.338 mmol, 56.7 % yield) as a white solid.

LCMS (M + H) = 180.1; Retention time (10 mmoL NH4HCO3) = 1.384 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), 2-(2,6-dimethylphenoxy)-N-methylethan-l-amine hydrochloride (35.9 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over NarSCL, and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 75-80% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,6- dimethylphenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (15 mg, 0.024 mmol, 28.6 % yield) as a yellow oil. LCMS (M + H) = 631.1; Retention time (10 mmoL NH4HCO3) = 2.180 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,6- dimethylphenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (l5mg, 0.024 mmol) in ethanol (5 mL) was added sodium hydroxide (19.02 mg, 0.476 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B:

MeCN; Gradient 55-60% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2,6-dimethylphenoxy)ethyl)(methyl)amino)- 4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (6.1 mg, 10.36 pmol, 43.6 % yield) as a white solid. LCMS (M + H) = 589.2; Retention time (10 mmoL NH4HCO3) = 1.636 min. ¾ NMR (400 MHz, MeOD): d 8.28 (d, J= 2.8 Hz, 1H), 8.17 (s, 1H), 7.43 (dd, J= 8.8, 2.9 Hz, 1H), 7.34 (d, J= 8.7 Hz, 1H), 6.98 (d, J= 7.5 Hz, 2H), 6.93- 6.85 (m, 1H), 5.76 (s, 1H), 4.05-3.98 (m, 3H), 3.90-3.80 (m, 2H), 3.25 (s, 3H), 3.16-3.13 (m, 1H), 2.85-2.72 (m, 2H), 2.66 (s, 3H), 2.18-2.17 (m, 6H), 1.45-1.35 (m, 4H), 1.20 (s, 9H), 0.81 (s, 6H).

Example 244

Step 1 : To a solution of 2-chloro-6-fluorophenol (1.0 g, 6.82 mmol) in DMF (15 mL) was added Cs2C03 (4.45 g, 13.65 mmol) and the mixture was stirred at 20 °C for 15 minutes. Then 2-((tert-butoxycarbonyl)amino)ethyl methane sulfonate (1.633 g, 6.82 mmol) was added at once and the mixture was stirred at 100 °C for 16 h. Then the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over Na2SC>4, and the solvent was removed in vacuo to give crude product as an oil which was purified by reversed phase column chromatography (C18 ODS, using 80 g; Mobile Phase A: Water (10 mmoL NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(2-chloro-6-fluorophenoxy)ethyl)carbamate (0.831 g, 2.87 mmol, 42.0 % yield) as a yellow oil. LCMS (M + Na) = 312.0; Retention time (10 mmoL NH4HCO3) = 1.825 min.

Step 2: To a 4M HC1 in dioxane (8 mL) was added tert-butyl (2-(2-chloro-6- fluorophenoxy)ethyl)carbamate (0.42 g, 1.450 mmol) at once. The reaction mixture was stirred at 20 °C for 12 h and filtered to give 2-(2-chloro-6-fluorophenoxy)ethan-l -amine hydrochloride (0.25 g, 1.058 mmol, 73.0 % yield) as a white solid. LCMS (M + H) = 190.0; Retention time (10 mmoL NLLHCCh) = 1 097min

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), 2-(2-chloro-6-fluorophenoxy)ethan-l -amine hydrochloride (37.6 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 84-88% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2- chloro-6-fluorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (30 mg, 0.045 mmol, 54.2 % yield) as a yellow oil. LCMS (M + H) = 641.1; Retention time (10 mmoL NH4HCO3) = 2.406 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-6- fluorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (30 mg, 0.047 mmol) in ethanol (5 mL) was added sodium hydroxide (37.4 mg, 0.936 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument Gilson 281 (PHG-009) ; Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 54-60% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-6-fluorophenoxy)ethyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (4.5 mg, 7.51 pmol,

16.05 % yield) as a white solid. LCMS (M + H) = 599.1; Retention time (10 mmoL

NH4HCO3) = 1.517 min. ¾ NMR (400 MHz, MeOD): d 8.14-8.13 (m, 2H), 7.27 (d, J= 1.7 Hz, 2H), 7.24 (dt, J= 7.9, 1.7 Hz, 1H), 7.18-7.08 (m, 2H), 5.76 (s, 1H), 4.30 (t, J= 5.2 Hz, 2H), 3.65 (dt, J= 14.8, 7.3 Hz, 2H), 3.25-3.08 (m, 2H), 2.88-2.74 (m, 2H), 2.65 (s, 3H), 1.48- 1.39 (m, 4H), 1.20 (s, 9H), 0.87 (s, 6H).

Example 245

Step 1 : To a solution oftert-butyl (2-(2-chloro-6-fluorophenoxy)ethyl)carbamate (0.4 g, 1.381 mmol) in DMF (10 mL) was added NaH (0.066 g, 2.76 mmol) at 0 °C and the mixture was stirred for 30 minutes. Then iodomethane (0.173 mL, 2.76 mmol) was added at once and stirred at 20 °C for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give tert-butyl (2-(2-chloro-6-fluorophenoxy)ethyl)(methyl)carbamate (0.4 g, 1.212 mmol, 88 % yield) as a pale yellow oil. LCMS (M-55) = 248.1; Retention time (10 mmoL NLLHCCb) = 1.630 min.

Step 2: To a 4M HC1 in dioxane (8 mL) was added tert-butyl (2-(2-chloro-6- fluorophenoxy)ethyl)(methyl)carbamate (0.4 g, 1.317 mmol) at once. The reaction mixture was stirred at 20 °C for 12 h and filtered to give 2-(2-chloro-6-fluorophenoxy)-N- methylethan-l -amine hydrochloride (0.25 g, 0.983 mmol, 74.7 % yield) as a white solid. LCMS (M + H) = 204.1 ; Retention time (10 mmoL NH4HCO3) = 1.129 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), 2-(2-chloro-6-fluorophenoxy)-N-methylethan-l- amine hydrochloride (39.9 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over Na2S0₄, and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 90-92% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2- chloro-6-fhiorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl- [2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.031 mmol, 36.7 % yield) as a yellow oil. LCMS (M + H) = 655.1; Retention time (10 mmoL NH4HCO3) = 2.575 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-6- fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (20 mg, 0.031 mmol) in ethanol (5 mL) was added sodium hydroxide (24.42 mg, 0.610 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B:

MeCN; Gradient 55-60% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-6- fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (8.0 mg, 0.013 mmol, 42.2 % yield) as a white solid. LCMS (M + H) = 613.1; Retention time (10 mmoL NH4HCO3) = 1.570 min. Ή NMR (400 MHz, MeOD): d 8.25 (d, J= 2.9 Hz, 1H), 8.16 (s, 1H), 7.41 (dd, J= 8.7, 3.0 Hz, 1H), 7.33 (d, J= 8.9 Hz, 1H), 7.23-7.20 (m, 1H), 7.16-7.07 (m, 2H), 5.76 (s, 1H), 4.32 (t, J= 5.0 Hz, 2H), 4.06-3.83 (m, 2H), 3.23 (s, 3H), 3.20-3.05 (m, 2H), 2.86-2.74 (m, 2H), 2.66 (s, 3H), 1.45-1.35 (m, 4H), 1.20 (s, 9H), 0.82 (s, 6H).

Example 246

Step 1 : To a solution of 2,4-dichlorophenol (1.0 g, 6.14 mmol) in DMF (15 mL) was added Cs2C03 (4.00 g, 12.27 mmol) at 20 °C and stirred for 15 minutes. Then 2-((tert- butoxycarbonyl)amino)ethyl methanesulfonate (1.468 g, 6.14 mmol) was added at once and the mixture was stirred at 100 °C for 16 h. The mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over Na2SC>4, and the solvent was removed in vacuo to give crude product as an oil which was purified by reversed phase column chromatography (Cl 8 ODS, using 80 g; Mobile Phase A: Water (10 mmoL NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(2,4- dichlorophenoxy)ethyl)carbamate (0.380 g, 1.184 mmol, 19.30 % yield) as a yellow oil. LCMS (M +Na) = 327.0; Retention time (10 mmoL NH4HCO3) = 1.628 min.

Step 2: To a 4M HC1 in dioxane (8 mL) was added tert-butyl (2-(2,4- dichlorophenoxy)ethyl)carbamate (0.18 g, 0.588 mmol) at once. The reaction mixture was stirred at 20 °C for 12 h and filtered to give 2-(2,4-dichlorophenoxy)ethan-l -amine hydrochloride (0.12 g, 0.468 mmol, 80 % yield) as a white solid. LCMS (M + H) = 206.0; Retention time (0.0l%TFA) = 1.233 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), 2-(2,4-dichlorophenoxy)ethan- 1 -amine hydrochloride (40.3 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over NarSOr. and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL

NH4HCO3); B: MeCN; Gradient 90-95% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,4-dichlorophenoxy)ethyl)amino)-4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.030 mmol, 35.9 % yield) as a yellow oil. LCMS (M + H) = 657.1; Retention time (10 mmoL NH4HCO3) = 2.553 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,4- dichlorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (20 mg, 0.030 mmol) in ethanol (5 mL) was added sodium hydroxide (24.33 mg, 0.608 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 55-60% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2,4-dichlorophenoxy)ethyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (12.5 mg, 0.020 mmol, 66.5 % yield) as a white solid. LCMS (M + H) = 615.0; Retention time (10 mmoL

NH4HCO3) = 1.582 min. ¾ NMR (400 MHz, MeOD): d 8.16 (d, J= 2.5 Hz, 1H), 8.13 (s, 1H), 7.42 (d, J= 2.5 Hz, 1H), 7.31-7.26 (m, 3H), 7.11 (d, J= 8.8 Hz, 1H), 5.76 (s, 1H), 4.27 (t, J= 5.3 Hz, 2H), 3.69 (t, J= 5.1 Hz, 2H), 3.23-3.02 (m, 2H), 2.85-2.74 (m, 2H), 2.65 (s, 3H), 1.47-1.35 (m, 4H), 1.20 (s, 9H), 0.89 (s, 6H). Example 247

Step 1 : To a solution oftert-butyl (2-(2,4-dichlorophenoxy)ethyl)carbamate (0.2 g, 0.653 mmol) in DMF (10 mL) was added NaH (0.031 g, 1.306 mmol) at 0 °C and stirred for 30 minutes. Then iodomethane (0.082 mL, 1.306 mmol) was added at once and stirred at 20 °C for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4, and the solvent was removed in vacuo to give tert-butyl (2-(2,4- dichlorophenoxy)ethyl)(methyl)carbamate (0.25 g, 0.642 mmol, 98 % yield) as a yellow oil. LCMS (M + Na) = 342.1; Retention time (10 mmoL NH4HCO3) = 1 709min

Step 2: To a 4M HC1 in dioxane (8 mL) was added tert-butyl (2-(2,4- dichlorophenoxy)ethyl)(methyl)carbamate (0.25 g, 0.781 mmol) at once. The reaction mixture was stirred at 20 °C for 12 h and filtered to give 2-(2,4-dichlorophenoxy)-N- methylethan-l -amine hydrochloride (0.15 g, 0.376 mmol, 48.2 % yield) as a white solid. LCMS (M + H) = 220.0; Retention time (10 mmoL NH4HCO3) = 1.273 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), 2-(2,4-dichlorophenoxy)-N-methylethan-l -amine hydrochloride (42.6 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4, and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 96-99% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,4- dichlorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (25 mg, 0.037 mmol, 44.8 % yield) as a yellow oil. LCMS (M + H) = 671.0; Retention time (10 mmoL NH4HCO3) = 2.752 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,4- dichlorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (25 mg, 0.037 mmol) in ethanol (5 mL) was added sodium hydroxide (29.8 mg, 0.744 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B:

MeCN; Gradient 40-55% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2,4-dichlorophenoxy)ethyl)(methyl)amino)- 4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (17.8 mg, 0.027 mmol, 73.7 % yield) as a white solid. LCMS (M + H) = 629.1; Retention time (10 mmoL NH4HCO3) = 1.643 min. ¾ NMR (400 MHz, MeOD): d 8.28 (d, J= 2.9 Hz, 1H), 8.14 (d, J = 1.3 Hz, 1H), 7.43 (dd, J= 8.8, 3.1 Hz, 1H), 7.40 (d, J= 2.5 Hz, 1H), 7.32 (d, J= 8.7 Hz, 1H), 7.27 (dd, J= 8.8, 2.5 Hz, 1H), 7.08 (d, J= 8.9 Hz, 1H), 5.77 (s, 1H), 4.30 (t, J= 4.9 Hz, 2H), 4.01-3.93 (m, 2H), 3.21 (s, 3H), 3.18-3.04 (m, 2H), 2.86-2.75 (m, 2H), 2.66 (s, 3H), 1.46-1.35 (m, 4H), 1.20 (s, 9H), 0.86 (s, 6H).

Example 248

Step 1 : To a solution of 4-chloro-2-fluorophenol (1.0 g, 6.82 mmol) in DMF (15 mL) was added Cs2C03 (4.45 g, 13.65 mmol) at 20 °C and stirred for 15 minutes. Then 2-((tert- butoxycarbonyl)amino)ethyl methanesulfonate (1.633 g, 6.82 mmol) was added at once and the mixture was stirred at 100 °C for 16 h. Then the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give crude product as an oil which was purified by reversed phase column chromatography (C18 ODS, using 80 g; Mobile Phase A: Water (10 mmoL NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(4-chloro-2- fluorophenoxy)ethyl)carbamate (0.85 g, 2.143 mmol, 31.4 % yield) as a yellow oil. LCMS (M + Na) = 311.0; Retention time (10 mmoL NH₄HCO3) = 1.552 min.

Step 2: To a 4M HC1 in dioxane (8 mL) was added tert-butyl (2-(4-chloro-2- fluorophenoxy)ethyl)carbamate (0.4 g, 1.381 mmol) at once. The reaction mixture was stirred at 20 °C for 12 h and filtered to give 2-(4-chloro-2-fluorophenoxy)ethan-l -amine hydrochloride (0.23 g, 1.017 mmol, 73.7 % yield) as a white solid. LCMS (M + H) = 190.1; Retention time (10 mmoL NLLHCCh) = 1.151 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), 2-(4-chloro-2-fluorophenoxy)ethan-l -amine hydrochloride (37.6 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4, and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 85-90% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4- chloro-2-fhiorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (25 mg, 0.039 mmol, 46.9 % yield) as a yellow oil. LCMS (M + H) = 641.2; Retention time (10 mmoL NH4HCO3) = 2.416 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2- fluorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (25 mg, 0.039 mmol) in ethanol (5 mL) was added sodium hydroxide (31.2 mg, 0.780 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 50-60% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2-fluorophenoxy)ethyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (14.1 mg, 0.023 mmol, 59.3 % yield) as a white solid. LCMS (M + H) = 599.1; Retention time (10 mmoL

NH4HCO3) = 1.549 min. ¾ NMR (400 MHz, MeOD): d 8.14-8.13 (m, 2H), 7.28 (d, J= 1.4 Hz, 2H), 7.22-7.18 (m, 1H), 7.15-7.11 (m, 2H), 5.76 (s, 1H), 4.27 (t, J= 5.2 Hz, 2H), 3.66 (t, J= 5.2 Hz, 2H), 3.23-3.03(m, 2H), 2.85-2.76 (m, 2H), 2.66 (s, 3H), 1.47-1.35 (m, 4H), 1.20 (s, 9H), 0.90 (s, 6H).

Example 249

Step 1 : To a solution of tert-butyl (2-(4-chloro-2-fluorophenoxy)ethyl)carbamate (0.45 g, 1.553 mmol) in DMF (10 mL) was added NaH (0.075 g, 3.11 mmol) at 0 °C and stirred for 30 minutes. Then iodomethane (0.194 mL, 3.11 mmol) was added at once and stirred at 20 °C for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give tert-butyl (2-(4- chloro-2-fluorophenoxy)ethyl)(methyl)carbamate (0.514 g, 1.278 mmol, 82 % yield) as a yellow oil. LCMS (M + Na) = 325.0; Retention time (10 mmoL NH4HCO3) = 1 654min

Step 2: To a 4M HC1 in dioxane (8 mL) was added tert-butyl (2-(4-chloro-2- fluorophenoxy)ethyl)(methyl)carbamate (0.514 g, 1.692 mmol) at once. The reaction mixture was stirred at 20 °C for 12 h and filtered to give 2-(4-chloro-2-fluorophenoxy)-N- methylethan-l -amine hydrochloride (0.26 g, 1.030 mmol, 60.9 % yield) as a white solid. LCMS (M + H) = 204.1 ; Retention time (10 mmoL NH4HCO3) = 1.182 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), 2-(4-chloro-2-fluorophenoxy)-N-methylethan-l- amine hydrochloride (39.9 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) at once. The reaction mixture was stirred at 100 °C for 12 h under N2. Then diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (40 mL), dried over Na2S0₄, and the solvent was removed in vacuo to give the crude product which was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient 85-90% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4- chloro-2-fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl- [2,3'-bipyridin]-5'-yl)acetate (22 mg, 0.034 mmol, 40.4 % yield) as a yellow oil. LCMS (M + H) = 655.2; Retention time (10 mmoL NH4HCO3) = 2.591 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2- fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (22 mg, 0.034 mmol) in ethanol (5 mL) was added sodium hydroxide (26.9 mg, 0.671 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 h, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009) ; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B:

MeCN; Gradient 40-55% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2- fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (12.9 mg, 0.021 mmol, 62.4 % yield) as a white solid. LCMS (M + H) = 613.1; Retention time (10 mmoL NH4HCO3) = 1.601 min. Ή NMR (400 MHz, MeOD): d 8.24 (d, J= 2.9 Hz, 1H), 8.15 (s, 1H), 7.41 (dd, J= 8.7, 3.0 Hz, 1H), 7.33 (d, J = 8.7 Hz, 1H), 7.20-7.16 (m, 1H), 7.13-7.06 (m, 2H), 5.77 (s, 1H), 4.31 (t, J= 5.1 Hz, 2H), 3.94 (t, J= 5.0 Hz, 2H), 3.18 (s, 3H), 3.16-3.03 (m, 2H), 2.86-2.74 (m, 2H), 2.66 (s, 3H), 1.46- 1.35 (m, 4H), 1.20 (s, 9H), 0.87 (s, 6H). Example 250

Step 1 : To a solution of 4-fluoro-3-methylphenol (0.8 g, 6.34 mmol) in DMF (15 mL) was added Cs2C03 (2.69 g, 8.25 mmol) at room temperature and stirred for l5minutes. Then 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.821 g, 7.61 mmol) was added and stirred at 100 °C for 16 h. Then, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (50 mL x 2), brine (50 mL x 2), dried over Na2SC>4, fdeted and concentrated in vacuo to give a crude oil. The oil was purified by silica gel column (EtO Ac/pet. ether = 7: 1-4: 1) to afford desired product tert-butyl (2-(4-fluoro-3-methylphenoxy)ethyl)carbamate (0.9 g, 2.67 mmol, 42.2 % yield) as a yellow oil. LCMS (M + H) = 259, Retention time (0.0l%TFA) = 1.446.

Step 2: To a 4M HC1 in dioxane (8 mL) was added tert-butyl (2-(4-fluoro-3- methylphenoxy)ethyl)carbamate (0.4 g, 1.485 mmol) at once. The reaction mixture was stirred at room temperature for 12 h, filtered and washed with Et20 to give desired product tert-butyl (2-(4-fluoro-3-methylphenoxy)ethyl)carbamate (0.4 g, 1.485 mmol). LCMS (M+H) = 170, Retention time (0.01% TF A) = 1.24.

Step 3: To a stirred mixture of 2-(4-fluoro-3-methylphenoxy)ethan-l -amine hydrochloride (30.8 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was diluted with ethyl acetate (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 ml ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4-fluoro-3- methylphenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.040 mmol, 53.8 % yield) as a white solid. LCMS (M+H) = 621.2, Retention time (0.0l% NH4HCO3) = 2.44.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((2-(4-fluoro-3-methylphenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.040 mmol) in ethanol (5 mL) and water (1 mL) was added NaOH (32.2 mg, 0.805 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give desired product (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-((2-(4-fluoro-3-methylphenoxy)ethyl)amino)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (13 mg, 0.022 mmol, 55.4 % yield) as a white solid. LCMS (M+H) = 579.2, Retention time (0.01% TFA) = 1.54. ¾ NMR: (400MHz, MeOD): d 8.14- 8.13 (m, 2H), 7.26-7.25 (m, 2H), 6.93 (t, J=8.4 Hz, 1H), 6.84-6.75 (m, 2H), 5.75 (s, 1H), 4.16 (t, J= 5.2 Hz, 2H), 3.60 (t, J= 5.2 Hz, 2H), 3.39-3.32 (m, 2H), 2.88-2.75 (m, 2H), 2.65 (s, 3H), 2.24 (s, 3H), 1.45-1.41 (m, 4H), 1.20 (s, 9H), 0.90 (s, 6H).

Example 251

Step 1 : To a solution oftert-butyl (2-(4-fluoro-3-methylphenoxy)ethyl)carbamate (500 mg, 1.857 mmol) in DMF (2 mL) was added NaH (223 mg, 5.57 mmol) at 0 °C under an atmosphere ofN2. The mixture was stirred for l5minutes and Mel (0.232 mL, 3.71 mmol) was added. The mixture was stirred at room temperature for 16 h. Ice water (10 mL) was added to the mixture and extracted with ethyl acetate (20 ml x3). The combined organic layers were washed with water (20 mL x2), brine (20 mL), dried with Na2S04 and concentrated to give tert-butyl (2-(4-fluoro-3-methylphenoxy)ethyl)(methyl)carbamate (480 mg, 1.220 mmol, 65.7 % yield) as a yellow oil. LCMS (M +23) = 306.1, Retention time (0.0l%TFA) = 2.06.

Step 2: To a 4M HC1 in dioxane (8 mL) was added added tert-butyl (2-(4-fluoro-3- methylphenoxy)ethyl)(methyl)carbamate (0.42 g, 1.482 mmol) at once. The reaction mixture was stirred at room temperature for 12 h, fdtered and washed with Et20 to give desired product 2-(4-fluoro-3-methylphenoxy)-N-methylethanamine hydrochloride (300 mg, 1.256 mmol, 85 % yield) as a white solid. LCMS (M+H) = 184.2, Retention time (0.01% TFA) = 1.34.

Step 3: To a stirred mixture of 2-(4-fluoro-3-methylphenoxy)-N-methylethan-l-amine hydrochloride (36.5 mg, 0.166 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (50 mg, 0.083 mmol), Cs2C03 (108 mg, 0.332 mmol), Pd2(dba)3 (7.61 mg, 8.31 pmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was diluted with ethyl acetate (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4-fluoro-3- methylphenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (28 mg, 0.044 mmol, 53.1 % yield) as a white solid. LCMS (M+H) = 635.2, Retention time (0.01%

NH4HCO3) = 4.28.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((2-(4-fluoro-3-methylphenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (25 mg, 0.039 mmol) in ethanol (5 mL) and water (1 mL) was added NaOH (31.5 mg, 0.788 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give desired product (S)-2-(tert-butoxy)- 2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4-fluoro-3-methylphenoxy)ethyl)(methyl)amino)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetic acid (12.0 mg, 0.020 mmol, 51.4 % yield) a white solid. LCMS (M+H) = 592.3, retention time = 1.64 min. ¾ NMR: (400MHz, MeOD): d 8.22 (d,

J= 3.2 Hz, 1H), d 8.13 (s, 1H), 7.39-7.31 (m, 2H), 6.90(t, =8.4 Hz, 1H), 6.77-6.68 (m, 2H), 5.76 (s, 1H), 4.21-4.17 (m, 2H), 3.89-3.37 (m, 2H), 3.39-3.32 (m, 2H), 3.26 (s, 3H), 2.91- 2.65 (m, 2H), 2.65 (s, 3H), 2.22 (s, 3H), 1.45-1.41 (m, 4H), 1.19 (s, 9H), 0.87 (s, 6H).

Example 252

Step 1 : To a solution of 4-fluorophenol (0.8 g, 7.14 mmol) in DMF (15 mL) was added Cs2C03 (3.02 g, 9.28 mmol) at room temperature and stirred for 15 minutes. Then 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (2.049 g, 8.56 mmol) was added and stirred at 100 °C for 16 h. The mixture was fdtered and purified by Prep-HPLC to afford desired product tert-butyl (2-(4-fluorophenoxy)ethyl)carbamate (0.9 g, 3.44 mmol, 48.3 % yield) as a yellow oil. LCMS (M + 23) = 324, Retention time (0.0l%TFA) = 1.92.

Step 2: To a solution of tert-butyl (2-(4-fluorophenoxy)ethyl)carbamate (0.3 g, 1.175 mmol) in DCM (6 mL) was added 2,2,2-trifluoroacetic acid (1 mL, 13.46 mmol) at once. The reaction mixture was stirred at room temperature for 12 h. The solvents were removed in vacuo, water (10 mL) was added to the solid with stirring and the pH value was adjusted to 8 with sat NaHC03 The mixture was extracted with DCM (20 mL x3), washed with water (50 mL), then organic layer was dried over NaiSOr and concentrated to afford a brown oil which was purified by chromatography on silica gel eluting with pet. Ether : EtOAc (5: 1) to give desired product 2-(4-fluorophenoxy)ethanamine (150 mg, 0.841 mmol, 71.6 % yield) as yellow solid. LCMS (M+H) = 156, Retention time (0.01% TFA) = 1.13. Step 3: To a stirred mixture of 2-(4-fluorophenoxy)ethan- 1 -amine (23.21 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5- (((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 mL ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-((2-(4-fluorophenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (23 mg, 0.032 mmol, 42.6 % yield) as a white solid. LCMS (M+H) = 606, Retention time (0.0l% NH4HCC>3) = 2.31.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((2-(4-fluorophenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (23 mg, 0.038 mmol) in ethanol (2 mL) and ater (0.40 mL)) was added NaOH (30.3 mg, 0.758 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give desired product (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-((2-(4-fluorophenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (11.0 mg, 0.019 mmol, 51.1 % yield) as a white solid. LCMS (M+H) = 565.2, Retention time (0.01% TFA) = 1.56. ¾ NMR: (400MHz, MeOD): d 7.99 (s, 1H), 7.95-7.94 (m, 1H), 7.13-7.12 (m, 2H), 6.92-6.82 (m, 4H), 5.60 (s, 1H), 4.06 (t, J= 5.2 Hz, 2H), 3.49 (t, J= 5.2 Hz, 2H), 3.39-3.32 (m, 2H), 2.73-2.55 (m, 2H), 2.51 (s, 3H), 1.40-1.27 (m, 4H), 1.20 (s, 9H), 0.90 (s, 6H). Example 253

Step 1 : To a solution oftert-butyl (2-(4-fluoro-3-methylphenoxy)ethyl)carbamate (500 mg, 1.857 mmol) in DMF (2 mL) was added NaH (223 mg, 5.57 mmol) at 0 °C under an atmosphere ofN2 and stirred for l5minutes. Then Mel (0.232 mL, 3.71 mmol) was added and the mixture was stirred at room temperature for 16 h. Ice water (10 ml) was added to the mixture and extracted with ethyl acetate (20 mL x3). The combined organic layers were washed with water (20 mL x 2), brine (20 mL), dried with Na2S04 and concentrated to give tert-butyl (2-(4-fluoro-3-methylphenoxy)ethyl)(methyl)carbamate (480 mg, 1.220 mmol,

65.7 % yield) as a yellow oil. LCMS (M -55) = 228, Retention time (0.0l%TFA) = 2.06.

Step 2: To a 4M HC1 in dioxane (8 mL) was added added tert-butyl (2-(4- fluorophenoxy)ethyl)(methyl)carbamate (0.52 g, 1.931 mmol) at once. The reaction mixture was stirred at room temperature for 12 h, filtered and washed with EtiO to give desired product 2-(4-fluorophenoxy)-N-methylethanamine hydrochloride (300 mg, 1.459 mmol,

76 % yield) as a white solid. LCMS (M+H) = 170.1, Retention time (0.0l% TFA) = 1.22.

Step 3: To a stirred mixture of 2-(4-fluorophenoxy)-N-methylethan-l -amine hydrochloride (34.2 mg, 0.166 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (50 mg, 0.083 mmol), Cs2C03 (108 mg, 0.332 mmol), Pd2(dba)3 (7.61 mg, 8.31 pmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 mL ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4- fluorophenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.040 mmol, 48.5 % yield) as a white solid. LCMS (M+H) = 621, Retention time (0.01%

NH4HCO3) = 4.12.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((2-(4-fluorophenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.040 mmol) in ethanol (2 mL) and water (0.400 mL)) was added NaOH (32.2 mg, 0.805 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give desired product ((S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-((2-(4-fluorophenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (14.4 mg, 0.024 mmol, 59.6 % yield) a white solid. LCMS (M+H) = 579.4, Retention time (0.01% TFA) = 1.6. ¾ NMR: (400MHz, MeOD): d 8.23 (d, .7=2.8 Hz, 1H), d 8.13 (s, 1H), 7.40-7.37 (m, 2H), 7.01-6.97 (m, 2H), 6.91-6.88 (m, 2H), 5.76 (s,

1H), 4.21 (t, J=5.2 Hz, 2H), 3.91-3.89 (m, 2H), 3.39-3.32 (m, 2H), 3.16 (s, 3H), 2.91-2.66 (m, 2H), 2.65 (s, 3H), 1.45-1.41 (m, 4H), 1.19 (s, 9H), 0.87 (s, 6H).

Example 254

Step 1 : To a solution of 4-chloro-2-methoxyphenol (0.8 g, 5.04 mmol) in DMF (15 mL) was added Cs2C03 (2.137 g, 6.56 mmol) at room temperature and stirred for 15 minutes. Then 2-((tert-butoxycarbonyl)amino)ethyl methane sulfonate (1.449 g, 6.05 mmol) was added and stirred at 100 °C for 16 h. The reaction mixture was filtered and purified by reverse Prep-HPLC to afford desired product tert-butyl (2-(4-chloro-2- methoxyphenoxy)ethyl)carbamate (0.9 g, 2.89 mmol, 57.3 % yield) as a yellow oil. LCMS (M + 23) = 324, Retention time (0.0l%TFA) = 1.92.

Step 2: To a solution oftert-butyl (2-(4-chloro-2-methoxyphenoxy)ethyl)carbamate (0.4 g, 1.326 mmol) in DCM (6 mL) was added 2,2,2-trifluoroacetic acid (1 mL, 13.46 mmol) at once. The reaction mixture was stirred at room temperature for 12 h. The solvents were removed in vacuo, water (10 mL) was added to the solid with stirring and pH was adjusted to 8 with sat NaHC03. The mixture was extracted with DCM (20 mL x3), washed with water (50 mL), then organic layer was dried over NaiSOr and concentrated to afford a brown oil. The brown oil was purified by silica gel chromatography eluting with pet. ether: EtO Ac (5: 1) to give desired product 2-(4-chloro-2-methoxyphenoxy)ethanamine (200 mg, 0.992 mmol, 74.8 % yield) as yellow solid. LCMS (M+H) = 202, Retention time (0.01% TFA) = 1.66.

Step 3: To a stirred mixture of 2-(4-chloro-2-methoxyphenoxy)ethan-l -amine (30.2 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl- 5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H- xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2.

The reaction mixture was diluted with EtO Ac (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 mL ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5- ((2-(4-chloro-2-methoxyphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl- [2,3'-bipyridin]-5'-yl)acetate (19 mg, 0.029 mmol, 38.9 % yield) as a white solid. LCMS (M+H) = 653, Retention time (0.01% NH4HCO3) = 2.37.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2- methoxyphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (19 mg, 0.029 mmol) in ethanol (2 mL) and ater (0.40 mL)) was added NaOH (23.27 mg, 0.582 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give desired product (S)-2-(tert-butoxy)- 2-(5-((2-(4-chloro-2-methoxyphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetic acid (8.7 mg, 0.014 mmol, 48.4 % yield) as a white solid. LCMS (M+H) = 611.1, Retention time (0.01% TFA) = 1.52. ¾ NMR: (400MHz, MeOD): d 8.13-8.12 (m, 2H), 7.28 (d, =l .2 Hz, 2H), 7.00-6.87 (m, 3H), 5.76 (s, 1H), 4.20 (t, =5.2 Hz, 2H), 3.85 (s, 3H), 3.62 (t, J= 5.2 Hz, 2H), 3.39-3.32 (m, 2H), 2.84-2.75 (m, 2H), 2.65 (s, 3H), 1.40-1.27 (m, 4H), 1.20 (s, 9H), 0.90 (s, 6H).

Example 255

Step 1 : To a solution of tert-butyl (2-(4-chloro-2-methoxyphenoxy)ethyl)carbamate (500 mg, 1.657 mmol) in DMF (2 mL) was added NaH (199 mg, 4.97 mmol) at 0 °C under an atmosphere ofN2. The mixture was stirred at 0 °C for l5minutes, then Mel (0.207 mL,

3.31 mmol) was added. The mixture was stirred at room temperature for 16 h. Ice water (10 ml) was added to the mixture and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (20 mL x 2), brine (20 mL), dried with Na2S04 and concentrated to give tert-butyl (2-(4-chloro-2-methoxyphenoxy)ethyl)(methyl)carbamate (480 mg, 1.368 mmol, 83 % yield) as a yellow oil. LCMS (M +23) = 338, Retention time (0.0l%TFA) = 2.02.

Step 2: To a 4M HC1 in dioxane (8 mL) was added added tert-butyl (2-(4-chloro-2- methoxyphenoxy)ethyl)(methyl)carbamate (0.6 g, 1.900 mmol) at once. The reaction mixture was stirred at room temperature for 12 h, filtered and washed with EtiO to give desired product 2-(4-chloro-2-methoxyphenoxy)-N-methylethanamine hydrochloride (400 mg, 1.586 mmol, 83 % yield) as a white solid. LCMS (M+H) = 253, Retention time (0.01% TFA) = 1.35.

Step 3: To a stirred mixture of 2-(4-chloro-2-methoxyphenoxy)-N-methylethan-l- amine hydrochloride (41.9 mg, 0.166 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (50 mg, 0.083 mmol), Cs2C03 (108 mg, 0.332 mmol), Pd2(dba)3 (7.61 mg, 8.31 pmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 mL ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2-methoxyphenoxy)ethyl)(methyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.037 mmol, 45.1 % yield) as a white solid. LCMS (M+H) = 667, Retention time (0.0l% NH4HCO3) = 4.17.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4-chloro-2- methoxyphenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (25 mg, 0.037 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (1.498 mg, 0.037 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95- 95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give desired product (S)-2- (tert-butoxy)-2-(5-((2-(4-chloro-2-methoxyphenoxy)ethyl)(methyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (14.8 mg, 0.023 mmol, 61.7 % yield) a white solid. LCMS (M+H) =625.3, Retention time (0.0l% NH4HCO3) = 1.58. ¾ NMR: (400MHz, MeOD): d 8.23 (d, J=2.8 Hz, 1H), d 8.15 (s, 1H), 7.42-7.40 (m, 1H), 7.33-7.31 (m, 1H), 6.96-6.84 (m, 3H), 5.75 (s, 1H), 4.22 (t, J=5.2 Hz, 2H), 3.91-3.84 (m, 2H), 3.80 (s, 3H) 3.39-3.32 (m, 2H), 3.15 (s, 3H), 2.84-2.76 (m, 2H), 2.66 (s, 3H), 1.45-1.41 (m, 4H), 1.17 (s, 9H), 0.87 (s, 6H). Example 256

Step 1 : To a solution of phenol (0.8 g, 8.50 mmol) in DMF (15 mL) was added Cs2C03 (3.60 g, 11.05 mmol) at room temperature and stirred for 15 minutes. Then 2-((tert- butoxycarbonyl)amino)ethyl methanesulfonate (2.441 g, 10.20 mmol) was added and heated at 100 °C for 16 h. The reaction mixture was filtered and purified by Prep-HPLC to afford desired product tert-butyl (2-phenoxyethyl)carbamate (1 g, 4.21 mmol, 49.6 % yield) as a yellow oil. LCMS (M + H) = 237, Retention time (0.0l%TFA) = 1.96.

Step 3: To a solution of tert-butyl (2-phenoxyethyl)carbamate (0.4 g, 1.686 mmol) in DCM (6 mF) was added 2,2,2-trifluoroacetic acid (1 mF, 13.46 mmol) at once. The reaction mixture was stirred at room temperature for 12 h. The solvents were removed in vacuo, water (10 mF) was added to the solid with stirring and pH was adjusted to 8 with sat NaHC03. The mixture was extracted with DCM (20 mF x3), washed with water (50 mF), then organic layer was dried over NaiSOi and concentrated to afford a brown oil. The brown oil was purified by silica gel chromatography eluting with pet. ether :EtOAc(5: 1) to give desired product 2- phenoxyethanamine (150 mg, 1.017 mmol, 60.3 % yield) as yellow solid. FCMS (M+H) = 138, Retention time (0.01% TFA) = 1.04.

Step 3: To a stirred mixture of 2-phenoxyethan-l -amine (20.52 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5- (((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mF) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 mF ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by prep-HPFC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-((2-phenoxyethyl)amino)-[2,3'-bipyridin]-5'-yl)acetate (12 mg, 0.020 mmol, 26.2 % yield) as a white solid. LCMS (M+H) = 589.2, Retention time (0.01% NH₄HC0₃) = 2.35.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-((2-phenoxyethyl)amino)-[2,3'-bipyridin]-5'-yl)acetate in ethanol (2 mL) and water (0.4 mL) was added at once. The resulting mixture was stirred at 90 °C for 10 h. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by prep- HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-5-((2-phenoxyethyl)amino)-[2,3'-bipyridin]-5'- yl)acetic acid (6.9 mg, 0.013 mmol) as a white solid. LCMS (M+H) = 547.2, Retention time (0.01% NH4HCO3) = 1.49. ¾ NMR: (400MHz, MeOD): d 8.14-8.13 (m, 2H), 7.30-7.26 (m, 4H), ), 6.97-7.26 (m, 3H), 5.76 (s, 1H), 4.20 (t, J= 5.2 Hz, 2H), 3.85 (s, 3H), 3.62 (t, J= 5.2 Hz, 2H), 3.39-3.32 (m, 2H), 2.84-2.75 (m, 2H), 2.65 (s, 3H), 1.40-1.27 (m, 4H), 1.20 (s, 9H), 0.90 (s, 6H).

Example 257

Step 1 : To a solution oftert-butyl (2-phenoxyethyl)carbamate (500 mg, 2.107 mmol) in DMF (2 mL) was added NaH (253 mg, 6.32 mmol) at 0 °C under an atmosphere of N2 and stirred for l5minutes. Then Mel (0.264 mL, 4.21 mmol) was added and the mixture was stirred at room temperature for 16 h. Ice water (10 ml) was added to the mixture and extracted with ethyl acetate (20 mL x3). The combined organic layers were washed with water (20 mL x 2), brine (20 mL), dried with Na2S04 and concentrated to give tert-butyl methyl(2-phenoxyethyl)carbamate (520 mg, 1.862 mmol, 88 % yield) as a yellow oil. LCMS (M +23) = 274, Retention time (0.0l%TFA) = 1.99.

Step 2: To a 4M HC1 in dioxane (8 mL) was added added tert-butyl methyl(2- phenoxyethyl)carbamate (0.52 g, 2.069 mmol) at once. The reaction mixture was stirred at room temperature for 12 h, filtered and washed with EtiO to give desired product N-methyl- 2-phenoxyethanamine hydrochloride (350 mg, 1.721 mmol, 83 % yield) as a white solid. LCMS (M+H) = 152.2, Retention time (0.01% TFA) = 1.17.

Step 3: To a stirred mixture of N-methyl-2-phenoxyethan-l -amine hydrochloride (31.2 mg, 0.166 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (108 mg, 0.332 mmol), Pd2(dba)3 (7.61 mg, 8.31 pmol) and (9,9-dimethyl-9H- xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2.

The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 mL ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(methyl(2-phenoxyethyl)amino)-[2,3'-bipyridin]-5'- yl)acetate (22 mg, 0.036 mmol, 43.9 % yield) as a white solid. LCMS (M+H) = 603, Retention time (0.01% NH4HCO3) = 4.16.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(methyl(2-phenoxyethyl)amino)-[2,3'-bipyridin]-5'-yl)acetate (22 mg, 0.036 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH at once. The resulting mixture was stirred at 90 °C for 10 h. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column:

Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL

NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give desired product (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(methyl(2-phenoxyethyl)amino)-[2,3'-bipyridin]-5'-yl)acetic acid (13.9 mg, 0.024 mmol) a white solid. LCMS (M+H) = 561.4, Retention time (0.0l% NH4HCO3) = 1.61. Ή NMR: (400MHz, MeOD): d 8.24 (d, J= 2.8 Hz, 1H), d 8.14 (s, 1H), 7.41-7.38 (m, 1H), 7.33- 7.23 (m, 3H), 6.94-6.89 (m, 3H), 5.75 (s, 1H), 4.23 (t, J= 5.2 Hz, 2H), 3.92-3.89 (m, 2H), 3.39-3.32 (m, 2H), 3.16 (s, 3H), 2.84-2.76 (m, 2H), 2.65 (s, 3H), 1.45-1.41 (m, 4H), 1.19 (s, 9H), 0.87 (s, 6H).

Example 258

Step 1 : To a solution of 3,4-dimethylphenol (0.8 g, 6.55 mmol) in DMF (15 mL) was added Cs2C03 (2.77 g, 8.51 mmol) at room temperature and stirred for 15 minutes. Then 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.880 g, 7.86 mmol) was added and heated at 100 °C for 16 h. The reaction was filtered and purified by Prep-HPLC to afford desired product tert-butyl (2-(3,4-dimethylphenoxy)ethyl)carbamate (600 mg, 2.035 mmol, 31.1 % yield) as a yellow oil. LCMS (M+Na) = 288, Retention time (0.01% TFA) = 2.0.

Step 2: To a 4M HC1 in dioxane (8 mF) was added added tert-butyl (2-(3,4- dimethylphenoxy)ethyl)carbamate (0.3 g, 1.131 mmol) at once. The reaction mixture was stirred at room temperature for 12 h. TFC showed reaction was completed. The mixture was filtered and washed with EtiO (5 ml) to give desired product 2-(3,4-dimethylphenoxy)ethan- l-amine hydrochloride (160 mg, 0.714 mmol, 63.1 % yield) as white solid. The solid was used in the next step without further purification. FCMS (M+H) = 168, Retention time (0.01% TFA) = 1.16.

Step 3: To a stirred mixture of 2-(3,4-dimethylphenoxy)ethan-l -amine hydrochloride (30.2 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H- xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mF) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2.

The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 mF ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by prep-HPFC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5- ((2-(3,4-dimethylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (22 mg, 0.036 mmol, 47.7 % yield) as a white solid. LCMS (M+H) = 617, Retention time (0.0l% NH₄HCC>3) = 2.50.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(3,4- dimethylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (19 mg, 0.031 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (24.64 mg, 0.616 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(5-((2-(3,4- dimethylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (8.1 mg, 0.014 mmol, 45.0 % yield) as a white solid. LCMS (M+H) = 575.2, Retention time (0.0l% NH₄HCO3) =1.67. Ή NMR: (400MHz, MeOD): d 8.10-8.09 (brs, 2H), 7.25-7.21 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 6.73-6.63 (m, 2H), 5.73 (s, 1H), 4.13 (t,

J= 5.2 Hz, 2H), 3.58 (t, J=5.2 Hz, 2H), 3.39-3.32 (m, 2H), 2.84-2.75 (m, 2H), 2.62 (s, 3H), 2.60 (s, 3H), 2.16 (s, 3H), 1.40-1.27 (m, 4H), 1.17 (s, 9H), 0.86 (s, 6H).

Example 259

Step 1 : To a solution oftert-butyl (2-(3,4-dimethylphenoxy)ethyl)carbamate (500 mg, 1.884 mmol) in DMF (2 mL) was added NaH (226 mg, 5.65mmol) at 0 °C under an atmosphere of N2 and stirred for l5minutes. Then Mel (0.236mL, 3.77mmol) was added and stirred at room temperature for 16 h. Then ice water (10 ml) was added to the mixture and extracted with ethyl acetate (20 ml x3). The combined organic layers were washed with water (20 ml x 2), brine (20 ml), dried with NaiSOr and concentrated to give the desired product tert-butyl (2-(3,4-dimethylphenoxy)ethyl)(methyl)carbamate (400 mg, 1.217 mmol, 64.6 % yield) as a yellow oil which was used in the next step without purification. LCMS (M + 23) = 301.

Step 2: To a 4M HC1 in dioxane (8 mL) was added added tert-butyl (2-(3,4- dimethylphenoxy)ethyl)(methyl)carbamate (0.3 g, l.074mmol) at once. The reaction mixture was stirred at room temperature for 12 h. TLC showed reaction was completed. The mixture was filtered and washed with Et20 (5 ml) to give the desired product 2-(3,4- dimethylphenoxy)-N-methylethan-l -amine hydrochloride (250 mg, 0.671 mmol, 62.5 % yield) as white solid which was used in the next step without further purification. LCMS (M + H) = 189.

Step 3: To a stirred mixture of 2-(3,4-dimethylphenoxy)-N-methylethan-l-amine hydrochloride (32.3 mg, 0T50mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (45 mg, 0.075mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)₃ (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg,

0.0l5mmol) in toluene (3mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The mixture was filtered and purified by HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} give the desired product isopropyl (S)-2-(tert-butoxy)- 2-(5-((2-(3,4-dimethylphenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.040mmol, 53.0 % yield). LCMS (M + H) = 631.

Step 4: To a solution of sodium hydroxide (31.4 mg, 0.785 mmol) in MeOH (3 mL) and H20 (0.5 ml) was added the isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4- chlorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (25 mg, 0.039mmol). The mixture was stirred at 90 °C for additional 16 h. The pH of the mixture was adjusted to ~7 with 1N HC1. The crude was purified by HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 42-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2- (tert-butoxy)-2-(5-((2-(4-chlorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (20.4 mg, 0.034 mmol, 87 % yield) as white solid. LCMS (M + H) = 589. ¾ NMR (400 MHz, MeOD) d 8.23-8.22 (m, 1H), 8.14 (s, 1H), 7.46- 7.28 (m, 2H), 7.00-6.99 (m, 1H), 6.73- 6.55 (m, 2H), 5.76 (s, 1H), 4.62-4.61 (m, 1H), 4.19 (t, J= 5.2 Hz, 2H), 3.89-3.88 (m, 2H), 3.16-3.15 (m, 4H), 2.93- 2.75 (m, 2H), 2.65 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H), 1.50-1.27 (m, 4H), 1.20 (s, 9H), 0.86 (s, 6H).

Example 260

Step 1 : To a solution of 4-chlorophenol (0.8 g, 6.22 mmol) in DMF (15 mL) was added Cs2C03 (2.64 g, 8.09 mmol) at room temperature and stirred for 15 minutes then 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.787 g, 7.47 mmol) was added and heated at 100 oC for 16 h. The reaction was filtered and purified by Prep-HPLC to afford tert-butyl (2-(4-chlorophenoxy)ethyl)carbamate (550 mg, 1.637 mmol, 26.3 % yield) as a yellow oil. LCMS (M+Na) =294, Retention time (0.01% TFA) = 1.97.

Step 2: To a solution of HC1 (8mL, 4M solution in l,4-Dioxane) was added tert-butyl (2-(4-chlorophenoxy)ethyl)carbamate (0.3 g, 1.104 mmol) at once. The reaction mixture was stirred at room temperature for 12 h, filtered and washed with EtiO (5 ml) to give desired product as a white solid 2-(4-chlorophenoxy)ethan-l -amine hydrochloride (180 mg, 0.779 mmol, 70.5 % yield). The solid was used in the next step without further purification. LCMS (M+H) =172, Retention time (0.01% TFA) =1.22.

Step 3: To a stirred mixture of 2-(4-chlorophenoxy)ethan-l -amine hydrochloride (31.1 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H- xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at l00°C overnight under N2. The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 mL ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by prep-HPLC

{Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(5- ((2-(4-chlorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (25 mg, 0.040 mmol, 53.6 % yield) as a white solid. LCMS (M+H)

=623, Retention time (0.01% NH HCO ) =2.44.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4- chlorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (25 mg, 0.040 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (32.1 mg, 0.802 mmol) was added at once. The resulting mixture was stirred at 90°C for 10 h. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by prep- HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(5-((2- (4-chlorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (15.2 mg, 0.026 mmol, 65.0 % yield) as a white solid. LCMS (M+H) = 581, Retention time (0.0l% NH₄HCO3) =1.56. Ή NMR: (400MHz, MeOD): d 8.13-8.12 (m, 2H), 7.28-7.25 (m, 4H), 6.95 (d, J=6.8 Hz, 2H), 5.76 (s, 1H), 4.20 (t, J= 5.2 Hz, 2H), 3.62 (t, J= 5.2 Hz, 2H), 3.39-3.32 (m, 2H), 2.84-2.75 (m, 2H), 2.65 (s, 3H), 1.45-1.27 (m, 4H), 1.20 (s, 9H), 0.89 (s, 6H).

Example 261

Step 1 : To a solution of 4-chlorophenol (0.8 g, 6.22mmol) in DMF (15 mL) was added Cs2C03 (2.64 g, 8.09 mmol) at room temperature and stirred for 15 minutes. Then 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.787 g, 7.47 mmol) was added and heated at 100 °C for 16 h. The reaction mixture was filtered and purified by Prep-HPLC to afford tert-butyl (2-(4-chlorophenoxy)ethyl)carbamate (550 mg, 1.637 mmol, 26.3 % yield) as a yellow oil. LCMS (M + 23) = 294.

Step 2: To a solution of tert-butyl (2-(4-chlorophenoxy)ethyl)carbamate (500 mg, 1.840 mmol) in DMF (2 mL) was added NaH (221 mg, 5.52 mmol) at 0 °C under an atmosphere of N2. The mixture was stirred at 0 °C for 15 minutes, then Mel (0.230 ml, 3.68 mmol) was added. The mixture was stirred at room temperature for 16 h. Then ice water (10 ml) was added and extracted with ethyl acetate (20 ml x3). The combined organic layers were washed with water (20 ml x 2), brine (20 ml), dried with NaiSOi and concentrated to give desired product tert-butyl (2-(4-chlorophenoxy)ethyl)(methyl)carbamate (500 mg, 1.487 mmol, 81 % yield). Which was used in the next step without purification. LCMS (M + 23) = 308.

Step 3 : To a 4M HC1 in dioxane (8 mL) was added added tert-butyl (2-(4- chlorophenoxy)ethyl)(methyl)carbamate (0.3 g, 1.050 mmol) at once. The reaction mixture was stirred at room temperature for 12 h, filtered and washed with EtiO (5 ml) to give desired product 2-(4-chlorophenoxy)-N-methylethan-l -amine hydrochloride (200 mg, 0.810 mmol,

77 % yield) as a white solid which was used in the next step without further purification. LCMS (M + H) = 186.

Step 4: To a stirred mixture of 2-(4-chlorophenoxy)-N-methylethan-l-amine hydrochloride (33.2 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The mixture was concentrated and the residue was purified by HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4-chlorophenoxy)ethyl)(methyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (23 mg, 0.036mmol, 48.3 % yield) as yellow solid. LCMS (M + H) = 638.

Step 5: To a solution of sodium hydroxide (31.4 mg, 0.785 mmol) in MeOH (3 mL) and FLO (0.5 ml) was added the isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4- chlorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (25 mg, 0.039 mmol). The mixture was stirred at 90 °C for additional 16 h. The pH of the mixture was adjusted to ~7 with 1N HC1 and purified by PRE- HPLC { Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-65%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2- (tert-butoxy)-2-(5-((2-(4-chlorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (20.4 mg, 0.034 mmol, 87 % yield) as white solid. LCMS (M + H) = 596. ¾ NMR (400 MHz, MeOD) d 8.24 (s, 1H), 8.15-8.14 (m, 1H), 7.39-7.38 (m, 1H), 7.33-7.32 (m, lH),7.27- 7.21 (m, 2H), 6.93- 6.86 (m, 2H), 5.77 (s, 1H), 4.23 (t, J= 5.2 Hz, 2H), 3.88-3.87 (m, 2H), 3.32- 3.24 (m, 2H), 3.16 (s, 3H), 2.81-2.80 (m, 2H), 2.66 (s, 3H), 1.39-1.38 (m, 4H), 1.20 (s, 9H), 0.88 (s, 6H).

Example 262

Step 1 : To a solution of 4-methoxyphenol (0.8 g, 6.44 mmol) in DMF (15 mL) was added Cs2C03 (2.73 g, 8.38 mmol) at room temperature and stirred for 15 minutes. Then 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.850 g, 7.73 mmol) was added and heated at 100 °C for 16 h. The reaction mixture filtered and the filtrate was purified by Prep- HPLC to afford tert-butyl (2-(4-methoxyphenoxy)ethyl)carbamate (400 mg, 1.347 mmol, 20.90 % yield) as a yellow oil. LCMS (M+H) = 290, Retention time (0.01% TFA) = 1.87.

Step 2: To a 4M HC1 in dioxane (8 mL) was added added tert-butyl (2-(4- methoxyphenoxy)ethyl)carbamate (0.3 g, 1.122 mmol) at once. The reaction mixture was stirred at room temperature for 12 h, filtered and washed with Et20 (5 ml) to give to give the desired product 2-(4-methoxyphenoxy)ethan-l -amine hydrochloride (150 mg, 0.589 mmol, 52.5 % yield) as white solid which was used in the next step without further purification. LCMS (M+H) = 168.2, Retention time (0.01% TFA) = 1.38. Step 3: To a stirred mixture of 2-(4-methoxyphenoxy)ethan-l -amine hydrochloride (30.5 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H- xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2.

The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 mL ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4'- (4,4-dimethylpiperidin-l-yl)-5-((2-(4-methoxyphenoxy)ethyl)amino)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (21 mg, 0.032 mmol, 42.2 % yield) as a white solid. LCMS (M+H) = 619, Retention time (0.0l% NH4HCC>3) = 2.25.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((2-(4-methoxyphenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (19 mg, 0.031 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (24.56 mg, 0.614 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-((2-(4-methoxyphenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (10.9 mg, 0.019 mmol, 60.8 % yield) as a white solid. LCMS (M+H) = 577.2, Retention time (0.0l% NH₄HCO3) = 1.54. Ή NMR: (400MHz, MeOD): d 8.13-8.12 (m, 2H), 7.26-7.25 (m, 2H), 6.92-6.83 (m, 4H), 5.76 (s, 1H), 4.15 (t, J=5.2 Hz, 2H), 3.75 (s, 3H), 3.59 (t, J= 5.2 Hz, 2H), 3.39-3.32 (m, 2H), 2.84-2.75 (m, 2H), 2.65 (s, 3H), 1.45-1.27 (m, 4H), 1.20 (s, 9H), 0.90 (s, 6H). Example 263

Step 1 : To a solution of 4-methoxyphenol (0.8 g, 6.44mmol) in DMF (15 mL) was added Cs2C03 (2.73 g, 8.38 mmol) at room temperature and stirred for 15 minutes. Then 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.850 g, 7.73mmol) was added and heated at 100 °C for 16 h. The reaction mixture was filtered and the filtrate was purified by Prep-HPLC to afford tert-butyl (2-(4-methoxyphenoxy)ethyl)carbamate (400 mg, 1.347 mmol, 20.90 % yield) as a yellow oil. LCMS: (M+23) = 290, Retention time (0.01% TFA) = 1.87.

Step 2: To a solution of tert-butyl (2-(4-methoxyphenoxy)ethyl)carbamate (300 mg, 1.122 mmol) in DMF (2 mF) was added NaH (135 mg, 3.37 mmol) at 0 °C under an atmosphere of N2 and stirred for l5minutes. Then Mel (0.140 ml, 2.244mmol) was added and stirred at room temperature for 16 h. Then ice water (10 ml) was added to the mixture and extracted with ethyl acetate (20 ml x3). The combined organic layers were washed with water (20 ml x 2), brine (20 ml), dried with NaiSOi and concentrated to give desired product tert- butyl (2-(4-methoxyphenoxy)ethyl)(methyl)carbamate (250 mg, 0.755 mmol, 67.3 % yield) as a yellow oil which was used in the next step without purification. FCMS: (M+23)⁺ =304, Retention time (0.01% TFA) =1.69.

Step 3: To a solution of HC1 (8mF, 4M solution in l,4-Dioxane) was added tert-butyl (2-(4-methoxyphenoxy)ethyl)(methyl)carbamate (0.3 g, l.066mmol) at once. The reaction mixture was stirred at room temperature for 12 h, filtered and washed with EtiO (5 ml) to give desired product -(4-methoxyphenoxy)-N-methylethan-l-amine hydrochloride (200 mg, 0.827 mmol, 78 % yield) as a white solid. The solid was used in the next step without further purification. FCMS: (M+23) = 181, Retention time (0.01% TFA) = 1.41.

Step 4: To a stirred mixture of 2-(4-methoxyphenoxy)-N-methylethan-l -amine hydrochloride (32.6 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 mihoΐ) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 mL ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4- methoxyphenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (18 mg, 0.028 mmol, 38.0 % yield) as a white solid. LCMS (M+H) = 633, Retention time (0.01%

NH4HCO3) = 2.42.

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((2-(4-methoxyphenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (18 mg, 0.028 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (22.75 mg, 0.569 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by prep-HPLC

{Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give desired product (S)-2-(tert-butoxy)- 2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4-methoxyphenoxy)ethyl)(methyl)amino)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetic acid (12.0 mg, 0.020 mmol, 71.2 % yield) a white solid. LCMS (M+H) = 591.2, Retention time (0.01% NH4HCO3) = 1.61. Ή NMR: (400MHz, MeOD): d 8.23 (d, J=2.8 Hz, 1H), d 8.15 (s, 1H), 7.40-7.31 (m, 2H), 6.84-6.8 l(m, 4H), 5.76 (s, 1H), 4.18 (t, J=5.2 Hz, 2H), 3.89-3.86 (m, 2H), 3.74 (s, 3H), 3.32-3.26 (m, 2H), 3.15 (s, 3H), 2.84-2.76 (m, 2H), 2.65 (s, 3H), 1.45-1.41 (m, 4H), l .20(s, 9H), 0.88 (s, 6H). Example 264

Step 1 : To a solution of 4-fluoro-2-methoxyphenol (1 g, 7.04 mmol) in DMF (15 mL) was added Cs2C03 (2.98 g, 9.15 mmol) at room temperature and stirred for 15 minutes.

Then 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (2.020 g, 8.44 mmol) was added and heated at 100 °C for 16 h. The reaction was filtered and the filtrate was purified by Prep- HPLC to afford tert-butyl (2-(4-fluoro-2-methoxyphenoxy)ethyl)carbamate (l .6g, 5.61 mmol, 80 % yield) as a yellow oil. LCMS (M+H) = 286, Retention time (0.01% NH4HCO3)

= 1.441 min.

Step 2: To a solution of tert-butyl (2-(4-fluoro-2-methoxyphenoxy)ethyl)carbamate (800 mg, 2.80 mmol) in DCM (10 mL) was added TFA (2.160 mL, 28.0 mmol) at 0 °C and stirred at 0 °C for 6 h. LCMS showed that the reaction was completed. The reaction was concentrated and the residue was purified by Prep-HPLC to afford 2-(4-fluoro-2- methoxyphenoxy)ethan-l -amine (500 mg, 2.55 mmol, 91 % yield) as a yellow oil. LCMS: Retention time (0.01% TFA) = 1.204 min, m/z = 186.1 [M+H]

Step 3: To a stirred mixture of 2-(4-fluoro-2-methoxyphenoxy)ethan-l -amine hydrochloride (33.2 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by Prep-HPLC to give isopropyl (S)-2-(tert- butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4-fluoro-2-methoxyphenoxy)ethyl)amino)- 6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (18 mg, 0.028 mmol, 37.8 % yield). LCMS: Retention time (0.01% NH4HCO3) = 2.37 min, m/z = 637 [M+H] Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-((2-(4-fluoro-2-methoxyphenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.031 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (25.1 mg, 0.628 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by prep-HPLC to give (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4-fluoro-2- methoxyphenoxy)ethyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (9.2 mg, 0.015 mmol, 49.3 % yield) as white solid. LCMS: Retention time (0.01% NH4HCO3) = 1.54 min, m/z = 595.2 [M+H] ¾ NMR (400 MHz, MeOD) d 8.15 (t, J= 1.6 Hz, 2H), 8.12 (d, J= 1.6 Hz, 2H), 7.00 (dd, J= 5.6, 8.8 Hz, 1H), 6.83 (dd, J= 10.4, 2.8 Hz, 1H), 6.63 (td, J= 8.0, 2.8 Hz, 1H), 5.77 (s, 1H), 4.20 (t, J= 5.2 Hz, 2H), 3.86 (s, 3H), 3.61 (t, J= 5.2 Hz, 2H), 3.34- 3.30 (m, 2H), 2.86-2.78 (m, 2H), 2.66 (s, 3H), 1.44-1.42 (brs, 4H), 1.20 (s, 9H), 0.90 (s, 6H).

Example 265

Then 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (2.020 g, 8.44 mmol) was added and heated at 100 °C for 16 h. The reaction mixture was filtered and the filtrate was purified by Prep-HPLC to afford the product tert-butyl (2-(4-fluoro-2- methoxyphenoxy)ethyl)carbamate (l .6g, 5.61 mmol, 80 % yield) as a yellow oil. LCMS (M+H) = 286, Retention time (0.01% NH4HCO3) = 1.441.

Step 2: To a solution of tert-butyl (2-(4-fluoro-2-methoxyphenoxy)ethyl)carbamate (800 mg, 2.80 mmol) in DMF (15 mL) was added sodium hydride (81 mg, 3.36 mmol) at 0 °C. The mixture was stirred at room temperature for 15 minutes, and then iodomethane (597 mg, 4.21 mmol) was added. After 16 h, the reaction mixture was diluted with ice water (10 ml) and extracted with ethyl acetate (20 ml x3). The combined organic layers were washed with water (20 ml x 2), brine (20 ml), dried with Na2SC>4 and concentrated. The residue was purified by Prep-HPLC to give desired product tert-butyl (2-(4-fluoro-2- methoxyphenoxy)ethyl)(methyl)carbamate (650 mg, 2.134 mmol, 76 % yield) as a yellow oil. LCMS (M+H) = 300.1, Retention time (0.01% NH4HCO3) = 1.537.

Step 3 : To a solution of tert-butyl (2-(4-fluoro-2- methoxyphenoxy)ethyl)(methyl)carbamate (650 mg, 2.171 mmol) in DCM (10 mL) was added TFA (1.673 mL, 21.71 mmol) at 0 °C and stirred at 0 °C for 6 h. The reaction was concentrated and the residue was purified by reverse Prep-HPLC to afford the product 2-(4- fluoro-2-methoxyphenoxy)-N-methylethan-l -amine (403 mg, 1.918 mmol, 88 % yield) as a yellow oil. LCMS (M+H) = 200.1, Retention time (0.01% TFA) = 1.222 min.

Step 4: To a stirred mixture of 2-(4-fluoro-2-methoxyphenoxy)-N-methylethan-l- amine hydrochloride (35.3 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was filtered and the filtrate was

concentrated. The crude product was purified by Prep-HPLC to give Isopropyl (S)-2-(tert- butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4-fluoro-2- methoxyphenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.031 mmol, 41.1 % yield). LCMS: Retention time (0.01% NH4HCO3) = 2.64min, m/z = 651.

Step 5: To a solution ofNaOH (9.22 mg, 0.230 mmol) in ethanol (3 mL) and H20 (0.500 mL) was added the isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5- ((2-(4-fluoro-2-methoxyphenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (15 mg, 0.023 mmol). The mixture was stirred at 90 °C for 20 h. The pH was adjusted to about 7 with acetic acid, filtered and the filtrate was purified by Prep-HPLC to give (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-((2-(4-fluoro-2- methoxyphenoxy)ethyl)(methyl)amino)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid ( 13.5 mg, 0.022 mmol, 96 % yield). LCMS (M+H) = 609.2, Retention time (0.0l% NH₄HCO3) = 1.59 min. ¾ NMR (400 MHz, MeOD) d 8.12 (d, J= 2.8 Hz, 1H), 8.03 (s, 1H), 7.29 (dd, J= 2.8, 8.8 Hz, 1H), 7.20 (d, J= 8.4 Hz, 1H), 6.78 (dd, J= 8.8, 5.6 Hz, 1H), 6.66 (dd, J= 10.4, 2.8 Hz, 1H), 6.45 (td, J= 8.4, 2.9 Hz, 1H), 5.64 (s, 1H), 4.08 (t, J= 5.1 Hz, 2H), 3.78 (m, 2H), 3.68 (s, 3H), 3.21-3.16 (m, 2H), 3.06 (s, 3H), 2.65-2.64 (brs, 2H), 2.54 (s, 3H), 1.30-1.22- 1.21 (brs, 4H), 1.08 (s, 9H), 0.74 (s, 6H). Example 266

Step 1 : To a solution of 2,4-dimethylphenol (1.5 g, 12.28 mmol) in DMF (15 mL) was added Cs2C03 (5.20 g, 15.96 mmol) at room temperature and stirred for 15 minutes. Then 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (3.53 g, 14.73 mmol) was added and heated at 100 °C for 16 h. The mixture was cooled, diluted with water (30 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (2x30 mL), dried over anhydrous NaiSOr and the solvent was removed in vacuum to give the crude product which was purified by column chromatography (Cl 8, Water (10 mmol/L NH₄HCO3 a.q.): Methanol = 60%) to give desired product tert-butyl (2-(2,4- dimethylphenoxy)ethyl)carbamate (1.5 g, 5.14 mmol, 41.9 % yield) as yellow solid. LCMS: Retention time (0.0l% NH₄HCC>3) = 2.01, m/z = 165 [M-100]

Step 2: To a 4M HC1 in dioxane (8 mL) was added added tert-butyl (2-(2,4- dimethylphenoxy)ethyl)carbamate (0.5 g, 1.884 mmol) at once. The reaction mixture was stirred at room temperature for 12 h. LCMS showed reaction was completed. The mixture was concentrated, washed with ether and filtered to give 2-(2,4-dimethylphenoxy)ethan-l- amine hydrochloride (330 mg, 1.636 mmol, 87 % yield) as a white solid which was used in the next step without further purification. LCMS: Retention time (0.01% NH4HCO3) = 1.451 min, m/z = 166.

Step 3: To a stirred mixture of N-(2-(2,4-dimethylphenoxy)ethyl)-l3-chloranamine (30.2 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H- xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was filtered and the filtrate was concetrated. The crude product was purified by Prep-HPLC to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,4- dimethylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate. LCMS: rt = 2.84 min, m/z = 631 [M+H]⁺.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,4- dimethylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (21 mg, 0.034 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (27.2 mg, 0.681 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by Prep-HPLC to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2,4- dimethylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (6 mg) as white solid. LCMS: Retention time (0.01% NH4HCO3) = 1.693 min, m/z = 575.1 [M+H] ¾ NMR (400 MHz, MeOD) d 8.03-8.02 (m, 2H), 7. l5 (d, J= l .6 Hz, 2H), 6.82 (d, J= 6.4 Hz, 2H), 6.69 (dd, J= 5.6, 2.8 Hz, 1H), 5.64 (s, 1H), 4.06 (t, J= 4.8 Hz, 2H), 3.54 (t, J= 5.2 Hz, 2H), 3.16-2.81 (m, 2H), 2.71-2.70 (brs, 2H), 2.54 (s, 3H), 2.12 (s, 3H), 2.04 (s, 3H), 1.31-1.30 (brs, 4H), 1.08 (s, 9H), 0.77 (s, 6H).

Example 267

Step 1 : To a solution oftert-butyl (2-(2,4-dimethylphenoxy)ethyl)carbamate (500 mg, 1.884 mmol) in DMF (8 mL) was added the NaH (226 mg, 5.65 mmol). Then iodomethane (401 mg, 2.83 mmol) was added. After stirring for 0.5 h, LCMS showed reaction was completed. The reaction mixture was diluted with ice-water and extracted with EtOAc (3 x 20 mL). The combined organic layers washed with water (2 x 20 mL), brine (20 mL), dried over anhydrous NaiSCL, filtered and evaporated in vacuo to give tert-butyl (2-(2,4- dimethylphenoxy)ethyl)(methyl)carbamate (480 mg, 0.309 mmol, 16.41 % yield) as a orange oil which was used in next step without further purification. LCMS: Retention time (0.01% NH4HCO3) = 1.891, m/z = 179.0 [M-100]

Step 2: To a 4M HC1 in dioxane (8 mL) was added added tert-butyl (2-(2,4- dimethylphenoxy)ethyl)(methyl)carbamate (480 mg, 1.718 mmol) at once. The reaction mixture was stirred at room temperature for 12 h. LCMS showed reaction was completed.

The mixture was concentrated, washed with ether and fdtered to give 2-(2,4- dimethylphenoxy)-N-methylethan-l -amine hydrochloride (320 mg, 1.483 mmol, 86 % yield) as a white solid which was in the next step without further purification. LCMS: Retention time (0.01% NH4HCO3) = 1.27, m/z = 179.9 [M+H]

Step 3: To a stirred mixture of 2-(2,4-dimethylphenoxy)-N-methylethan-l -amine hydrochloride (32.3 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by Prep-HPLC to give isopropyl (S)-2-(tert- butoxy)-2-(5-((2-(2,4-dimethylphenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (21 mg, 0.033 mmol, 44.5 % yield). LCMS:

Retention time (0.01% NH4HCO3) = 2.84 min, m/z = 631 [M+H]

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2,4- dimethylphenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (21 mg, 0.033 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (26.6 mg, 0.666 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by prep-HPLC to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2,4- dimethylphenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (12.8 mg, 0.022 mmol, 65.3 % yield) as white solid. LCMS: Retention time (0.0l% NH₄HCC>3) = 1.74 min, m/z = 589.2 [M+H] Ή NMR (400 MHz, MeOD) d 8.26 (d, J= 2.8 Hz, 1H), 8.14 (s, 1H), 7.42 (dd, J= 8.8, 2.8 Hz, 1H), 7.33 (d, J=

11.2 Hz, 1H), 6.92 (d, J= 4.8 Hz, 2H), 6.77 (t, J= 4.4 Hz, 1H), 5.76 (s, 1H), 4.2 (t, J= 4.8 Hz, 2H), 3.96-3.94 (m, 2H), 3.34-3.32 (m, 2H), 3.18 (s, 3H), 2.83- 2.79 (m, 2H), 2.66 (s, 3H), 2.23 (s, 3H), 2.08 (s, 3H), 1.49- 1.36 (m, 4H), 1.20 (s, 9H), 0.86 (s, 6H). Example 268

Step 1 : To a solution of 2-chloro-6-methylphenol (1.5 g, 10.52 mmol) in DMF (15 mL) was added Cs2C03 (4.46 g, 13.68 mmol) at room temperature and stirred for 15 minutes. Then 2-((tert-butoxycarbonyl)amino)ethyl methane sulfonate (3.02 g, 12.62 mmol) was added and heated at 100 °C for 16 h. LCMS showed that the reaction was completed.

The reaction mixture was filtered and purified by Prep-HPLC to afford the desired product tert-butyl (2-(2-chloro-6-methylphenoxy)ethyl)carbamate (0.8 g, 2.52 mmol, 23.95 % yield) as a yellow oil. LCMS: Retention time (0.01% NH4HCO3) = 1.59 min , m/z = 287 [M+H]

Step 2: To a 4M HC1 in dioxane (8 mL) was added added tert-butyl (2-(2-chloro-6- methylphenoxy)ethyl)carbamate (0.5 g, 1.750 mmol) at once. The reaction mixture was stirred at room temperature for 12 h. LCMS showed reaction was completed. The mixture was concentrated, washed with ether and filtered to give 2-(2-chloro-6-methylphenoxy)ethan- 1 -amine hydrochloride (250 mg, 1.126 mmol, 64.3 % yield) as a white solid which was used in the next step without further purification. LCMS: Retention time (0.1% TFA) = 1.23 min , /z— 186 [M+H]

Step 3: To a stirred mixture of 2-(2-chloro-6-methylphenoxy)ethan-l -amine hydrochloride (33.2 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by Prep-HPLC to give isopropyl (S)-2-(tert- butoxy)-2-(5-((2-(2-chloro-6-methylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.031 mmol, 42.0 % yield. LCMS: Retention time (0.01% NH4HCO3) = 2.64 min, m/z = 631.2 [M+H] Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-6- methylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (20 mg, 0.031 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (25.1 mg, 0.628 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by prep-HPLC to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-6- methylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (7.2 mg, 0.012 mmol, 38.5 % yield) as white solid. LCMS: Retention time (0.01% NH4HCO3) = 1.64 min , m/z = 595. l [M+H] ¾ NMR: (400MHz, MeOD): d 8.17 (m, 2H), 7.29 (d, .7=2.4 Hz, 2H), 7.24 (d, 7=8.0 Hz, 1H), 7.15 (d, 7=7.2 Hz, 1H), 7.02 (t, 7=8.0 Hz, 1H), 5.76 (s, 1H), 4.14 (t, 7=5.2 Hz, 2H), 3.72-3.64 (m, 2H), 3.32-3.29 (m, 2H), 2.89- 2.75 (brs, 2H), 2.66 (s, 3H), 2.30 (s, 3H), 1.51-1.34 (m, 4H), 1.20 (s, 9H), 0.87 (s, 6H).

Example 269

Step 1 : To a solution of 2-chloro-6-methylphenol (1.5 g, 10.52 mmol) in DMF (15 mL) was added Cs2C03 (4.46 g, 13.68 mmol) at room temperature and stirred for 15 minutes. Then 2-((tert-butoxycarbonyl)amino)ethyl methane sulfonate (3.02 g, 12.62 mmol) was added and heated at 100 °C for 16 h. LCMS showed that the reaction was completed. The reaction mixture was filtered and purified by Prep-HPLC to afford the desired product tert-butyl (2-(2-chloro-6-methylphenoxy)ethyl)carbamate (0.8 g, 2.52 mmol, 23.95 % yield) as a yellow oil. LCMS: Retention time (0.01% NH4HCO3) = 1.59 min , m/z = 287 [M+H] Step 2: To a solution of tert-butyl (2-(2-chloro-6-methylphenoxy)ethyl)carbamate (500 mg, 1.750 mmol) in DMF (8 mL) was added the NaH (210 mg, 5.25 mmol). Then iodomethane (373 mg, 2.62 mmol) was added. After stirring for 0.5 h, LCMS showed reaction was completed. The reaction mixture was diluted with ice-water, extracted with EtOAc(3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), brine (20 mL), dried over anhydrous NaiSOy filtered and evaporated in vacuo to give the desired product tert-butyl (2-(2-chloro-6-methylphenoxy)ethyl)(methyl)carbamate (320 mg, 1.067 mmol, 61.0 % yield) as a orange oil which was used in next step without purification.

Retention time (0.01% NH4HCO3) = 1.74 min , m/z = 300 [M+H]

Step 3 : To a 4M HC1 in dioxane (8 mL) was added added tert-butyl (2-(2-chloro-6- methylphenoxy)ethyl)(methyl)carbamate (0.25 g, 0.834 mmol) at once. The reaction mixture was stirred at room temperature for 12 h. LCMS showed reaction was completed. The mixture was concentrated, washed with ether and filtered to give 2-(2-chloro-6- methylphenoxy)-N-methylethan-l -amine hydrochloride (120 mg, 0.508 mmol, 60.9 % yield) as a white solid which was used in the next step without further purification. LCMS:

Retention time (0.01% NH₄HCO3) = 1.43 min , m/z = 200 [M+H]

Step 4: To a stirred mixture of 2-(2-chloro-6-methylphenoxy)-N-methylethan-l -amine hydrochloride (35.3 mg, 0.150 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'- yl)acetate (45 mg, 0.075 mmol), Cs2C03 (97 mg, 0.299 mmol), Pd2(dba)3 (6.85 mg, 7.48 pmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (8.66 mg, 0.015 mmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by Prep-HPLC to give isopropyl (S)-2-(tert- butoxy)-2-(5-((2-(2-chloro-6-methylphenoxy)ethyl)(methyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (21 mg, 0.032 mmol, 43.1 % yield). LCMS: Retention time (0.01% NH4HCO3) = 2.83 min, m/z = 651 [M+H]

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-chloro-6- methylphenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (12 mg, 0.018 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (14.74 mg, 0.369 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by Prep-HPLC to give the desired product (S)-2-(tert-butoxy)-2-(5-((2-(2- chloro-6-methylphenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl- [2,3'-bipyridin]-5'-yl)acetic acid (4.7 mg, 7.71 pmol, 41.9 % yield) as white solid. LCMS: Retention time (0.0l% NH₄HCC>3) = 1.70 min, m/z = 609.2 [M+H] Ή NMR: (400MHz, MeOD): d 8.27 (d, J= 2.8 Hz, 1H), 8.17 (s, 1H), 7.44 (dd, J=8.8, 2.8 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.22 (dd, J= 3.6, 1.2 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.02 (t, J=8.0 Hz, 1H), 5.76 (s, 1H), 4.14 (t, J=5.2 Hz, 2H), 4.09-4.03 (m, 1H), 3.92-3.85 (m, 1H), 3.33-3.32 (brs, 2H), 3.25 (s, 3H), 2.85-2.76 (brs, 2H), 2.66 (s, 3H), 2.24 (s, 3H), 1.14-1.30 (m, 4H), 0.92 (s, 9H), 0.81 (s, 6H).

Example 270 and 271

Step 1 : To a solution of 4-hydroxybenzonitrile (1.0 g, 8.39 mmol) in DMF (15 mL) was added Cs2C03 (5.47 g, 16.79 mmol) at room temperature and stirred for 15 minutes. Then 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (2.009 g, 8.39 mmol) was added and heated at 100 °C for 16 h. showed that the reaction was completed. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (10 ml x 2) and the filtrate was diluted with water (200 ml) and ethyl acetate (100). The organic layer separated and washed with brine (200 ml x 3), dried over anhydrous NaiSOi. filtered and concentrated to give a yellow oil which was purified by silica gel column (pet. ether /EtOAc = 20: 1 to 15: 1) to afford tert-butyl (2-(4-cyanophenoxy)ethyl)carbamate (0.7 g, 1.687 mmol, 20.09 % yield) as a yellow oil. LCMS: R.T. (0.1% TFA): 1.232 min, m/z: (M+H) =163 (M-100)

Step 2: To a 4M HC1 in dioxane (8 mF) was added tert-butyl (2-(4- cyanophenoxy)ethyl)carbamate (0.35 g, 1.334 mmol) at once. The reaction mixture was stirred at room temperature for 12 h. FCMS showed reaction was completed. The solvent was removed in vacuo and the resulting solid was triturated with ether (10 ml), filtered and the solid was washed with ether (10 ml), dried to give 4-(2-aminoethoxy)benzonitrile hydrochloride (0.21 g, 0.781 mmol, 58.5 % yield) as a white solid which was used in the next step without further purification.. FCMS (M+H) = 163, Retention time (0.1% TFA): 0.930 min.

Step 3: To a stirred mixture of 4-(2-aminoethoxy)benzonitrile hydrochloride (33.0 mg, 0.166 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl- 5-(((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis (diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mF) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. LCMS showed that the reaction was completed. The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 ml x 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by Prep-TLC (pet. ether : EtOAc = 1 : 1) to give isopropyl (S)-2-(tert- butoxy)-2-(5-((2-(4-cyanophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl- [2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.039 mmol, 47.3 % yield) as a white solid. LCMS: Retention time (10 M NH4HCO3) = 2.146 min, m/z (M+H) = 614.

Step 4: To a stirred solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4- cyanophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (15 mg, 0.024 mmol) in l,4-dioxane (3 mL) and Water (1 mL) was added LiOH (1.756 mg, 0.073 mmol) in one-portion. The reaction mixture was stirred at 90 °C for 16 h. LCMS showed the reaction was completed . The pH was adjusted to about 7 with acetic acid, then concentrated under vacuum and purified by Prep-HPLC. (Instrument: Gilson 281 ( PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give (S)-2-(tert-butoxy)-2-(5-((2-(4- carbamoylphenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin- 1 -yl)-6'-methyl-[2,3'-bipyridin] - 5'-yl)acetic acid (4 mg, 6.53 pmol, 26.7 % yield); LCMS: (M+H) = 590, Retention time (10 M NH4HCO3): 1.322 min. ¾ NMR (400 MHz, MeOD) d 8.15 (t, J = 1.7 Hz, 1H), 8.14 (s, 1H), 7.27 (d, J = 1.7 Hz, 2H), 7.15-7.10 (m, 2H), 6.93- 6.88 (m, 1H), 5.76 (s, 1H), 4.20 (t, J = 5.2 Hz, 2H), 3.67 (dd, J = 5.4, 3.8 Hz, 2H), 3.15-3.14 (brs, 2H), 2.83-2.82 (brs, 2H), 2.66 (s, 3H), 1.44-1.42 (brs, 4H), 1.20 (s, 9H), 0.89 (s, 6H). and

(S)-2-(tert-butoxy)-2-(5-((2-(4-cyanophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)- 6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (3.1 mg, 5.32 pmol, 21.76 % yield) as a white solid. LCMS: (M+H) = 572, Retention time (10 M NH4HCO3): 1.488 min. 1H NMR (400 MHz, MeOD) d 8.13-8.12 (m, 2H), 7.68 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 2.3 Hz, 2H), 7.13 (d, J = 8.9 Hz, 2H), 5.77 (s, 1H), 4.30 (t, J = 5.2 Hz, 2H), 3.67 (t, J = 5.1 Hz, 2H), 3.15-3.14 (brs, 2H), 2.87- 2.70 (m, 2H), 2.65 (s, 3H), 1.37-1.30 (m, 4H), 1.20 (s, 9H), 0.90 (s, 6H). Example 272 and 273

Step 1 : To a solution oftert-butyl (2-(4-cyanophenoxy)ethyl)carbamate (0.35 g, 1.334 mmol) in DMF (10 mL) was added NaH (0.064 g, 2.67 mmol) at 0 °C and the mixture was stirred at for 30 minutes. Then iodomethane (0.167 mL, 2.67 mmol) was added and stirred at room temperature for 3 h. LCMS showed that the reaction was completed. The reaction mixture was water (50 mL) and ethyl acetate (50 mL). Organic layer separated, washed with water (50 mL x 2), brine (50 mL x 2), dried over Na2S04, filtered and concentrated in vacuo to give tert-butyl (2-(4-cyanophenoxy)ethyl)(methyl)carbamate (0.44 g, 0.733 mmol, 54.9 % yield) as a crude oil. LCMS: R.T. (0. l% TFA): l .482min, m/z: (M+Na) = 298.

Step 2: To a 4M HC1 in dioxane (8 mL) was added tert-butyl (2-(4- cyanophenoxy)ethyl)(methyl)carbamate (0.44 g, 1.592 mmol) at once. The reaction mixture was stirred at room temperature for 12 h. LCMS showed reaction was completed. The solvent was removed in vacuo and the resulting solid was triturated with ether (10 ml), filtered and the filter cake was washed with ether (10 ml), dried to give the desired product 4-(2- (methylamino)ethoxy)benzonitrile hydrochloride (0.19 g, 0.674 mmol, 42.3 % yield) as a white solid. LCMS: R.T. (0.1% TFA) = 0.961 min, (M+H) = 177.

Step 3 : To a stirred mixture of 4-(2-(methylamino)ethoxy)benzonitrile hydrochloride (35.3 mg, 0.166 mmol), isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol), Cs2C03 (81 mg, 0.249 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol) and Pd2(dba)3 (7.61 mg, 8.31 pmol) in toluene (3 mL) was placed under N2 atm (vac/fill ^c 3). The mixture was heated at 100 °C overnight under N2. LCMS showed that the reaction was completed. The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 ml x 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by Prep-TLC (pet. etherEtOAc = 1 : 1) to give isopropyl (S)-2-(tert- butoxy)-2-(5-((2-(4-cyanophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.024 mmol, 29.1 % yield) as a white solid. LCMS: Retention time: 2.263 min (10 M NH4HC03), m/z [M+H] = 628.

Step 4: To a stirred solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(4- cyanophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (15 mg, 0.024 mmol) in l,4-dioxane (3 mL) and water (1 mL) was added LiOH (1.716 mg, 0.072 mmol) in one-portion. The reaction mixture was stirred at 90 °C for 1 h. LCMS showed the reaction was completed . The pH was adjusted to about 7 with acetic acid and purified by prep-HPLC (Instrument: Gilson 281 (PHG-009; Column:

Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL

NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give (S)-2-(tert-butoxy)-2-(5-((2-(4-carbamoylphenoxy)ethyl)(methyl)-amino)-4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (2.1 mg, 3.33 pmol, 13.93 % yield); LCMS: Retention time (10 M NH4HCO3): 1.385 min, (M+H) = 604. Ή NMR (400 MHz, MeOD) d 8.14 (d, J = 2.8 Hz, 1H), 8.03 (s, 1H), 7.77 - 7.71 (m, 2H), 7.30 (dd, J = 8.8, 3.0 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 6.90- 6.85 (m, 2H), 5.66 (s, 1H), 4.22 (t, J = 5.1 Hz, 2H), 3.84 (t, J = 5.1 Hz, 2H), 3.22- 3.13 (m, 2H), 3.07 (s, 3H), 2.71-2.70-2.69 (brs, 2H), 2.55 (s, 3H), 1.34- 1.20 (m, 4H), 1.09 (s, 9H), 0.77 (s, 6H). and (S)-2-(tert-butoxy)-2-(5- ((2-(4-cyanophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (2.0 mg, 3.30 pmol, 13.82 % yield) as a white solid. LCMS: Retention time (10 M NH4HCO3): 1.535 min, (M+H) = 586. Ή NMR (400 MHz, MeOD) d 8.14 (d, J = 2.9 Hz, 1H), 8.04 (s, 1H), 7.58- 7.53 (m, 2H), 7.30 (dd, J = 8.8, 3.0 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 8.9 Hz, 2H), 5.68 (s, 1H), 4.23 (t, J = 5.2 Hz, 2H), 3.84 (t, J = 5.2 Hz, 2H), 3.06-3.05 (brs, 5H), 2.71-2.70 (brs, 2H), 2.55 (s, 3H), 1.27-1.20 (m, 4H), 1.10 (s, 9H), 0.78 (s, 6H).

Example 274 and 275

Step 1: To a stirred solution of 5-fluoro-2-hydroxybenzonitrile (1 g, 7.29 mmol) in DMF (30 ml) was added Cs2C03 (4.57 g, 14.02 mmol) in one-portion . The reaction mixture was stirred at 20 °C for 0.5 h. Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.677 g, 7.01 mmol) was added and heated at 100 °C for 16 h. LCMS showed most of the starting material was consumed. The reaction mixture was diluted with water (100 ml) and ethyl acetate (200 ml), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous Na2S04, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert- butyl (2-(2-cyano-4-fluorophenoxy)ethyl)carbamate (1.2 g, 4.12 mmol, 58.7 % yield) as a yellow oil. LCMS: R.T.: 1.262 min (0.1% TFA), m/z: (M+Na) = 303.

Step 2: To tert-butyl (2-(2-cyano-4-fluorophenoxy)ethyl)carbamate (0.6 g, 2.141 mmol) added 4H HC1 in dioxan (5.00 ml, 20 mmoL) at once. The reaction mixture was stirred at 15 °C for 12 h. TLC (pet. ether : EtOAc = 1: 1) showed reaction was completed. The solvent was removed in vacuo and the resulting solid was triturated with ether (10 ml), filtered and the filter cake was washed with ether (10 ml), dried to obtain the desired product 2-(2-aminoethoxy)-5-fhiorobenzonitrile (0.3 g, 1.046 mmol, 48.8 % yield) as a white solid. LCMS: retention time = 0.701 min (0.1% TFA), (M+H) = 181.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol) in toluene (3 mL) was added 2-(2-aminoethoxy)-5-fluorobenzonitrile (29.9 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol), Pd2(dba)3 (7.61 mg, 8.31 pmol) and cesium carbonate (81 mg, 0.249 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed reaction was completed. The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 ml ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by Prep- HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00)) to give isopropyl (S)-2-(tert- butoxy)-2-(5-((2-(2-cyano-4-fhiorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.032 mmol, 38.1 % yield) as a white solid. LCMS: Retention time: 2.549 min (10 M NH4HC03), m/z [M+H] = 632. Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-cyano-4- fluorophenoxy)ethyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (20 mg, 0.032 mmol, 38.1 /o yield) m ethanol (5 mL) and water (1 mL) was added NaOH (63.6 mg, 1.583 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give (S)-2-(2- ((5'-(tert-butoxy(carboxy)methyl)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]- 5-yl)amino)ethoxy)-5-fluorobenzoic acid (2.9 mg, 4.69 pmol, 5.92 % yield) as a white solid; LCMS: Retention time (10 M NH4HCO3): 1.247 min, (M+H) = 609. Ή NMR (400 MHz, MeOD) d 8.04-8.03 (m, 2H), 7.31 (dd, J = 8.8, 3.1 Hz, 1H), 7.17 (s, 2H), 7.06 (ddd, J = 13.4, 8.4, 3.8 Hz, 2H), 5.63 (s, 1H), 4.19 (t, J = 5.1 Hz, 2H), 3.49 (t, J = 5.1 Hz, 2H), 3.05-3.04 (brs, 2H), 2.71-2.70 (brs, 2H), 2.55 (s, 3H), 1.33-1.32 (brs, 4H), 1.09 (s, 9H), 0.79 (s, 6H) and (S)-2-(tert-butoxy)-2-(5-((2-(2-cyano-4-fluorophenoxy)ethyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (6 mg, 10.17 pmol, 12.86 % yield) as a white solid. LCMS: Retention time (10 M NH4HCO3): 1.485 min, (M+H) =

590. ¾ NMR (400 MHz, MeOD) d 8.34 (s, 1H), 8.05 (s, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.18 (td, J = 8.5, 3.2 Hz, 1H), 7.05 (dd, J = 8.9, 4.7 Hz, 1H), 5.69 (s, 1H), 4.18 (t, J = 5.5 Hz, 2H), 3.27 (t, J = 5.5 Hz, 2H), 3.15 - 2.85 (m, 2H), 2.70-2.69 (brs, 2H), 2.54 (s, 3H), 1.41 - 1.21 (m, 4H), 1.09 (s, 9H), 0.80 (s, 6H).

Example 276 and 277

Step 1 : To a stirred solution of tert-butyl (2-(2-cyano-4- fluorophenoxy)ethyl)carbamate (600 mg, 2.141 mmol) in DMF (5 mL) was added NaH (103 mg, 4.28 mmol) in one-portion at 0 °C and stirred for 0.5h. Then Mel (0.268 mL, 4.28 mmol) was added and warm up to 15 °C for 0.5 h. TLC (pet. ether : EtOAc = 1: 1) showed reaction was completed . The reaction mixture was diluted with water (100 ml) and ethyl acetate (200 ml), organic layer separated and washed with brine (200 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(2- cyano-4-fluorophenoxy)ethyl)(methyl)carbamate (480 mg, 1.124 mmol, 52.5 % yield) as a colorless oil. LCMS: R.T.: 1.35 min (0.1% TFA), m/z: (M+Na) = 317.

Step 2: To tert-butyl (2-(2-cyano-4-fluorophenoxy)ethyl)(methyl)carbamate (0.48 g, 1.631 mmol) was added 4M HC1 in dioxane (5.00 ml, 20 mmoL) at once. The reaction mixture was stirred at 15 °C for 12 h. LCMS showed reaction was completed. The solvent was removed in vacuo and the resulting solid was triturated with ether (10 ml), filtered and the filter cake was washed with ether (10 ml), dried to obtain the desired product 5-fluoro-2- (2-(methylamino)ethoxy)benzonitrile (280 mg, 1.244 mmol, 76 % yield) as a white solid. LCMS: retention time = 0.824 min (0.1% TFA), (M+H) = 195.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((trifhioromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.083 mmol) in toluene (3 mL) was added 5-fluoro-2-(2-(methylamino)ethoxy)benzonitrile (32.3 mg, 0.166 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (9.62 mg, 0.017 mmol),Pd2(dba)3 (7.61 mg, 8.31 pmol) and cesium carbonate (81 mg, 0.249 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed reaction was completed. The reaction mixture was diluted with EtOAc (50 ml) and H20 (20 ml), organic layer separated and aqueous layer extracted with ethyl acetate (50 ml ^c 3). The combined organic layers were dried with Na2S04 and concentrated. The residue was purified by Prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00)) to give isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-cyano-4-fluorophenoxy)ethyl)(methyl)amino)-4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.031 mmol, 37.3 % yield) as a white solid. LCMS: Retention time: 2.293 min (10 M NH4HC03), m/z [M+H] = 646.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-((2-(2-cyano-4- fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (25 mg, 0.039 mmol) in l,4-dioxane (3 mL) and ater (1 mL) was added LiOH (2.78 mg, 0.116 mmol) at once. The resulting mixture was stirred at 90 °C for 10 h. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by prep-HPLC (Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmoL NH4HCO3); B: MeCN; Gradient: 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give (S)-2- (tert-butoxy)-2-(5-((2-(2-carbamoyl-4-fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (2 mg, 3.05 pmol, 7.88 % yield) as a white solid. LCMS: N66832-61-A1, Retention time (10 M NH4HCO3): 1.411 min, (M+H) = 622. ¹H NMR (400 MHz, MeOD) 5 8.11 (d, J = 2.9 Hz, 1H), 8.03 (s, 1H), 7.46 (dd, J = 9.2, 3.1 Hz, 1H), 7.28 (dd, J = 8.7, 2.9 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.15 - 7.04 (m, 2H), 5.63 (s, 1H), 4.29 (dd, J = 10.8, 5.4 Hz, 2H), 3.87 (t, J = 5.2 Hz, 2H), 3.24-3.23 (brs,

2H), 3.04 (s, 3H), 2.68-2.67 (brs, 2H), 2.53 (s, 3H), 1.30-1.29 (brs, 2H), 1.26-1.17 (m, 2H), 1.07 (s, 9H), 0.75 (s, 6H); and (S)-2-tert-butoxy-2-(5-((2-(2-cyano-4-fluorophenoxy)ethyl) (methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-2,3'-bipyridin-5'-yl)acetic acid (2.6 mg, 4.28 pmol, 11.05% yield) as a white solid. LCMS: Retention time (10 M NH4HCO3): 1.552 min, (M+H) = 604. ¾ NMR (400 MHz, MeOD) 5 8.23 (d, J = 2.9 Hz, 1H), 8.15 (s, 1H), 7.51- 7.37 (m, 3H), 7.33 (d, J = 8.7 Hz, 1H), 7.21 (dd, J = 9.3, 4.1 Hz, 1H), 5.74 (s, 1H), 4.37 (t, J = 4.8 Hz, 2H), 4.09-3.91 (m, 2H), 3.30- 2.95 (m, 5H), 2.82-2.81 (brs, 2H), 2.66 (s, 3H), 1.43-1.42 (brs, 2H), 1.36- 1.31 (m, 2H), 1.20 (s, 9H), 0.89 (s, 6H).

Example 278

Step 1 : To a solution of p-cresol (1.0 g, 9.25 mmol) in DMF (15 mL) was added CS2CO3 (6.03 g, 18.49 mmol) at 20 °C and stirred for 15 minutes. Then, 2-((tert- butoxycarbonyl)amino)ethyl methanesulfonate (2.213 g, 9.25 mmol) was added at once and the mixture was stirred at 100 °C for 16 hours. Then, the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over NaiSCL, and the solvent was removed in vacuo to give the crude product as an oil. The crude oil was purified by reversed phase column chromatography (Cl 8 ODS, using 80 g; Mobile Phase A: Water (10 mmol

NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(p-tolyloxy)ethyl)carbamate (0.97 g, 3.86 mmol, 41.7 % yield) as yellow oil. LCMS (M + Na) = 274.1; Retention time (10 mmol NHiHCCb) = 1.831 min.

Step 2: To a solution of tert-butyl (2-(p-tolyloxy)ethyl)carbamate (0.47 g, 1.870 mmol) in DCM (6 mL) was added 2,2,2-trifluoroacetic acid (2 mL, 1.870 mmol) at once. The reaction mixture was stirred at 20 °C for 12 hours. The solvent was removed in vacuo, the solid was diluted with DCM (50 ml), washed with saturated NaiCC (50 ml x2) and water (50 ml x2). The organic layer was dried over NaiSOr and concentrated to afford the desired product 2-(p-tolyloxy)ethanamine (0.2 g, 1.079 mmol, 57.7 % yield) as a yellow oil. LCMS (M + H) = 152.1; Retention time (10 mmol NTLHCCh) = 1.137 min.

Step 3: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (20 mg, 0.042 mmol) in NMP (0.5 mL) was added K2CO3 (41.0 mg, 0.297 mmol) and 2-(p-tolyloxy)ethanamine (31.8 mg, 0.170 mmol) at once. The reaction mixture was stirred at 120 °C for 12 hours. Then, the mixture was cooled and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol

NH4HCO3); B: MeCN; Gradient 80-83%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6-methyl-6'- ((2-(p-tolyloxy)ethyl)amino)-[3,3'-bipyridin]-5-yl)acetate (7 mg, 0.012 mmol, 27.4 % yield) as yellow oil. LCMS (M + H) = 603.2; Retention time (10 mmol NH4HCO3) = 2.445 min.

Step 4: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6-methyl-6'-((2-(p-tolyloxy)ethyl)amino)-[3,3'-bipyridin]-5-yl)acetate (20 mg, 0.033 mmol) in ethanol (5 mL) was added sodium hydroxide (26.5 mg, 0.664 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 hours, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 50-53% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6-methyl-6'-((2-(p-tolyloxy)ethyl)amino)-[3,3'-bipyridin]-5-yl)acetic acid (11.0 mg, 0.020 mmol, 59.1 % yield) as a white solid. LCMS (M + H) = 561.2;

Retention time (10 mmol NH4HCO3) = 1.545 min. Ή NMR (400 MHz, MeOD): d 8.07 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.7, 2.1 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.7 Hz, 1H), 5.71 (s, 1H), 4.15 (t, J = 5.5 Hz, 2H), 3.74-3.78 (m, 3H), 2.69-2.81 (m, 3H), 2.66 (s, 3H), 2.27 (s, 3H), 1.41-1.50 (m, 4H), 1.20 (s, 9H), 0.92 (s, 6H).

Example 279

Step 1 : To a solution of p-cresol (1.0 g, 9.25 mmol) in DMF (15 mL) was added CS2CO3 (6.03 g, 18.49 mmol) at 20 °C and stirred for 15 minutes. Then, 2-((tert- butoxycarbonyl)amino)ethyl methanesulfonate (2.213 g, 9.25 mmol) was added at once and the mixture was stirred at 100 °C for 16 hours. Then, the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give the crude product as an oil. The crude product was purified by reversed phase column chromatography (Cl 8 ODS, using 80 g; Mobile Phase A: Water (10 mmol

NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(p-tolyloxy)ethyl)carbamate (0.97 g, 3.86 mmol, 41.7 % yield) as yellow oil. LCMS (M + Na⁺) = 274.1; Retention time (10 mmol NH4HCO3) = 1.831 min.

Step 2: To a solution of tert-butyl (2-(p-tolyloxy)ethyl)carbamate (0.47 g, 1.870 mmol) in DMF (10 mL) was added NaH (0.090 g, 3.74 mmol) at 0 °C and stirred at 0 °C for 30 minutes. Then, iodomethane (0.140 mL, 2.244 mmol) was added at once and the mixture was stirred at 20 °C for 3 hours. Then, water (50 mL) was added to the mixture and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4, and the solvent was removed in vacuo to give tert-butyl methyl(2- (p-tolyloxy)ethyl)carbamate (0.42 g, 1.583 mmol, 85 % yield) as a pale yellow oil. LCMS (M -55) = 210.1; Retention time (10 mmol NH4HCO3) = 1.651 min.

Step 3: To a solution of HC1 (8 mL, 4M solution in 1, 4-dioxane) was added tert-butyl methyl(2-(p-tolyloxy)ethyl)carbamate (0.42 g, 1.583 mmol) at once and stirred at 20 °C for 12 hours. Then, the mixture was filtered to give N-methyl-2-(p-tolyloxy)ethanamine hydrochloride (0.309 g, 1.087 mmol, 68.7 % yield) as a white solid. LCMS (M + H) = 166.2; Retention time (10 mmol NHiHCCh) = 1.315 min.

Step 4: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (0.5 mL) was added K2CO3 (103 mg, 0.742 mmol) and N-methyl-2-(p-tolyloxy)ethanamine hydrochloride (86 mg, 0.424 mmol) at once. The reaction mixture was stirred at 120 °C for 12 hours. Then, the mixture was cooled and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 90-92% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6- methyl-6'-(methyl(2-(p-tolyloxy)ethyl)amino)-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.061 mmol, 57.6 % yield) as yellow oil. LCMS (M + H) = 617.3; Retention time (10 mmol NH4HCO3) = 2.728 min.

Step 5: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6-methyl-6'-(methyl(2-(p-tolyloxy)ethyl)amino)-[3,3'-bipyridin]-5-yl)acetate (40 mg,

0.065 mmol) in ethanol (5 mL) was added sodium hydroxide (51.9 mg, 1.297 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 hours, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 53-55% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6-methyl-6'-(methyl(2-(p-tolyloxy)ethyl)amino)-[3,3'-bipyridin]-5- yl)acetic acid (10 mg, 0.017 mmol, 26.6 % yield) as white solid. LCMS (M + H) = 575.2; Retention time (10 mmol NH4HCO3) = 1.640 min. Ή NMR (400 MHz, MeOD): d 8.09 (s, 1H), 8.05 (d, J= 2.2 Hz, 1H), 7.52 (dd, J= 8.8, 2.4 Hz, 1H), 7.06 (d, J= 8.3 Hz, 2H), 6.86 (d, J= 8.8 Hz, 1H), 6.80 (d, J= 8.5 Hz, 2H), 5.71 (s, 1H), 4.20 (t, J= 5.4 Hz, 2H), 3.90-4.10 (m, 3H), 3.23 (s, 3H), 2.73-2.79 (m, 3H), 2.66 (s, 3H), 2.26 (s, 3H), 1.40-1.45 (m, 4H), 1.20 (s, 9H), 0.90 (s, 6H). Example 280

Step 1 : To a solution of 2,6-dimethylphenol (1.0 g, 8.19 mmol) in DMF (15 mL) was added CS2CO3 (5.33 g, 16.37 mmol) at 20 °C and stirred at 20 °C for 15 minutes. Then, 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.959 g, 8.19 mmol) was added at once and the mixture was stirred at 100 °C for 16 hours. Then, the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over NaiSCL, and the solvent was removed in vacuo to give the crude product as an oil. The crude oil was purified by reversed phase column chromatography (Cl 8 ODS, using 80 g; Mobile Phase A: Water (10 mmol

NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(2,6-dimethylphenoxy)ethyl)carbamate (1.06 g, 3.62 mmol, 44.2 % yield) as yellow oil. LCMS (M + Na⁺) = 288.1; Retention time (10 mmol NLLHCCh) = 1.897 min.

Step 2: To a solution of tert-butyl (2-(2,6-dimethylphenoxy)ethyl)carbamate (0.5 g, 1.884 mmol) in DMF (10 mL) was added NaH (0.090 g, 3.77 mmol) at 0 °C and stirred at 0 °C for 30 minutes. Then, iodomethane (0.177 mL, 2.83 mmol) was added at once and the mixture was stirred at 20 °C for 3 hours. Then, water (50 mL) was added to the mixture and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give tert-butyl (2-(2,6-dimethylphenoxy)ethyl)(methyl)carbamate (0.66 g, 1.740 mmol, 92 % yield) as a pale yellow oil. LCMS (M + Na⁺) = 302.2; Retention time (0.0l%TFA) = 1.772 min.

Step 3: To a solution of HC1 (8 mL, 4M solution in 1, 4-dioxane) was added tert-butyl (2-(2,6-dimethylphenoxy)ethyl)(methyl)carbamate (0.66 g, 2.362 mmol) at once. The reaction mixture was stirred at 20 °C for 12 hours. Then, the mixture was filtered to give 2- (2,6-dimethylphenoxy)-N-methylethanamine hydrochloride (0.377 g, 1.338 mmol, 56.7 % yield) as a white solid. LCMS (M + H) = 180.1; Retention time (10 mmol NH4HCO3) =

1.384 min. Step 4: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (0.5 mL) was added K2CO3 (103 mg, 0.742 mmol) and 2-(2,6-dimethylphenoxy)-N-methylethanamine hydrochloride (91 mg, 0.424 mmol) at once. The reaction mixture was stirred at 120 °C for 12 hours. Then, the mixture was cooled and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 94-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-isopropyl 2-(tert-butoxy)-2-(6'-((2-(2,6- dimethylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (50 mg, 0.065 mmol, 61.0 % yield) as yellow oil. LCMS (M + H) = 630.0; Retention time (10 mmol NH4HCO3) = 2.833 min.

Step 5: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(6'-((2-(2,6- dimethylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (40 mg, 0.063 mmol) in ethanol (5 mL) was added sodium hydroxide (25.4 mg, 0.634 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 hours, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 55-58% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2- (tert-butoxy)-2-(6'-((2-(2,6-dimethylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin- l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (10.6 mg, 0.018 mmol, 28.4 % yield) as a white solid. LCMS (M + H) = 589.2; Retention time (10 mmol NH4HCO3) = 1.672 min. Ή NMR (400 MHz, MeOD): d 8.10 (s, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.52-7.57 (m, 1H), 6.98 (d, J = 7.4 Hz, 2H), 6.87-6.93 (m, 2H), 5.70 (s, 1H), 4.12-4.17 (m, 2H), 3.91-4.05 (m, 4H), 3.32 (s, 3H), 2.70-2.82 (m, 2H), 2.66 (s, 3H), 2.18 (s, 6H), 1.40-1.50 (m, 4H), 1.20 (s, 9H), 0.85 (s, 6H).

Example 281

Step 1 : To a solution oftert-butyl (2-(2,6-dimethylphenoxy)ethyl)carbamate (0.5 g, 1.884 mmol) in DCM (6 mL) was added 2,2,2-trif uoroacetic acid (2 mL, 1.870 mmol) at once. The reaction mixture was stirred at 20 °C for 12 hours. The solvent was removed in vacuo, the solid was diluted with DCM (50 ml), washed with saturated NaiCCh (50 ml x2) and water (50 ml x2). The organic layer was dried over NaiSOr and concentrated to afford the desired product 2-(2,6-dimethylphenoxy)ethanamine (0.26 g, 1.370 mmol, 72.7 % yield) as yellow oil. LCMS (M + H) = 166.2; Retention time (0.0l%TFA) = 1.178 min.

Step 2: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (30 mg, 0.064 mmol) in NMP (0.5 mL) was added K2CO3 (61.5 mg, 0.445 mmol) and 2-(2,6-dimethylphenoxy)ethanamine (51.3 mg, 0.254 mmol) at once. The reaction mixture was stirred at 120 °C for 12 hours. Then, the mixture was cooled and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009);

Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 83-85% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-isopropyl 2-(tert-butoxy)-2-(6'-((2-(2,6-dimethylphenoxy)ethyl)amino)-4- (4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (15 mg, 0.024 mmol,

38.2 % yield) as yellow oil. LCMS (M + H) = 617.3; Retention time (10 mmol NH4HCO3) = 2.535 min.

Step 3: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(6'-((2-(2,6- dimethylphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin- 1 -yl)-6-methyl-[3 ,3 -bipyridin] -5 - yl)acetate (30 mg, 0.049 mmol) in ethanol (5 mL) was added sodium hydroxide (38.9 mg, 0.973 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 hours, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC { Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3) ; B: MeCN; Gradient 51-54% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2- (tert-butoxy)-2-(6'-((2-(2,6-dimethylphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6- methyl-[3,3'-bipyridin]-5-yl)acetic acid (11.3 mg, 0.020 mmol, 40.4 % yield) as a white solid. LCMS (M + H) = 575.2; Retention time (10 mmol NH4HCO3) = 1.566 min. Ή NMR (400 MHz, MeOD): d 8.09 (s, 1H), 7.95-7.93 (m, 1H), 7.46 (dd, J = 8.7 Hz, 1H), 6.99 (d, J = 7.5 Hz, 2H), 6.87-6.92 (m, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.71 (s, 1H), 3.93-4.01 (m, 2H), 3.72- 3.87 (m, 4H), 2.71-2.78 (m, 2H), 2.66 (s, 3H), 2.25 (s, 6H), 1.41-1.54 (m, 4H), 1.20 (s, 9H), 0.89 (s, 6H).

Example 282

Step 1 : To a solution of 2,4-dichlorophenol (1.0 g, 6.14 mmol) in DMF (15 mL) was added CS2CO3 (4.00 g, 12.27 mmol) at 20 °C and stirred for 15 minutes. Then, 2-((tert- butoxycarbonyl)amino)ethyl methanesulfonate (1.468 g, 6.14 mmol) was added at once and stirred at 100 °C for 16 hours. Then, the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give the crude product as an oil. The crude oil was purified by reversed phase column

chromatography (C18 ODS, using 80 g; Mobile Phase A: Water (10 mmol NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2- (2,4-dichlorophenoxy)ethyl)carbamate (0.380 g, 1.184 mmol, 19.30 % yield) as yellow oil. LCMS (M + Na⁺) = 327.0; Retention time (10 mmol NH4HCO3) = 1.628 min.

Step 2: To a solution of HC1 (8 mL, 4M solution in 1, 4-dioxane) was added tert-butyl (2-(2,4-dichlorophenoxy)ethyl)carbamate (0.18 g, 0.588 mmol) at once. The reaction mixture was stirred at 20 °C for 12 hours. Then, the mixture was filtered to give 2-(2,4- dichlorophenoxy)ethan-l -amine hydrochloride (0.12 g, 0.468 mmol, 80 % yield) as a white solid. LCMS (M + H) = 206.0; Retention time (10 mmol NH4HCO3) = 1.233 min. Step 3: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (90 mg, 0.191 mmol) in NMP (0.5 mL) was added K2CO3 (185 mg, 1.336 mmol) and 2-(2,4-dichlorophenoxy)ethan-l -amine hydrochloride (109 mg, 0.746 mmol) at once. The reaction mixture was stirred at 120 °C for 12 hours. Then, the mixture was cooled and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 85-87%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2,4- dichlorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (40 mg, 0.061 mmol, 31.9 % yield) as yellow oil. LCMS (M + H) = 657.1;

Retention time (10 mmol NH4HCO3) = 2.607 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2,4- dichlorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (37 mg, 0.056 mmol) in ethanol (5 mL) was added sodium hydroxide (45.0 mg, 1.125 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 hours, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 55-57% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2- (tert-butoxy)-2-(6'-((2-(2,4-dichlorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6- methyl-[3,3'-bipyridin]-5-yl)acetic acid (2.4 mg, 3.90 pmol, 6.93 % yield) as a white solid. LCMS (M + H) = 615.0; Retention time (10 mmol NH4HCO3) = 1.704 min. Ή NMR (400 MHz, MeOD): d 8.06 (s, 1H), 7.95 (m, 1H), 7.41-7.45 (m, 2H), 7.27 (dd, J = 8.8, 2.5 Hz,

1H), 7.12 (d, J = 8.9 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 5.71 (s, 1H), 4.26 (t, J = 5.5 Hz, 2H), 3.83 (t, J = 5.3 Hz, 2H), 3.11-3.25 (m, 2H), 2.70-2.81 (m, 2H), 2.65 (s, 3H), 1.32-1.45 (m, 2H), 1.20-1.31 (m, 2H), 1.20 (s, 9H), 0.91 (s, 6H).

Example 283

Step 1 : To a solution oftert-butyl (2-(2,4-dichlorophenoxy)ethyl)carbamate (0.2 g, 0.653 mmol) in DMF (10 mL) was added NaH (0.031 g, 1.306 mmol) at 0 °C and stirred for 30 minutes. Then, iodomethane (0.082 mL, 1.306 mmol) was added at once and the mixture was stirred at 20 °C for 3 hours. Then, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give tert-butyl (2-(2,4-dichlorophenoxy)ethyl)(methyl)carbamate (0.25 g, 0.642 mmol, 98 % yield) as yellow oil. LCMS (M + Na⁺) = 342.1; Retention time (10 mmol NLLHCCh) = l .709min.

Step 2: To a solution of HC1 (8 mL, 4M solution in 1, 4-dioxane) was added tert-butyl (2-(2,4-dichlorophenoxy)ethyl)(methyl)carbamate (0.25 g, 0.781 mmol) at once. The reaction mixture was stirred at 20 °C for 12 hours. Then, the mixture was filtered to give 2-(2,4- dichlorophenoxy)-N-methylethan-l -amine hydrochloride (0.15 g, 0.376 mmol, 48.2 % yield) as a white solid. LCMS (M + H) = 220.0; Retention time (10 mmol NLLHCCh) = 1.273 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-chloro-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.102 mmol) in toluene (3 mL) was added 2-(2,4-dichlorophenoxy)-N-methylethan-l-amine (22.55 mg, 0.102 mmol), dicyclohexyl(2',6'-diisopropoxy-[l,r-biphenyl]-2-yl)phosphane (9.56 mg, 0.020 mmol), Pd2(dba)3 (9.38 mg, 10.24 pmol) and cesium carbonate (100 mg, 0.307 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 hours. LCMS showed reaction was completed. The reaction mixture was filtered, concentrated and purified by Prep-HPLC to afford isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2,4- dichlorophenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (20 mg, 0.030 mmol, 29.1 % yield) as white solid. LCMS (M+H) = 671.7. Retention time (10 mmol NH4HCO3) = 3.001 min. Step 4: To a solution ofNaOH (11.91 mg, 0.298 mmol) in ethanol (3 mL) and H20 (0.500 mL) was added the isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2,4- dichlorophenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (20 mg, 0.030 mmol). The mixture was stirred at 90 °C for additional 20 h. The LCMS showed the reaction was completed. The pH was adjusted to about 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC to give (S)- 2-(tert-butoxy)-2-(6'-((2-(2,4-dichlorophenoxy)ethyl)(methyl)amino)-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (4.8 mg, 7.43 pmol,

24.95 % yield) was obtained. LCMS: m/z=629.2 , Retention time (10 mmol NH4HCO3) = 1.577 min, purity: 100%. ¾NMR (400 MHz, MeOD): d 8.07 (s, 1H), 8.05 (d, J= 2.4 Hz, 1H), 7.54 (dd, J= 8.8, 2.4 Hz, 1H), 7.41 (d, J= 2.4 Hz, 1H), 7.26 (dd, J= 8.8, 2.4 Hz, 1H), 7.09 (d, J= 8.8 Hz, 1H), 6.88 (d, J= 8.8 Hz, 1H), 5.71 (s, 1H), 4.32 (t, J= 5.0 Hz, 2H), 4.10- 4.08 (m, 2H), 3.28 (s, 3H), 3.25-3.11 (m, 2H), 2.76-2.75 (brs, 2H), 2.66 (s, 3H), 1.45-1.37 (m, 4H), 1.20 (s, 9H), 0.89 (s, 6H).

Example 284

Step 1 : To a solution of 2,4-difluorophenol (1.0 g, 7.69 mmol) in DMF (15 mL) was added CS2CO3 (5.01 g, 15.37 mmol) at 20 °C and stirred for 15 minutes. Then, 2-((tert- butoxycarbonyl)amino)ethyl methanesulfonate (1.839 g, 7.69 mmol) was added at once and stirred at 100 °C for 16 hours. Then, the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over NaiSOi. and the solvent was removed in vacuo to give the crude product as an oil. The crude oil was purified by reversed phase column

chromatography (C18 ODS, using 80 g; Mobile Phase A: Water (10 mmol NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2- (2,4-difluorophenoxy)ethyl)carbamate (0.25 g, 0.915 mmol, 11.90 % yield) as yellow oil. LCMS (M + Na⁺) = 296.1; Retention time (0.0l%TFA) = 1.600 min.

Step 2: To a solution of HC1 (8 mL, 4M solution in 1, 4-dioxane) was added tert-butyl (2-(2,4-difluorophenoxy)ethyl)carbamate (0.25 g, 0.915 mmol) at once. The reaction mixture was stirred at 20 °C for 12 hours. Then, the mixture was filtered to give 2-(2,4- difluorophenoxy)ethan-l -amine hydrochloride (0.15 g, 0.716 mmol, 55.9 % yield) as a white solid. LCMS (M + H) = 174.1; Retention time (0.0l%TFA) =0.726 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (0.5 mL) was added K2CO3 (103 mg, 0.742 mmol) and 2-(2,4-difluorophenoxy)ethan-l -amine hydrochloride (89 mg, 0.424 mmol) at once. The reaction mixture was stirred at 120 °C for 12 hours. Then, the mixture was cooled and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 76-78%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2,4- difhiorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (20 mg, 0.032 mmol, 30.2 % yield) as yellow oil. LCMS (M + H) = 625.2;

Retention time (10 mmol NH4HCO3) = 2.319 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2,4- difhiorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (20 mg, 0.032 mmol) in ethanol (5 mL) was added sodium hydroxide (25.6 mg, 0.640 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 hours, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 52-55% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2- (tert-butoxy)-2-(6'-((2-(2,4-difluorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6- methyl-[3,3'-bipyridin]-5-yl)acetic acid (3.9 mg, 6.57 pmol, 20.52 % yield) as a white solid. LCMS (M + H) = 583.0; Retention time (10 mmol NH4HCO3) = 1.591 min. Ή NMR (400 MHz, MeOD): d 8.07 (s, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.44 (dd, J= 8.7, 2.4 Hz, 1H), 7.12- 7.17 (m, 1H), 6.96-7.01 (m, 1H), 6.84-6.90 (m, 1H), 6.75 (d, J= 8.5 Hz, 1H), 5.71 (s, 1H), 4.24 (t, J= 5.5 Hz, 2H), 3.75-3.83 (m, 2H), 2.89-3.30 (m, 2H), 2.71-2.77 (m, 2H), 2.66 (s, 3H), 1.42-1.46 (m, 2H), 1.30-1.41 (m, 2H), 1.20 (s, 9H), 0.92 (s, 6H). Example 285

Step 1 : To a solution of 4-chloro-2-fluorophenol (1.0 g, 6.82 mmol) in DMF (15 mL) was added CS2CO3 (4.45 g, 13.65 mmol) at 20 °C and stirred for 15 minutes. Then, 2-((tert- butoxycarbonyl)amino)ethyl methanesulfonate (1.633 g, 6.82 mmol) was added at once and the mixture was stirred at 100 °C for 16 hours. Then, the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give the crude product as an oil. The crude oil was purified by reversed phase column chromatography (Cl 8 ODS, using 80 g; Mobile Phase A: Water (10 mmol

NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(4-chloro-2-fluorophenoxy)ethyl)carbamate (0.85 g, 2.143 mmol, 31.4 % yield) as yellow oil. LCMS (M + Na⁺) = 311.0; Retention time (10 mmol NH4HCO3) = 1.552 min.

Step 2: To a solution of HC1 (8 mL, 4M solution in 1, 4-dioxane) was added tert-butyl (2-(4-chloro-2-fluorophenoxy)ethyl)carbamate (0.4 g, 1.381 mmol) at once. The reaction mixture was stirred at 20 °C for 12 hours. Then, the mixture was filtered to give 2-(4-chloro- 2-fluorophenoxy)ethan-l -amine hydrochloride (0.23 g, 1.017 mmol, 73.7 % yield) as a white solid. LCMS (M + H) = 190.1; Retention time (10 mmol NH4HCO3) = 1.151 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (0.5 mL) was added K₂CO3 (103 mg, 0.742 mmol) and 2-(4-chloro-2-fluorophenoxy)ethan-l -amine hydrochloride (96 mg, 0.424 mmol) at once. The reaction mixture was stirred at 120 °C for 12 hours. Then, the mixture was cooled and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A:

Water (10 mmol NH4HCO3); B: MeCN; Gradient 80-85% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(4-chloro-2- fluorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (25 mg, 0.039 mmol, 36.8 % yield) as yellow oil. LCMS (M + H) = 641.2;

Retention time (10 mmol NH4HCO3) = 2.450 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(4-chloro-2- fluorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (25 mg, 0.039 mmol) in ethanol (5 mL) was added sodium hydroxide (31.2 mg, 0.780 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 hours, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 54-58% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2- (tert-butoxy)-2-(6'-((2-(4-chloro-2-fluorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l- yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (3.5 mg, 5.84 pmol, 14.98 % yield) as a white solid. LCMS (M + H) = 599.1; Retention time (10 mmol NH4HCO3) = 1.655 min. ¾ NMR (400 MHz, MeOD): d 7.95 (s, 1H), 7.84 (d, J= 2.0 Hz, 1H), 7.32 (dd, J= 8.6, 2.3 Hz, 1H), 6.97-7.09 (m, 3H), 6.63 (d, J= 8.7 Hz, 1H), 5.59 (s, 1H), 4.14 (t, J= 5.5 Hz, 2H), 3.67-3.70 (m, 2H), 2.81-3.13 (m, 2H), 2.59-2.69 (m, 2H), 2.54 (s, 3H), 1.31-1.34 (m, 2H), 1.18-1.30 (m, 2H), 1.08 (s, 9H), 0.79 (s, 6H).

Example 286

Step 1 : To a solution of tert-butyl (2-(4-chloro-2-fluorophenoxy)ethyl)carbamate (0.45 g, 1.553 mmol) in DMF (10 mL) was added NaH (0.075 g, 3.11 mmol) at 0 °C and stirred for 30 minutes. Then, iodomethane (0.194 mL, 3.11 mmol) was added at once and the mixture was stirred at 20 °C for 3 hours. Then, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SC>4, and the solvent was removed in vacuo to give tert-butyl (2-(4-chloro-2-fluorophenoxy)ethyl)(methyl)carbamate (0.514 g, 1.278 mmol, 82 % yield) as yellow oil. LCMS (M + Na⁺) = 325.0; Retention time (10 mmol NH4HCO3) =

1 654min

Step 2: To a solution of HC1 (8 mL, 4M solution in 1, 4-dioxane) was added tert-butyl (2-(4-chloro-2-fluorophenoxy)ethyl)(methyl)carbamate (0.514 g, 1.692 mmol) at once. The reaction mixture was stirred at 20 °C for 12 hours. Then, the mixture was filtered to give 2- (4-chloro-2-fluorophenoxy)-N-methylethan-l -amine hydrochloride (0.26 g, 1.030 mmol,

60.9 % yield) as a white solid. LCMS (M + H) = 204.1; Retention time (10 mmol NH4HCO3) = 1.182 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-chloro-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.102 mmol) in toluene (3 mL) was added 2-(4-chloro-2-fluorophenoxy)-N-methylethan-l -amine (20.86 mg, 0.102 mmol), dicyclohexyl(2',6'-diisopropoxy-[l, r-biphenyl]-2-yl)phosphane (9.56 mg, 0.020 mmol), Pd2(dba)3 (9.38 mg, 10.24 pmol) and cesium carbonate (100 mg, 0.307 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 hours. LCMS showed reaction was completed. The solvent was removed in vacuo. The brown paste was purified by Prep-HPLC to afford isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(4-chloro-2- fluorophenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (16 mg, 0.024 mmol, 23.84 % yield) as white solid. LCMS (M+H) = 655.7; rt = 2.830 min.

Step 4: To a solution of NaOH (9.16 mg, 0.229 mmol) in ethanol (3 mL) and H20 (0.500 mL) was added the isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(4-chloro-2- fluorophenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (15 mg, 0.023 mmol). The mixture was stirred at 90 °C for 20 h. LCMS showed the reaction was completed. The pH was adjusted to about 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC to give (S)-2-(tert- butoxy)-2-(6'-((2-(4-chloro-2-fhiorophenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin- l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (3.8 mg, 5.95 pmol, 26.0 % yield) was obtained. LCMS: m/z = 613.3, Retention time (10 mmol NH4HCO3) = 1.524. Ή NMR (400 MHz, MeOD): d 8.05 (d, J= 2.8 Hz, 2H), d 7.54 (dd, J= 2.4, 8.8 Hz, 1H), 7.19 (dd, Ji= 2.0, Ji= 0.8, J= 10.6 Hz, 1H), 7.10-7.09 (m, 1H), 7.09 (d, J= 2.0 Hz, 1H), 6.86 (d, J= 8.8 Hz, 1H), 5.71 (s, 1H), 4.32 (t, J= 5.4 Hz, 2H), 4.09-4.05 (m, 2H), 3.32-3.31 (brs, 1H), 3.23 (s, 3H), 2.92-2.91 (brs, 1H), 2.65-2.64 (brs, 2H), 2.65 (s, 3H), 1.48-1.35 (m, 4H), 1.20 (s, 9H), 0.88 (s, 6H). Example 287

Step 1 : To a solution of 3-fluoro-4-methylphenol (l .Og, 7.93 mmol) in DMF (15 mL) was added CS2CO3 (5.17 g, 15.86 mmol) at 20 °C and stirred for 15 minutes. Then, 2-((tert- butoxycarbonyl)amino)ethyl methanesulfonate (1.897 g, 7.93 mmol) was added at once and the mixture was stirred at 100 °C for 16 hours. Then, the mixture was cooled, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give the crude product as a crude oil. The crude oil was purified by reversed phase column chromatography (Cl 8 ODS, using 80 g; Mobile Phase A: Water (10 mmol

NH4HCO3), B: Methanol; eluting with 50% methanol to 60% methanol in water) to give the tert-butyl (2-(3-fluoro-4-methylphenoxy)ethyl)carbamate (1.0 g, 3.51 mmol, 44.3 % yield) as yellow oil. LCMS (M + Na⁺) = 292.1; Retention time (0.0l%TFA) = 1.655 min

Step 2: To a solution of HC1 (8 mL, 4M solution in 1, 4-dioxane) was added tert-butyl (2-(3-fluoro-4-methylphenoxy)ethyl)carbamate (0.5 g, 1.857 mmol) at once. The reaction mixture was stirred at 20 °C for 12 hours. Then, the mixture was filtered to give 2-(3-fluoro- 4-methylphenoxy)ethanamine hydrochloride (0.419 g, 1.428 mmol, 77 % yield) as a white solid. LCMS (M + H) = 170.1; Retention time (10 mmol NH4HCO3) = 1.358 min.

Step 3: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (0.5 mL) was added K2CO3 (103 mg, 0.742 mmol) and 2-(3-fhioro-4-methylphenoxy)ethanamine hydrochloride (87 mg, 0.424 mmol) at once. The reaction mixture was stirred at 120 °C for 12 hours. Then, the mixture was cooled and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 80-83% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'- ((2-(3 -fluoro-4-methylphenoxy)ethyl)amino)-6-methyl- [3 ,3 '-bipyridin] -5 -yl)acetate (35 mg, 0.056 mmol, 53.2 % yield) as yellow oil. LCMS (M + H) = 621.2; Retention time (10 mmol NH4HCO3) = 2.454 min.

Step 4: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(3-fluoro-4-methylphenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (35 mg, 0.056 mmol) in ethanol (5 mL) was added sodium hydroxide (45.1 mg, 1.128 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 hours, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep- HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 40-68% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-((2-(3-fhioro-4-methylphenoxy)ethyl)amino)-6-methyl-[3,3'- bipyridin] -5 -yl)acetic acid (21.8 mg, 0.038 mmol, 66.8 % yield) as a white solid. LCMS (M + H) = 579.2; Retention time (10 mmol NH4HCO3) = 1.666 min. Ή NMR (400 MHz, MeOD): 5 8.08 (s, 1H), 7.96 (d, J= 2.0 Hz, 1H), 7.44 (dd, J= 8.6, 2.3 Hz, 1H), 7.11 (t, J= 8.9 Hz,

1H), 6.75 (d, J= 8.8 Hz, 1H), 6.67-6.71 (m, 2H), 5.71 (s, 1H), 4.16 (t, J= 5.5 Hz, 2H), 3.73- 3.82 (m, 2H), 2.91-3.28 (m, 2H), 2.73-2.84 (m, 2H), 2.66 (s, 3H), 2.19 (s, 3H), 1.40-1.55 (m, 4H), 1.20 (s, 9H), 0.92 (s, 6H).

Example 288

Step 1 : To a solution oftert-butyl (2-(3-fluoro-4-methylphenoxy)ethyl)carbamate (0.5 g, 1.857 mmol) in DMF (10 mL) was added NaH (0.089 g, 3.71 mmol) at 0 °C and stirred for 30 minutes. Then, iodomethane (0.232 mL, 3.71 mmol) was added at once and the mixture was stirred at 20 °C for 3 hours. Then, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over NaiSOr. and the solvent was removed in vacuo to give tert-butyl (2-(3-fluoro-4-methylphenoxy)ethyl)(methyl)carbamate (0.5 g, 1.706 mmol, 92 % yield) as a pale yellow oil. LCMS (M + H) = 306.1; Retention time (0.0l%TFA) = 1.733 min.

Step 2: To a solution of HC1 (8 mL, 4M solution in 1, 4-dioxane) was added tert-butyl (2-(3-fluoro-4-methylphenoxy)ethyl)(methyl)carbamate (0.6 g, 2.118 mmol) at once. The reaction mixture was stirred at 20 °C for 12 hours. Then, the mixture was filtered to give 2- (3-fluoro-4-methylphenoxy)-N-methylethanamine hydrochloride (0.369 g, 1.388 mmol,

65.6 % yield) as a white solid. LCMS (M + H) = 184.2; Retention time (10 mmol NH4HCO3) = 1.379 min.

Step 3: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (0.5 mL) was added K2CO3 (103 mg, 0.742 mmol) and 2-(3-fluoro-4-methylphenoxy)-N- methylethanamine hydrochloride (93 mg, 0.424 mmol) at once. The reaction mixture was stirred at 120 °C for 12 hours. Then, the mixture was cooled and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-98% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-((2-(3-fhioro-4-methylphenoxy)ethyl)(methyl)amino)-6-methyl- [3,3'-bipyridin]-5-yl)acetate (30 mg, 0.047 mmol, 44.6 % yield) as yellow oil. LCMS (M +

H) = 635.2; Retention time (10 mmol NH4HCO3) = 2.740 min.

Step 4: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(3-fluoro-4-methylphenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (30 mg, 0.047 mmol) in ethanol (5 mL) was added sodium hydroxide (37.8 mg, 0.945 mmol) in water (1 ml) at once. The mixture was stirred at 90 °C for 10 hours, cooled and the pH was adjusted to 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 40-68% B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2- (tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-((2-(3-fluoro-4- methylphenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (7.4 mg, 0.012 mmol, 26.4 % yield) as white solid. LCMS (M + H) = 593.2; Retention time (10 mmol NH4HCO3) = 1.748 min. ¾ NMR (400 MHz, MeOD): d 8.08 (s, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.8, 2.4 Hz, 1H), 7.09 (t, J = 8.9 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.62- 6.66 (m, 2H), 5.72 (s, 1H), 4.21 (t, J = 5.4 Hz, 2H), 3.94-4.11 (m, 2H), 3.22 (s, 3H), 2.85-3.15 (m, 2H), 2.72-2.80 (m, 2H), 2.66 (s, 3H), 2.18 (s, 3H), 1.43-1.48 (m, 2H), 1.30-1.42 (m, 2H), 1.20 (s, 9H), 0.90 (s, 6H).

Example 289

Step 1 : To a solution of 4-fluoro-3-methylphenol (0.8 g, 6.34 mmol) in DMF (15 mL) was added CS2CO3 (2.69 g, 8.25 mmol) at room temperature and stirred for 15 minutes. Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.821 g, 7.61 mmol) was added and the mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled, diluted with water (100 mL) and the product was extracted with ethyl acetate(l00 mL). The organic layer was washed with water (50 mL x2), brine (50 mL x2), dried over Na/SOr. and the solvent was removed in vacuo to give a crude oil. The oil was purified on silica gel column (ethyl acetate/petroleum ether =7: 1-4: 1) to afford desired product tert-butyl (2-(4-fluoro-3- methylphenoxy)ethyl)carbamate (0.9 g, 2.67 mmol, 42.2 % yield) as yellow oil. LCMS (M + H) = 259, Retention time (0.0l%TFA) = 1 446min

Step 2: To a solution of tert-butyl (2-(4-fluoro-3-methylphenoxy)ethyl)carbamate (500 mg, 1.857 mmol) in DMF (2 mL) was added NaH (223 mg, 5.57 mmol) at 0 °C under an atmosphere ofN2. The mixture was stirred at 0 °C for 15 minutes and Mel (0.232 mL,

3.71 mmol) was added. The mixture was stirred at room temperature for 16 hours. Then, quenched with an ice water (10 ml) and extracted with ethyl acetate(20 mL x3). The combined organic layers were washed with water (20 mL x 2), brine (20 mL), dried by Na2SC>4 and concentrated to give tert-butyl (2-(4-fluoro-3- methylphenoxy)ethyl)(methyl)carbamate (480 mg, 1.220 mmol, 65.7 % yield) as yellow oil. LCMS (M + Na) = 306.1, Retention time (0.0l%TFA) = 2.06 min.

Step 3: To a solution of HC1 (8 mL, 4M solution in l,4-dioxane) was added tert-butyl (2-(4-fluoro-3-methylphenoxy)ethyl)(methyl)carbamate (0.42 g, 1.482 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. The mixture was filtered and washed with EtiO to give desired product 2-(4-fluoro-3-methylphenoxy)-N- methylethanamine hydrochloride (300 mg, 1.256 mmol, 85 % yield) as a white solid. LCMS (M+H) = 184.2, Retention time (0.01% TFA) = 1.34 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (60 mg, 0.127 mmol) in NMP (2 mL) was added 2-(4-fluoro-3-methylphenoxy)-N-methylethan-l-amine hydrochloride (112 mg, 0.509 mmol) and K2CO3 (176 mg, 1.272 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours. The mixture was filtered and the filtrate was directly subjected to Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-((2-(4-fhioro-3-methylphenoxy)ethyl)(methyl)amino)-6-methyl- [3,3'-bipyridin]-5-yl)acetate (13 mg, 0.020 mmol, 16.10 % yield) as yellow solid. LCMS (M+H) =635, Retention time (0.01% NH4HCO3) = 4.28 min.

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(4-fluoro-3-methylphenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (10 mg, 0.016 mmol) in ethanol (5 mL) and water (1 mL) was added NaOH (12.60 mg, 0.315 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by Prep- HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give product (S)-2-(tert-butoxy)-2- (4-(4,4-dimethylpiperidin-l-yl)-6'-((2-(4-fluoro-3-methylphenoxy)ethyl)(methyl)amino)-6- methyl-[3,3'-bipyridin]-5-yl)acetic acid (7 mg, 0.012 mmol, 74.2 % yield) a white solid. LCMS (M+H) = 592.3, Retention time (0.01% TFA) = 1.64 min. Ή NMR (400MHz, MeOD): d 8.04 (s, 1H), d 7.98-7.96 (m, 1H), 7.53-7.50 (m, 1H), 6.92- 6.77 (m, 3H), 6.73- 6.70 (m, 1H), 5.70 (s, 1H), 4.20-4.17 (m, 2H), 4.06-3.93 (m, 3H), 3.39-3.32 (m, 4H), 2.77- 2.63 (m, 5H), 2.22 (s, 3H), 2.66 (s, 3H), 1.44-1.41 (m, 4H), 1.17 (s, 9H), 0.87 (s, 6H). Example 290

Step 1 : To a solution of 4-fluoro-3-methylphenol (0.8 g, 6.34 mmol) in DMF (15 mL) was added CS2CO3 (2.69 g, 8.25 mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes, Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.821 g, 7.61 mmol) was added. The mixture was stirred at 100 °C for 16 hours, cooled, diluted with water (100 mL) and extracted with ethyl acetate(l00 mL). The organic layer was washed with water (50 mL x2), brine (50 mL x2), dried over NaiSOr. and the solvent was removed in vacuo to give a crude oil. The oil was purified on silica gel column (ethyl acetate/petroleum ether =7: 1-4: 1) to afford desired product tert-butyl (2-(4-fluoro-3- methylphenoxy)ethyl)carbamate (0.9 g, 2.67 mmol, 42.2 % yield) as yellow oil. LCMS (M + H) = 259, Retention time (0.0l%TFA) = 1.446 min.

Step 2: To a solution of HC1 (8 mL, 4M solution in l,4-dioxane) was tert-butyl (2-(4- fluoro-3-methylphenoxy)ethyl)carbamate (0.4 g, 1.485 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. The mixture was filtered and washed with Et20 to give desired product tert-butyl (2-(4-fluoro-3-methylphenoxy)ethyl)carbamate (0.4 g,

1.485 mmol). LCMS (M+H) = 170, Retention time (0.01% TFA) = 1.24 min.

Step 3: To a solution isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)- 6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mL) was added 2-(4-fluoro-3-methylphenoxy)ethan-l -amine hydrochloride (87 mg, 0.424 mmol) and K2C03 (147 mg, 1.060 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours and cooled. The mixture was filtered and the filtrate was purified by Prep-HPLC to give isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-((2-(4-fluoro-3- methylphenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (10 mg, 0.016 mmol, 15.19 % yield) as yellow solid. LCMS (M+H) =621, Retention time (0.01% NH4HCO3) = 2.42 min. Step 4: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(4-fluoro-3-methylphenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (10 mg, 0.016 mmol) in ethanol (5 mL) and water (1 mL) was added NaOH (12.89 mg, 0.322 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give product (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-((2-(4-fluoro-3-methylphenoxy)ethyl)amino)-6-methyl-[3,3'- bipyridin]-5-yl)acetic acid (4.3 mg, 7.41 pmol, 46.0 % yield) as a white solid. LCMS (M+H) = 579.2, Retention time (0.01% TFA) = 1.55 min._¹H NMR (400MHz, MeOD): d 7.99 (s,

1H), d 7.94-7.93 (m, 1H), 7.44-7.42 (m, 1H), 6.94- 6.83 (m, 2H), 6.78-6.72 (m, 2H), 5.70 (s, 1H), 4.15-4.12 (m, 2H), 3.79-3.73 (m,2H), 3.39-3.32 (m, 2H), 2.67-2.63 (m, 5H), 2.24 (s, 3H), 1.48-1.42 (m, 4H), 1.18 (s, 9H), 0.89 (s, 6H).

Example 291

Step 1 : To a solution of 4-fluorophenol (0.8 g, 7.14 mmol) in DMF (15 mL) was added CS2CO3 (3.02 g, 9.28 mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes, Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (2.049 g, 8.56 mmol) was added. The mixture was stirred at 100 °C for 16 hours, cooled and filtered. The filtrate was purified by Prep-HPLC to give tert-butyl (2-(4- fluorophenoxy)ethyl)carbamate (0.9 g, 3.44 mmol, 48.3 % yield) was obtained as yellow oil. LCMS (M + Na) = 278, Retention time (0.0l%TFA) = 1.92 min.

Step 2: To a solution of tert-butyl (2-(4-fluoro-3-methylphenoxy)ethyl)carbamate (500 mg, 1.857 mmol) in DMF (2 mL) was added NaH (223 mg, 5.57 mmol) at 0 °C under an atmosphere of N2. The mixture was stirred at 0 °C for 15 minutes, Then, Mel (0.232 mL,

3.71 mmol) was added and stirred at room temperature for 16 hours. Then, diluted with an ice water (10 ml) and extracted with ethyl acetate(20 mL x3). The combined organic layers were washed with water (20 mL x 2), brine (20 mL), dried by NaiSOr and concentrated to give tert-butyl (2-(4-fluoro-3-methylphenoxy)ethyl)(methyl)carbamate (480 mg, 1.220 mmol,

65.7 % yield) as yellow oil. LCMS (M -55) = 228, Retention time (0.0l%TFA) = 2.06 min.

Step 3: To a solution of HC1 (8 mL, 4M solution in l,4-dioxane) was added tert-butyl (2-(4-fluorophenoxy)ethyl)(methyl)carbamate (0.52 g, 1.931 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. The mixture was fdtered and washed with EtiO to give desired product 2-(4-fluorophenoxy)-N-methylethanamine hydrochloride (300 mg, 1.459 mmol, 76 % yield) as a white solid. LCMS (M+H) = 170.1, Retention time (0.01% TFA) = 1.22 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (30 mg, 0.064 mmol) in NMP (2 mL) was added 2-(4-fluorophenoxy)-N-methylethan-l -amine hydrochloride (52.3 mg, 0.254 mmol) and K2C03 (88 mg, 0.636 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours and cooled. The mixture was fdtered and the fdtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NFLdTCCh); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-((2-(4-fluorophenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (13 mg, 0.021 mmol, 32.9 % yield) as yellow solid. LCMS (M+H) = 620, Retention time (0.01% NH4HCO3) = 4.12 min.

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(4-fluorophenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (13 mg, 0.021 mmol) in ethanol (2.5 mL) and water (0.5 mL) was added NaOH (16.75 mg, 0.419 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-((2-(4-fluorophenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'- bipyridin]-5-yl)acetic acid (7.5 mg, 0.013 mmol, 61.9 % yield) a white solid. LCMS (M+H) =579.2, Retention time (0.01% TFA) = 1.59 min. Ή NMK (400MH_z, MeOD): d 8.04 (s, 1H), d 8.00-7.98 (m, 1H), 7.01-6.96 (m, 2H), 6.93- 6.85 (m, 2H), 6.84 (d, J=8.8 Hz, 1H), 5.70 (s, 1H), 4.20 (t, J= 2.8 Hz, 2H), 4.09-3.95 (m, 2H), 3.39-3.32 (m, 2H), 3.22 (s, 3H), 2.77-2.65 (m, 2H), 2.64 (s, 3H), 1.44-1.41 (m, 4H), 1.18 (s, 9H), 0.88 (s, 6H).

Example 292

Step 1 : To a solution of 4-fluorophenol (0.8 g, 7.14 mmol) in DMF (15 mL) was added CS2CO3 (3.02 g, 9.28 mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes, Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (2.049 g, 8.56 mmol) was added. The mixture was stirred at 100 °C for 16 hours, cooled and filtered. The filtrate was purified by Prep-HPLC to give tert-butyl (2-(4- fluorophenoxy)ethyl)carbamate (0.9 g, 3.44 mmol, 48.3 % yield) was obtained as yellow oil. LCMS (M + 23) = 278, Retention time (0.0l%TFA) = 1.92 min.

Step 2: To a solution of tert-butyl (2-(4-fluorophenoxy)ethyl)carbamate (0.3 g, 1.175 mmol) in DCM (6 mF) was added 2,2,2-trifluoroacetic acid (1 mF, 13.46 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. The solvents were removed in vacuo, water (10 mF) was added to the solid with stirring and the pH value was adjusted to 8 with saturated NaHC03. The mixture was extracted with DCM (20 mF x3), the combined organic layers were washed with water (50 mF), dried over NaiSOi and concentrated to afford a brown oil. The brown oil was purified on silica gel eluting with petroleum ether/EtOAc (5: 1) to give 2-(4-fluorophenoxy)ethanamine (150 mg, 0.841 mmol, 71.6 % yield) as yellow solid. FCMS (M+H) = 156, Retention time (0.01% TFA) = 1.13 min.

Step 3: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mF) was added 2-(4-fluorophenoxy)ethanamine (65.8 mg, 0.424 mmol) and K2CO3 (44.0 mg, 0.318 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours and cooled. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'- ((2-(4-fluorophenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (15 mg, 0.025 mmol, 23.32 % yield) as yellow solid. LCMS (M+H) =607, Retention time (0.01%

NH4HCO3) = 2.3 min.

Step 4: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(4-fluorophenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (15 mg,

0.025 mmol) in ethanol (5 mL) and water (1 mL) was added NaOH (19.78 mg, 0.494 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give product (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-((2-(4-fluorophenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (8.0 mg, 0.014 mmol, 57.2 % yield) a white solid. LCMS (M+H) = 656.2, Retention time (0.0l% NH₄HCO3) = 1.51 min. Ή NMR (400MHz. MeOD): d 8.05 (s, 1H), d 7.95 (d, J= 1.6 Hz, 1H), 7.44-7.42 (m, 1H), 7.03- 6.94 (m, 4H), 6.74 (d, J=8.4 Hz, 1H), 5.71 (s, 1H), 4.63-4.61 (brs, 1H), 4.17-4.15 (m, 2H), 3.78-3.74(m, 2H), 3.39-3.32 (m, 2H), 2.77- 2.63 (m, 5H), 1.45-1.41 (m, 4H), 1.19 (s, 9H), 0.91 (s, 6H).

Example 293

Step 1 : To a solution of 4-chloro-2-methoxyphenol (0.8 g, 5.04 mmol) in DMF (15 mL) was added CS2CO3 (2.137 g, 6.56 mmol) at room temperature and stirred for 15 minutes. Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.449 g, 6.05 mmol) was added and stirred at 100 °C for 16 hours. The reaction was cooled, filtered and the filtrate was purified by Prep-HPLC to afford tert-butyl (2-(4-chloro-2-methoxyphenoxy)ethyl)carbamate (0.9 g, 2.89 mmol, 57.3 % yield) as yellow oil. LCMS (M + 23) = 324, Retention time (0.0l%TFA) = 1.92 min.

Step 2: To a solution of tert-butyl (2-(4-chloro-2-methoxyphenoxy)ethyl)carbamate (500 mg, 1.657 mmol) in DMF (2 mL) was added NaH (199 mg, 4.97 mmol) at 0 °C under an atmosphere of N2 and stirred for 15 minutes. Then, Mel (0.207 mL, 3.31 mmol) was added and stirred at room temperature for 16 hours. Then, diluted with an ice water (10 ml) and extracted with ethyl acetate(20 mL x3). The combined organic layers were washed with water (20 mL x 2), brine (20 mL), dried by NaiSOi and concentrated to give tert-butyl (2-(4- chloro-2-methoxyphenoxy)ethyl)(methyl)carbamate (480 mg, 1.368 mmol, 83 % yield) as yellow oil. LCMS (M +Na) = 338, Retention time (0.0l%TFA) = 2.02 min.

Step 3: To a solution of HC1 (8 mL, 4M solution in l,4-dioxane) was added tert-butyl (2-(4-chloro-2-methoxyphenoxy)ethyl)(methyl)carbamate (0.6 g, 1.900 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. The mixture was filtered and washed with EtiO to give desired product 2-(4-chloro-2-methoxyphenoxy)-N- methylethanamine hydrochloride (400 mg, 1.586 mmol, 83 % yield) as a white solid. LCMS (M+H) = 253, Retention time (0.01% TFA) = 1.35 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mL) was added 2-(4-chloro-2-methoxyphenoxy)-N-methylethan-l -amine hydrochloride (107 mg,

0.424 mmol) and K2CO3 (147 mg, 1.060 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours. The mixture was cooled, filtered and the filtrate was purified by Prep- HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2- (6'-((2-(4-chloro-2-methoxyphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6- methyl-[3,3'-bipyridin]-5-yl)acetate (8 mg, 0.012 mmol, 11.31 % yield) as yellow solid. LCMS (M+H) = 667, Retention time (0.01% NH4HCO3) = 4.20 min.

Step 5 : To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(4-chloro-2- methoxyphenoxy) ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (8 mg, 0.012 mmol) in ethanol (5 mL) and water (1 mL) was added NaOH (9.59 mg, 0.240 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours and cooled. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2- (tert-butoxy)-2-(6'-((2-(4-chloro-2-methoxyphenoxy)ethyl)(methyl)amino)-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (3 mg, 4.69 pmol, 39.1 % yield) as a white solid. LCMS (M+H) =625, Retention time (0.01% TFA) = 1.60 min. Ή NMR (400MHz, MeOD): d 8.07 (s, 1H), d 8.04-8.03 (m, 1H), 7.53-7.51 (m, 1H), 6.96- 6.90 (m, 2H), 6.87- 6.83 (m, 2H), 5.71 (s, 1H), 4.23 (t, J= 2.4 Hz, 2H), 4.07-3.95 (m, 2H), 3.82 (s, 3H), 3.39-3.32 (m, 2H), 3.22 (s, 3H), 2.77-2.65 (m, 2H), 2.65 (s, 3H), 1.44-1.41 (m, 4H), 1.19 (s, 9H), 0.88 (s, 6H).

Example 294

Step 1 : To a solution of tert-butyl (2-(4-chloro-2-methoxyphenoxy)ethyl)carbamate (0.4 g, 1.326 mmol) in DCM (6 mL) was added 2,2,2-trifluoroacetic acid (1 mL, 13.46 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. The solvents were removed in vacuo, water (10 mL) was added to the solid with stirring and the pH value was adjusted to 8 with saturated NaHC03. The mixture was extracted with DCM (20 mL x3), and combined organic layers were washed with water (50 mL), dried over NaiSCri and concentrated to afford a brown oil. The brown oil was purified on silica gel eluting with Pet. etherEtOAc (5: 1) to give 2-(4-chloro-2-methoxyphenoxy)ethanamine (200 mg, 0.992 mmol, 74.8 % yield) yellow solid. LCMS (M+H) =202, Retention time (0.01% TFA) = 1.66 min.

Step 2: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (60 mg, 0.127 mmol) in NMP (2 mL) was added 2-(4-chloro-2-methoxyphenoxy)ethanamine (103 mg, 0.509 mmol) and K2CO₃ (52.7 mg, 0.382 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours and cooled. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A:

Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min;

Flow Rate (ml/min) 30.00} to give (S)-isopropyl 2-(tert-butoxy)-2-(6'-((2-(4-chloro-2- methoxyphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (8 mg, 0.012 mmol, 9.63 % yield) as yellow solid. LCMS (M+H) =653, Retention time (0.01% NH4HCO3) = 2.37 min.

Step 3: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(6'-((2-(4-chloro-2- methoxyphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (8 mg, 0.012 mmol) in ethanol (5 mL) and water (1 mL) was added NaOH (9.80 mg, 0.245 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours and cooled. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95- 95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2- (6'-((2-(4-chloro-2-methoxyphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl- [3,3'-bipyridin]-5-yl)acetic acid (3.7 mg, 5.78 pmol, 47.2 % yield) a white solid. LCMS (M+H) =611.1, Retention time (0.01% NH4HCO3) = 1.54 min. Ή NMR (400MHz, MeOD): d 8.02 (s, 1H), d 7.94 (d, J= 2.0 Hz, 1H), 7.45-7.42 (m, 1H), 6.99- 6.96 (m, 2H), 6.89- 6.87 (m, 1H), 6.73 (d, J=8.8 Hz, 1H), 5.70 (s, 1H), 4.20-4.17 (m, 2H), 3.86 (s, 3H), 3.78-3.74(m, 2H), 3.39-3.32 (m, 2H), 2.77-2.64 (m, 5H), 1.45-1.41 (m, 4H), 1.19 (s, 9H), 0.90 (s, 6H).

Example 295

Step 1 : To a solution of phenol (0.8 g, 8.50 mmol) in DMF (15 mL) was added CS2CO3 (3.60 g, 11.05 mmol) at room temperature and stirred for 15 minutes. Then, 2-((tert- butoxycarbonyl)amino)ethyl methanesulfonate (2.441 g, 10.20 mmol) was added and stirred at 100 °C for 16 hours. The reaction was cooled, filtered and the filtrate was purified by Prep- HPLC to afford tert-butyl (2-phenoxyethyl)carbamate (1 g, 4.21 mmol, 49.6 % yield) as yellow oil. LCMS (M + H) = 237, Retention time (0.0l%TFA) = 1.96 min.

Step 2: To a solution of tert-butyl (2-phenoxyethyl)carbamate (0.4 g, 1.686 mmol) in DCM (6 mL) was added 2,2,2-trifluoroacetic acid (1 mL, 13.46 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. The solvents were removed in vacuo, water (10 mL) was added to the solid with stirring and the pH value was adjusted to 8 with saturated NaHC03. The mixture was extracted with DCM (20 mL x3) and the combined organic layers were washed with water (50 mL), dried over NaiSOi and concentrated to afford a brown oil. The brown oil was purified on silica gel eluting with Pet. ether: EtO Ac (5: 1) to give desired product 2-phenoxyethanamine (150 mg, 1.017 mmol, 60.3 % yield) yellow solid. LCMS (M+H) = 138, Retention time (0.01% TFA) = 1.04 min.

Step 3: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fhioro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mL) was added 2-phenoxyethanamine (58.2 mg, 0.424 mmol) and K2CO3 (44.0 mg, 0.318 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours and cooled. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6-methyl-6'- ((2-phenoxyethyl)amino)-[3,3'-bipyridin]-5-yl)acetate (10 mg, 0.017 mmol, 16.02 % yield) as yellow solid. LCMS (M+H) =589, Retention time (0.01% TFA) = 1.60 min.

Step 4: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6-methyl-6'-((2-phenoxyethyl)amino)-[3,3'-bipyridin]-5-yl)acetate (10 mg, 0.017 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (13.59 mg, 0.340 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours and cooled. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6-methyl-6'-((2-phenoxyethyl)amino)-[3,3'-bipyridin]-5-yl)acetic acid (3.8 mg, 6.72 pmol, 39.6 % yield) a white solid. LCMS (M+H) =547.2, Retention time (0.01% NH4HCO3) = 1.50 min. ¾ NMR (400MHz, MeOD): d 8.07 (s, 1H), d 7.95 (d, J= 2.0 Hz, 1H), 7.45-7.42 (m, 1H), 7.29-7.25 (m, 2H), 6.97- 6.93 (m, 3H), 6.75 (d, =8.8 Hz, 1H), 5.71 (s, 1H), 4.18 (t, J= 5.2 Hz, 2H), 3.80-3.77 (m, 2H), 3.32-3.30 (m, 2H), 2.77-2.64 (m, 2H), 2.65 (s, 3H), 1.46- 1.41 (m, 4H), 1.19 (s, 9H), 0.91 (s, 6H).

Example 296

Step 1 : To a solution oftert-butyl (2-phenoxyethyl)carbamate (500 mg, 2.107 mmol) in DMF (2 mL) was added NaH (253 mg, 6.32 mmol) at 0 °C under an atmosphere of N2 and stirred for 15 minutes. Then, Mel (0.264 mL, 4.21 mmol) was added and stirred at room temperature for 16 hours. Then, diluted with an ice water (10 ml) and extracted with ethyl acetate(20 mL x3). The combined organic layers were washed with water (20 mL x 2), brine (20 mL), dried by NaiSOr and concentrated to give tert-butyl methyl(2- phenoxyethyl)carbamate (520 mg, 1.862 mmol, 88 % yield) as yellow oil. LCMS (M + Na) = 274, Retention time (0.0l%TFA) = 1.99 min.

Step 2: To a solution of HC1 (8 mL, 4M solution in l,4-dioxane) was added tert-butyl methyl(2-phenoxyethyl)carbamate (0.52 g, 2.069 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. The mixture was fdtered and washed with EtiO to give N-methyl-2-phenoxyethanamine hydrochloride (350 mg, 1.721 mmol, 83 % yield) as a white solid. LCMS (M+H) = 152.2, Retention time (0.01% TFA) = 1.17 min.

Step 3: To a solution isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)- 6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (30 mg, 0.064 mmol) in NMP (2 mL) was added N-methyl-2-phenoxyethan-l -amine hydrochloride (47.8 mg, 0.254 mmol) and K2CO3 (88 mg, 0.636 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours and cooled. The mixture was fdtered and the fdtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6-methyl-6'-(methyl(2-phenoxyethyl)amino)-[3,3'-bipyridin]-5- yl)acetate (12 mg, 0.020 mmol, 31.3 % yield) as yellow solid. LCMS (M+H) = 603.2, Retention time (0.01% NH4HCO3) =4.16 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6-methyl-6'-(methyl(2-phenoxyethyl)amino)-[3,3'-bipyridin]-5-yl)acetate (12 mg, 0.020 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (15.92 mg, 0.398 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours and cooled. The pH of the reaction mixture was adjusted to about 7 with acetic acid and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give product (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6-methyl-6'-(methyl(2-phenoxyethyl)amino)-[3,3'-bipyridin]-5- yl)acetic acid (7.0 mg, 0.012 mmol, 62.7 % yield) as a white solid. LCMS (M+H) =561.2, Retention time (0.01% TFA) = 1.58 min. Ή NMR (400MHz, MeOD): d 8.06 (s, 1H), d 8.05 (s, 1H), 7.54-7.51 (m, 1H), 7.27- 7.23 (m, 2H), 6.94- 6.85 (m, 4H), 5.70 (s, 1H), 4.25-4.12 (m, 2H), 4.09-3.97 (m, 2H), 3.39-3.32 (m, 2H), 3.23 (s, 3H), 2.77-2.65 (m, 2H), 2.65 (s, 3H), 1.44-1.41 (m, 4H), 1.19 (s, 9H), 0.90 (s, 6H).

Example 297

Step 1 : To a solution of 3,4-dimethylphenol (0.8 g, 6.55mmol) in DMF (15 mL) was added CS2CO3 (2.77 g, 8.5 lmmol) at room temperature and stirred for 15 minutes. Then, 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (l .880g, 7.86mmol) was added and stirred at 100 °C for 16 hours. The reaction was cooled, filtered and purified by Prep-HPLC to afford tert-butyl (2-(3,4-dimethylphenoxy)ethyl)carbamate (600 mg, 2.035mmol, 31.1 % yield) as yellow oil. LCMS: Retention time (0.0l%TFA) = 2.00 min, m/z = 288 (M+H). Step 2: To a solution of HC1 (8 mL, 4M solution in l,4-dioxane) was added tert-butyl (2-(3,4-dimethylphenoxy)ethyl)(methyl)carbamate (0.3 g, 1.074 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. TLC showed reaction was completed. The mixture was filtered and washed with Et20 (5 ml) to give 2-(3,4-dimethylphenoxy)-N,N- dimethylethan-l -amine hydrochloride (250 mg, 0.979 mmol, 91 % yield) as white solid. LCMS: Retention time (0.0l%TFA) = 1.279 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mL) was added 2-(3,4-dimethylphenoxy)ethan-l -amine hydrochloride (86 mg, 0.424 mmol) and K2CO3 (147 mg, 1.060 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours and cooled. The mixture was purified by Prep-HPLC to give isopropyl (S)-2-(tert- butoxy)-2-(6'-((2-(3,4-dimethylphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6- methyl-[3,3'-bipyridin]-5-yl)acetate (15 mg, 0.024 mmol, 22.94 % yield) as yellow solid. LCMS (M+H) = 617.3; Retention time (10 mmol NH4HCO3) = 2.525 min.

Step 4: To a solution of sodium hydroxide (32.4 mg, 0.811 mmol) in MeOH (3 mL) and H20 (0.5 ml) was added the isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(3,4- dimethylphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin- 1 -yl)-6-methyl-[3 ,3 -bipyridin] -5 - yl)acetate (25 mg, 0.041 mmol). The mixture was stirred at 90 °C for additional 36 h and cooled. The pH of the mixture was adjusted to ~7 with 1M HC1 and purified by Prep-HPLC to give (S)-2-(tert-butoxy)-2-(6'-((2-(3,4-dimethylphenoxy)ethyl)amino)-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (5.2 mg, 9.05 pmol,

22.32 % yield) as white solid. LCMS: Retention time (10 mmol NH4HCO3) = 1.673 min, m/z = 575 (M+H). ¾ NMR (400 MHz, MeOD): d 8.01 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 8.6, 2.3 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.77-6.72 (m, 3H), 5.70 (s, 1H), 4.62-4.61 (brs, 1H), 4.14 (t, J = 5.5 Hz, 2H), 3.84- 3.63 (m, 2H), 3.15 (s, 2H), 2.71-2.70 (m, 2H), 2.64 (s,

3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.39-1.35 (m, 4H), 1.18 (s, 9H), 0.90 (s, 6H).

Example 298

Step 1 : To a solution oftert-butyl (2-(3,4-dimethylphenoxy)ethyl)carbamate (500 mg, 1.884 mmol) in DMF (2 mL) was added NaH (226 mg, 5.65mmol) at 0 °C under an atmosphere of N2 and stirred for 15 minutes. Then, Mel (0.236mL, 3.77mmol) was added and stirred at room temperature for 16 hours. Then, diluted with an ice water (10 ml) and extracted with ethyl acetate (20 ml x3). The combined organic layers were washed with water (20 ml x 2), brine (20 ml), dried with NaiSOr and concentrated to give tert-butyl (2-(3,4- dimethylphenoxy)ethyl)(methyl)carbamate (400 mg, l .2l7mmol, 64.6 % yield) as yellow oil which was used in the next step without purification. LCMS: Retention time (0.0l%TFA) = 2.06 min, m/z = 301 (M+Na).

Step 2: To a solution of HC1 (8 mF, 4M solution in l,4-dioxane) was added tert-butyl (2-(3,4-dimethylphenoxy)ethyl)(methyl)carbamate (0.3 g, l .074mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. TFC showed reaction was completed. The mixture was filtered and washed with Et20 (5 ml) to give 2-(3,4-dimethylphenoxy)-N- methylethan-l -amine hydrochloride (250 mg, 0.671 mmol, 62.5 % yield) as white solid. The solid was used in the next step without further purification. FCMS: Retention time

(0.0l%TFA) = 1.279 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0. l06mmol) in NMP (2mF) was added 2-(3,4-dimethylphenoxy)-N-methylethan-l-amine hydrochloride (91 mg, 0.424mmol) and K2CO3 (147 mg, l .060mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours. The mixture was purified by Prep-HPFC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol

NH4HCO3); B: MeCN; Gradient 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} get the desired product isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(3,4- dimethylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (20 mg, 0.041 mmol, 22.44 % yield) as yellow solid. LCMS (M + H)

= 631 : Retention time (10 mmol NH4HCO3) = 2.85 min.

Step 4: To a solution of sodium hydroxide (31.7 mg, 0.793 mmol) in MeOH (3mL) and H2O (0.5 ml) was added the isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(3,4- dimethylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (25 mg, 0.040 mmol). The mixture was stirred at 90 °C for additional 16 h and cooled. The pH of the mixture was adjusted to ~7 with 1N HC1 and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 50- 68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2- (6'-((2-(3,4-dimethylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl- [3,3'-bipyridin]-5-yl)acetic acid (14.7 mg, 0.025 mmol, 62.7 % yield) as white solid. LCMS (M + H) = 589. Retention time (10 mmol NH4HCO3) = l .77lmin. Ή NMR (400 MHz, MeOD) d 7.97- 7.81 (m, 2H), 7.39 (dd, J = 8.8, 2.4 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.59 (dd, J = 2.5 Hz, 1H), 6.51 (dd, J = 8.3, 2.7 Hz, 1H), 5.59 (s, 1H), 4.06 (t, J = 5.4 Hz, 2H), 3.99- 3.90 (m, 1H), 3.82-3.81 (m, 1H), 3.20-3.19 (m, 2H), 3.10 (s, 3H), 2.60- 2.59 (m, 2H), 2.51 (s, 3H), 2.10-2.06 (m, 6H), 1.24-1.25 (m, 1.29-1.23, 4H), 1.05 (s, 9H),

0.75 (s, 6H).

Example 299

Step 1 : To a solution of 4-chlorophenol (0.8 g, 6.22 mmol) in DMF (15 mL) was added CS2CO3 (2.64 g, 8.09 mmol) at room temperature and stirred for 15 minutes. Then, 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.787 g, 7.47 mmol) was added and stirred at 100 °C for 16 hours. The reaction was cooled, filtered and the filtrate was purified by Prep-HPLC to afford the desired product tert-butyl (2-(4-chlorophenoxy)ethyl)carbamate (550 mg, 1.637 mmol, 26.3 % yield) as yellow oil. LCMS [M+Na] = 294; Retention time (0.0l%TFA) = 1.97 min.

Step 2: To a solution of HC1 (8 mL, 4M solution in l,4-dioxane) was added tert-butyl (2-(4-chlorophenoxy)ethyl)(methyl)carbamate (0.3 g, 1.050 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours and filtered and washed with EtiO (5 ml) to give 2-(4-chlorophenoxy)-N,N-dimethylethan-l -amine hydrochloride (200 mg, 0.762 mmol, 72.6 % yield) as white solid. LCMS (M+H) = 168.1; Retention time (0.0l%TFA) = 1.16 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mL) was added 2-(4-chlorophenoxy)ethan-l -amine hydrochloride (88 mg, 0.424 mmol) and K2CO3 (147 mg, 1.060 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours. The mixture was filtered and the filtrate was purified by Prep-HPLC to give isopropyl (S)-2-(tert- butoxy)-2-(6'-((2-(4-chlorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl- [3,3'-bipyridin]-5-yl)acetate (25 mg, 0.040 mmol, 30.70 % yield) as yellow solid. LCMS (M+H) = 623.2; Retention time (10 mmol NH4HCO3) = 2.46 min,

Step 4: To a solution of sodium hydroxide (32.1 mg, 0.802 mmol) in MeOH (3 mL)and H20 (0.5 ml) was added the isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(4- chlorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (25 mg, 0.040 mmol). The mixture was stirred at 90 °C for 36 h and cooled. The pH of the mixture was adjusted to ~7 with 1M HC1 and purified by Prep-HPLC to give (S)-2- (tert-butoxy)-2-(6'-((2-(4-chlorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6- methyl-[3,3'-bipyridin]-5-yl)acetic acid (6.6 mg, 0.011 mmol, 27.8 % yield) as white solid. LCMS (M+H) = 581; Retention time (10 mmol NH4HCO3) = 1.649 min. Ή NMR (400 MHz, MeOD) d 8.05 (s, 1H), 7.95-7.94 (m, 1H), 7.43 (d, J= 6.2 Hz, 1H), 7.26 (d, J= 8.9 Hz, 2H), 6.96 (d, J= 9.0 Hz, 2H), 6.74 (d, J= 8.6 Hz, 1H), 5.71 (s, 1H), 4.62-4.61 (m, 2H), 4. l8 (t, J= 5.5 Hz, 2H), 3.78 (d, J= 3.8 Hz, 2H), 3.15-3.14 (m, 2H), 2.72-2.70 (m, 2H), 2.65 (s, 3H), 1.45 (m, 4H), 1.20 (s, 9H), 0.91 (s, 6H). Example 300

Step 1 : To a solution oftert-butyl (2-(4-chlorophenoxy)ethyl)carbamate (500 mg, l .840mmol) in DMF (2mL) was added NaH (221 mg, 5.52mmol) at 0 °C under an atmosphere of N2 and stirred at 0 °C for 15 minutes. Then, Mel (0.230mL, 3.68mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with an ice water (10 ml) and extracted with ethyl acetate(20 ml x3). The combined organic layes were washed with water (20ml x 2), brine (20 ml), dried with NaiSOr and concentrated to give tert-butyl (2-(4-chlorophenoxy)ethyl)(methyl)carbamate (500 mg, 1.487 mmol, 81 % yield) which was used in the next step without purification. LCMS (M-55) = 228; Retention time (0.0l%TFA) = 2.06 min

Step 2: To a solution of HC1 (8 mF, 4M solution in l,4-dioxane) was added tert-butyl (2-(4-chlorophenoxy)ethyl)(methyl)carbamate (0.3 g, l .050mmol) at once and stirred at room temperature for 12 hours. The mixture was filtered and washed with EtiO (5 ml) to give 2-(4- chlorophenoxy)-N-methylethan-l-amine hydrochloride (200 mg, 0.810 mmol, 77 % yield) as a white solid. The solid was used in the next step without further purification. FCMS (M+H) = 186; Retention time (0.0l%TFA) = 1.451 nm.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0. l06mmol) in NMP (2mF) was added 2-(4-chlorophenoxy)-N-methylethan-l-amine hydrochloride (94 mg, 0.424mmol) and K2CO3 (147 mg, l .060mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours, cooled, filtered and purified by Prep-HPFC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(4-chlorophenoxy)ethyl) (methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetate as yellow solid. LCMS (M+H) = 631; Retention time (10 mmol NH4HCO3) = 2.84 min.

Step 4: To a solution of sodium hydroxide (25. lmg, 0.628mmol) in MeOH (3mL)and H2O (0.5 ml) was added the isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(4- chlorophenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin- 1 -yl)-6-methyl- [3,3'- bipyridin]-5-yl)acetate (20 mg, 0.03 lmmol). The mixture was stirred at 90 °C for additional 16 h and cooled. The pH of the mixture was adjusted to ~7 with 1N HC1 and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 um; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 55- 68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-

(6'-((2-(4-chlorophenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl- [3,3'-bipyridin]-5-yl)acetic acid (2.0 mg, 3.36 pmol, 10.71 % yield) as white solid. LCMS (M+H) = 595; Retention time (10 mmol NH4HCO3) = 1.742 min. Ή NMR (400 MHz, MeOD) d 8.05-8.04 (m, 2H), 7.52 (d, J= 6.2 Hz, 1H), 7.24 (d, J= 9.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 6.84 (d, J= 6.2 Hz, 1H), 5.71 (s, 1H), 4.64-4.63 (m, 2H), 4.23 (t, J= 5.4 Hz,

2H), 3.32 - 3.28 (m, 2H), 3.16 (s, 3H), 2.85- 2.84 (m, 2H), 2.65 (s, 3H), 1.42-1.36 (m, 4H), 1.19 (s, 9H), 0.91 (s, 6H).

Example 301

Step 1 : To a solution of 4-methoxyphenol (0.8 g, 6.44 mmol) in DMF (15 mL) was added CS2CO3 (2.73 g, 8.38 mmol) at room temperature and stirred for 15 minutes. Then, 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.850 g, 7.73 mmol) was added and stirred at 100 °C for 16 hours. The reaction mixture was cooled, filtered and the filtrate was purified by Prep-HPLC to afford tert-butyl (2-(4-methoxyphenoxy)ethyl)carbamate (400 mg, 1.347 mmol, 20.90 % yield) as yellow oil. LCMS (M+Na) = 290; Retention time

(0.0l%TFA) = 1.87 min.

Step 2: To a solution of HC1 (8 mL, 4M solution in l,4-dioxane) was added tert-butyl (2-(4-methoxyphenoxy)ethyl)(methyl)carbamate (0.3 g, 1.066 mmol) at once and stirred at room temperature for 12 hours. The mixture was filtered and washed with EtiO (5 ml) to give product 2-(4-methoxyphenoxy)-N,N-dimethylethan-l-amine hydrochloride (200 mg, 0.777 mmol, 72.9 % yield) as white solid. LCMS (M+H) = 170.1; Retention time (0.0l%TFA) = 1.22 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mL) was added 2-(4-methoxyphenoxy)ethan- 1 -amine hydrochloride (86 mg, 0.424 mmol) and K2CC>3(l47 mg, 1.060 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours, cooled, filtered and the filterate was purified by Prep-HPLC to give isopropyl (S)-2- (tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-((2-(4-methoxyphenoxy)ethyl)amino)-6- methyl-[3,3'-bipyridin]-5-yl)acetate (15 mg, 0.024 mmol, 22.86 % yield) as yellow solid. LCMS (M+H) = 619.2; Retention time (10 mmol NH4HCO3) = 2.28 min.

Step 4: To a solution of sodium hydroxide (32.3 mg, 0.808 mmol) in MeOH (3 mL)and H20 (0.5 ml) was added the isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-((2-(4-methoxyphenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (25 mg, 0.040 mmol). The mixture was stirred at 90 °C for 36 h and cooled. The pH of the mixture was adjusted to ~7 with lMol HC1 and purified by Prep-HPLC to give (S)- 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-((2-(4-methoxyphenoxy)ethyl)amino)-6- methyl-[3,3'-bipyridin]-5-yl)acetic acid (10.7 mg, 0.019 mmol, 45.9 % yield) as white solid. LCMS (M+H) = 577; Retention time (10 mmol NH4HCO3) = l .552min. Ή NMR (400 MHz, MeOD) d 8.08 (s, 1H), 7.95 (d, J= 1.9 Hz, 1H), 7.44 (dd, J= 8.7, 2.3 Hz, 1H), 6.94 - 6.82 (m, 4H), 6.75 (d, J= 8.6 Hz, 1H), 5.71 (s, 1H), 4.14 (t, J= 5.5 Hz, 2H), 3.90- 3.64 (m, 5H), 3.10-3.09 (m, 2H), 2.75-2.74 (m, 2H), 2.66 (s, 3H), 1.41-1.38 (m, 4H), 1.20 (s, 9H), 0.92 (s, 6H). Example 301

Step 1 : To a solution oftert-butyl (2-(4-methoxyphenoxy)ethyl)carbamate (300 mg, l . l22mmol) in DMF (2 mL) was added NaH (135 mg, 3.37 mmol) at 0 °C under an atmosphere of N2 and stirred for 15 minutes. Mel (0. l40mL, 2.244mmol) was added and the mixture was stirred at room temperature for 16 hours. Then, diluted with ice water (10 ml) and extracted with ethyl acetate(20 ml x3). The combined organic layers were washed with water (20 ml x 2), brine (20 ml), dried by NaiSOr and concentrated to give tert-butyl (2-(4- methoxyphenoxy)ethyl)(methyl)carbamate (250 mg, 0.755 mmol, 67.3 % yield) as yellow oil which was used in the next step without purification. LCMS (M-55) = 228; Retention time (0.0l%TFA) = 2.06 min

Step 2: To a solution of HC1 (8mF, 4M solution in l,4-dioxane) was added tert-butyl (2-(4-methoxyphenoxy)ethyl)(methyl)carbamate (0.3 g, l.066mmol) at once and stirred at room temperature for 12 hours. The mixture was filtered and washed with EtiO (5 ml) to give 2-(4-methoxyphenoxy)-N-methylethan-l -amine hydrochloride (200 mg, 0.827 mmol, 78 % yield) as a white solid. FCMS (M+H) = 170.1; Retention time (0.0l%TFA) = 1.22 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mF) was added 2-(4-methoxyphenoxy)-N-methylethan-l -amine hydrochloride (92 mg, 0.424 mmol) and K2CO3 (147 mg, 1.060 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours, cooled, filtered and the filterate was purified by Prep-HPFC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A:

Water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin- l-yl)-6'-((2-(4-methoxyphenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate as yellow solid. LCMS (M+H) = 633; Retention time (10 mmol NH4HCO3) = 2.42 min.

Step 4: To a solution of sodium hydroxide (31.6 mg, 0.790mmol) in MeOH (3 mL) and H2O(0.5 ml) was added the isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(4-methoxyphenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (25 mg, 0.040 mmol). The mixture was stirred at 90 °C for 16 h and cooled. The pH of the mixture was adjusted to ~7 with 1N HC1 and purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A:

Water (10 mmol NH4HCO3); B: MeCN; Gradient 48-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'- ((2-(4-methoxyphenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (10 mg, 0.017 mmol, 42.4 % yield) as white solid. LCMS (M+H) = 591; Retention time (10 mmol NH4HCO3) = 1.646 min. ¾ NMR (400 MHz, MeOD) d 8.15- 7.95 (m, 2H), 7.52-7.51 (m,lH), 6.93- 6.73 (m, 5H), 5.71 (s, 1H), 4.18 (t, J= 5.5 Hz, 2H), 4.11- 3.91 (m, 2H), 3.75 (s, 3H), 3.23-3.19 (m, 5H), 2.76-2.75 (m, 2H), 2.65 (s, 3H), 1.50- 1.32 (m, 4H), 1.20 (s, 9H),

0.91 (s,6H).

Example 303

Step 1 : To a stirred solution of 3,5-difluorophenol (1 g, 7.69 mmoL) in DMF (30mL) was added CS2CO3 (4.57 g, 14.02 mmoL) one-portion and stirred at 20 °C for 0.5 h. Then, 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.677 g, 7.01 mmoL) was added and stirred at 100 °C for 16 hrs. LCMS showed most of starting material consumed. The reaction mixture was filtered, the cake was washed with EtOAc (10 ml x 2), and the filtrate was diluted with water (200 ml) and EtOAc (100), aqueous phase separated and the organic phase was washed with brine (200 ml x 3), dried over anhydrous Na2S04, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% EtO Ac/pet. ether) to give tert-butyl (2-(3, 5-difluorophenoxy)ethyl)carbamate (1,400 mg,

2.88 mmoL, 41.0 % yield) as yellow oil. LCMS (M+Na) = 296; Retention time (0.1% TFA): l .945min.

Step 2: To tert-butyl (2-(3, 5-difluorophenoxy)ethyl)carbamate (0.6 g, 2.196 mmoL) added 4M HC1 in dioxane (5.00 ml, 20 mmoL) at once. The reaction mixture was stirred at 15 °C for 12 hours. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with ether (10 ml), filtered and the cake was washed with ether (10 ml), dried to give 2-(3, 5-difluorophenoxy)ethan-l-amine HC1 (300 mg, 1.373 mmoL, 62.5 % yield) was obtained as a white solid. LCMS (M+H) = 174; Retention time (0.1% TFA): 0.763 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) dissolved in NMP (0.5 mL) was added 2-(3,5-difluorophenoxy)ethan-l-amine HC1 (18.36 mg, 0.106 mmol) and K2CO₃ (44.0 mg, 0.318 mmol). The reaction mixture was stirred at 120 °C for 16 hours. LCMS showed the starting material remained and target product was found. The reaction mixture was filtered and concentrated to obtain light yellow oil. The crude product purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HC03); B: MeCN; Gradient 36- 68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert- butoxy)-2-(6'-((2-(3,5-difluorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6- methyl-[3,3'-bipyridin]-5-yl)acetate (8.6 mg, 0.014 mmol, 12.98 % yield) was obtained as a white solid. LCMS (M+H) = 625; Retention time: 2.293 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(3,5- difluorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (10 mg, 0.016 mmol) in methanol (5 mL) and water (1 mL) was added NaOH (12.80 mg, 0.320 mmol) at once. The resulting mixture was stirred at 90 °C for 10 hours. LCMS showed reaction was completed. The mixture was cooled and the pH was adjusted to ~7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(6'-((2-(3,5- difluorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (3.4 mg, 5.83 pmol, 36.5 % yield) as white solid. LCMS (M+H) = 583; Retention time (10 mM NH4HC03) = 1.627 min. Ή NMR (400 MHz, MeOD) d 8.07 (s, 1H), 7.97-7.96 (m, 1H), 7.44 (dd, J = 8.6, 2.3 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 6.66- 6.58 (m, 2H), 6.52 (tt, J = 9.2, 2.2 Hz, 1H), 5.71 (s, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.85-3.71 (m, 2H), 3.15-3.10 (brs, 2H), 2.78-2.70 (brs, 2H), 2.66 (s, 3H), 1.46-1.40 (brs, 2H), 1.32-1.30 (brs, 2H), 1.20 (s, 9H), 0.92 (s, 6H).

Example 304

Step 1 : To a stirred solution oftert-butyl (2-(3,5-difluorophenoxy)ethyl)carbamate (600 mg, 2.196 mmoL) in DMF (5 mL) was added NaH (105 mg, 4.39 mmoL) one-portion at 0 °C and stirred for 0.5 h. Then, Mel (0.275 mL, 4.39 mmoL) was added and warmed up to 25 °C, stirred for 0.5 hrs. TLC (pet. etherEtOAc = 2: 1) showed reaction was completed. The reaction mixture was diluted with water (100 ml) and EtOAc (200 ml), aqueous phase separated and the organic phase was washed with brine (200 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% EtOAc/pet. ether) to give tert-butyl (2-(3,5- difluorophenoxy)ethyl)(methyl)carbamate(540 mg, 1.709 mmoL, 78 % yield) as yellow oil. LCMS (M+Na) = 310; Retention time (0. l% TFA): 1.47 min.

Step 2: To tert-butyl (2-(3, 5-difhiorophenoxy)ethyl)(methyl)carbamate (0.54 g, 1.880 mmoL) added HC1 (5.00 ml, 20 mmoL) at once and stirred at 15 °C for 12 hours. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with ether (10 ml), filtered and the cake was washed with ether (10 ml), dried to obtain 2-(3, 5-difhiorophenoxy)-N-methylethan-l-amine HC1 (310 mg, 1.568 mmoL, 83 % yield) as a white solid. LCMS (M+H) = 188; Retention time (0.1% TFA) = 0.886 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6,6'-dimethyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.107 mmol) in toluene (3 mL) was added 2-(3,5-difhiorophenoxy)-N-methylethan-l-amine HC1 (40.0 mg, 0.214 mmol), (9,9- dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (12.37 mg, 0.021 mmol), Pd2(dba)3 (9.79 mg, 10.69 mihoΐ) and cesium carbonate (105 mg, 0.321 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 hours. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with DCM (50 ml), washed with water (50 ml x3), Then, organic layer was dried over NaiSOr and concentrated to afford a brown oil. The crude product purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A:

Water (10 mmol NH4HC03); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(3,5- difluorophenoxy)ethyl) (methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (20 mg, 0.031 mmol, 29.3 % yield) was obtained as a white solid. LCMS (M+H) = 639; Retention time (10 mM NH4HC03): 2.776 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-4- methylphenoxy)ethyl) (methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (20 mg, 0.031 mmol) in methanol (5 mL) and water (1 mL) was added NaOH (24.56 mg, 0.614 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours. LCMS showed reaction was completed. The mixture was cooled and the pH was adjusted to ~7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep- HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(6'-((2-(2- chloro-4-methylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl- [3,3'-bipyridin]-5-yl)acetic acid (3 mg, 4.92 pmol, 16.04 % yield) as white solid. LCMS (M+H) = 609; Retention time (10 mM NH4HC03) = 1.764 min. Ή NMR (400 MHz,

MeOD) d 7.97- 7.87 (m, 2H), 7.40 (dd, J = 8.8, 2.4 Hz, 1H), 7.06 (d, J = 1.7 Hz, 1H), 6.92 (dd, J = 8.4, 1.5 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 5.58 (s, 1H), 4.14 (t, J = 5.1 Hz, 2H), 4.03-3.87 (m, 2H), 3.21-3.13 (m, 5H), 2.61 (brs, 2H), 2.54 (s, 3H), 2.14 (s, 3H), 1.33-1.22 (m, 4H), 1.07 (s, 9H), 0.76 (s, 6H). Example 305

Step 1 : To a stirred solution of 2-chloro-4-fluorophenol (1 g, 6.82 mmoL) in DMF (15 mL) was added CS2CO3 (4.45 g, 13.65 mmoL) in one-portion at 20 °and stirred for 0.5 h. Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.633 g, 6.82 mmoL) was added and stirred at 100 °C for 16 hrs. LCMS showed most of starting material consumed. The reaction mixture was filtered and the cake was washed with EtOAc (10 ml x 2). The filtrate was diluted with water (200 ml) and EtOAc (100), aqueous phase separated and the organic phase was washed with brine (200 ml x 3), dried over anhydrous Na2S04, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel

chromatography (5%~l0% EtOAc/pet. ether) to give tert-butyl (2-(2-chloro-4- fluorophenoxy)ethyl)carbamate (800 mg, 2.76 mmoL, 40.5 % yield). LCMS (M + H) = 312 & 314, Retention time (0.1% TFA): 1.639 min.

Step 2: To tert-butyl (2-(2-chloro-4-fluorophenoxy)ethyl)carbamate (0.4 g, 1.381 mmoL) was added 4M HC1 in dioxane (5.00 ml, 20 mmoL) at once and stirred at 15 °C for 12 hours. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with ether (10 ml), filtered and washed with ether (10 ml), dried to give 2- (2-chloro-4-fluorophenoxy)ethan-l-amine HC1 (250 mg, 1.318 mmoL, 96 % yield) was obtained as a white solid. LCMS (M+H) = 190 & 192, Retention time(0. l% TFA): 1.158 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) dissolved in NMP (0.5 mL) was added 2-(2-chloro-4-fluorophenoxy)ethan-l -amine HC1 (20.10 mg, 0.106 mmol) and K2CO₃ (44.0 mg, 0.318 mmol). The reaction mixture was stirred at 90 °C for 16 hours. LCMS showed some starting material remained and target product was found. The reaction mixture was filtered and concentrated to obtain light yellow oil. The crude product was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 mih; Mobile Phase A: Water (10 mmol NH4HC03); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-4-fluorophenoxy)ethyl)amino)-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (6.6 mg, 10.29 pmol, 9.71 % yield) as a white solid. LCMS (M+H) = 641; Retention time: 2.441 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-4- fluorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (10 mg, 0.016 mmol) in methanol (5 mL) and water (1 mL) was added NaOH (12.48 mg, 0.312 mmol) at once. The resulting mixture was stirred at 90 °C for 10 hours. LCMS showed reaction was completed. The mixture was cooled and the pH was adjusted to ~7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-4- fluorophenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (2.6 mg, 4.34 pmol, 27.8 % yield) as white solid. LCMS (M+H) = 599;

Retention time (10 mM NH4HC03) = 1.635 min. Ή NMR (400 MHz, MeOD) d 8.07 (s,

1H), 7.96 (d, J = 1.8 Hz, 1H), 7.44 (dd, J = 8.6, 2.2 Hz, 1H), 7.21 (dd, J = 8.2, 3.0 Hz, 1H), 7.14 (dd, J = 9.1, 4.9 Hz, 1H), 7.07- 7.00 (m, 1H), 6.77 (d, J = 8.7 Hz, 1H), 5.71 (s, 1H), 4.24 (t, J = 5.5 Hz, 2H), 3.82 (dd, J = 5.8, 4.5 Hz, 2H), 3.15-3.10 (brs, 2H), 2.78-2.70 (brs, 2H), 2.66 (s, 3H), 1.46-1.40 (brs, 2H), 1.34 -l .30(brs, 2H), 1.20 (s, 9H), 0.91 (s, 6H).

Example 306

Step 1 : To a stirred solution of 4-chloro-2-methylphenol (1 g, 7.01 mmoL) in DMF (15 mL) was added CS2CO3 (4.57 g, 14.02 mmoL) in one-portion and stirred at 20 °C for 0.5 h. Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.677 g, 7.01 mmoL) was added and stirred at 120 °C for 16 hrs. LCMS showed most of the starting material consumed. The reaction mixture was diluted with water (100 ml) and EtOAc (200 ml), aqueous phase separated and the organic phase was washed with brine (200 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% EtOAc/pet. ether) to obtain tert-butyl (2-(4- chloro-2-methylphenoxy)ethyl)carbamate (0.6 g, 2.034 mmoL, 29.0 % yield) as a white solid. LCMS (M+Na) = 308; Retention time (0.1% TFA): 1.716 min.

Step 2: To a stirred solution of tert-butyl (2-(4-chloro-2- methylphenoxy)ethyl)carbamate (300 mg, 1.050 mmoL) in DMF (10 mL) was added NaH (50.4 mg, 2.100 mmoL) in one-portion at 0 °C and stirred for 0.5 h. Then, Mel (0.066 mL, 1.050 mmoL) was added, warmed to 25 °C and stirred for 0.5 hrs. LCMS showed reaction was completed. The reaction mixture was diluted with water (100 ml) and EtOAc (200 ml), aqueous phase separated and the organic phase was washed with brine (200 ml x 3), dried over anhydrous NaiSOi. filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% EtOAc/pet. ether) to give tert-butyl (2-(4- chloro-2-methylphenoxy)ethyl)(methyl)carbamate (180 mg, 0.481 mmoL, 45.8 % yield) as a colorless oil. LCMS (M+H) = 300; Retention time (0.1% TFA): l .745min.

Step 3 : To a solution of tert-butyl (2-(4-chloro-2- methylphenoxy)ethyl)(methyl)carbamate (0.18 g, 0.600 mmoL) in DCM (6 mL) was added 2,2,2-trifhioroacetic acid (1 mL, 13.46 mmoL) at once and stirred at 15 °C for 12 hours. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with DCM (50 ml), washed with water (50 ml x3), Then, organic layer was dried over Na2SC>4 and concentrated to afford a brown oil. The brown oil was purified by silica gel chromatography eluting with pet. etherEtOAc (10: 1) to afford the desired product 2-(4- chloro-2-methylphenoxy)-N-methylethanamine (110 mg, 0.551 mmoL, 92 % yield) as yellow solid. LCMS (M+H) = 200 & 202; Retention time (0.1% TFA) = 1.287 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fhioro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) dissolved in NMP (0.5 mL) was added 2-(4-chloro-2-methylphenoxy)-N-methylethan-l -amine (21.17 mg, 0.106 mmol) and K2CO₃ (44.0 mg, 0.318 mmol). The reaction mixture was stirred at 120 °C for 16 hours. LCMS showed some starting material remained and target product was found. The reaction mixture was filtered and concentrated to obtain light yellow oil. The crude product purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep Cl 8 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HC03); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(4-chloro-2-methylphenoxy)ethyl)(methyl)amino)-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (9 mg, 0.014 mmol, 13.03 % yield) was obtained as a white solid. LCMS (M+H) = 651; Retention time (10 mM

NH4HC03): 2.947 min.

Step 5 : To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(4-chloro-2- methylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (10 mg, 0.015 mmol) in methanol (5 mL) and water (1 mL) was added NaOH (12.28 mg, 0.307 mmol) at once. The resulting mixture was stirred at 90 °C for 10 hours. LCMS showed reaction was completed. The mixture was cooled and the pH was adjusted to ~7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep- HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(6'-((2-(4- chloro-2-methylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl- [3,3'-bipyridin]-5-yl)acetic acid (5.2 mg, 8.54 pmol, 55.6 % yield) as white solid. LCMS (M+H) = 609; Retention time (10 mM NH4HC03) = 1.839 min. Ή NMR (400 MHz,

MeOD) d 8.05 (d, J = 3.1 Hz, 2H), 7.53 (dd, J = 8.8, 2.4 Hz, 1H), 7.17- 7.04 (m, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.71 (s, 1H), 4.23 (t, J = 5.2 Hz, 2H), 4.12 - 4.04 (m, 2H), 3.25-3.20 (brs, 2H), 2.75-2.70 (brs, 2H), 2.66 (s, 3H), 2.15 ( s, 3H), 1.44-1.40 (brs, 2H), 1.38-1.28 (m, 2H), 1.20 (s, 9H), 0.89 (s, 6H).

Example 307

Step 1 : To a solution oftert-butyl (2-(4-chloro-2-methylphenoxy)ethyl)carbamate (0.3 g, 1.050 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (1 ml, 13.46 mmol) at once and stirred at 15 °C for 12 hours. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with DCM (50 ml), washed with saturated Na2C03 (50 ml x2) and water (50 ml x3). Then, organic layer was dried over NaiSOi and concentrated to afford a brown oil. The brown oil was purified by silica gel chromatography eluting with pet. ether: EtO Ac (10: 1) to afford 2-(4-chloro-2-methylphenoxy)ethanamine (160 mg, 0.862 mmol, 82 % yield) as a yellow solid. LCMS (M + H) = 186 & 188; Retention time (0.1% TFA): 1.635 min.

Step 2: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) dissolved in NMP (0.5 mL) was added 2-(4-chloro-2-methylphenoxy)ethan-l -amine (59.0 mg, 0.318 mmol) and K2CO3 (44.0 mg, 0.318 mmol). The reaction mixture was stirred at 120 °C for 16 hours. LCMS showed presence desired compound mass. The reaction mixture was filtered and the filtrate was diluted with water (50 ml) and EtO Ac (50 ml). The organic phase was separated and washed with brine (50 ml x 3), dried over anhydrous NaiSOi. filtered and concentrated to obtain 55 mg crude oil which was used in the next step without further purification. LCMS (M+H) = 637; Retention time (10M NH4HCO3): 2.589 min.

Step 3 : To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(4-chloro-2- methylphenoxy)ethyl) amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (55 mg, 0.086 mmol) in ethanol (5 mL) and water (1 mL) was added NaOH (69.0 mg, 1.726 mmol) at once. The resulting mixture was stirred at 90 °C for about 2 hours and cooled. The pH was adjusted to about 7 with acetic acid and purified by Prep-HPLC

(Instrument: Gilson 281 (PHG-009; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 40-68%B in 8.0 min, stop at 13.0 min; Plow Rate (ml/min) 30.00) to give (S)-2-(tert-butoxy)-2-(6'-((2-(4-chloro-2- methylphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (8.9 mg, 0.015 mmol, 17.33 % yield) as white solid. LCMS (M+H) = 595 & 597; Retention time (10M NH4HC03): 1.586 min. ¾ NMR (400 MHz, CDC13) d 8.17 (s, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.34 (dd, J = 8.5, 2.3 Hz, 1H), 7.19-7.18 (m, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.57 (d, J = 8.6 Hz, 1H), 6.04 (s, 1H), 4.22 (t, J = 5.0 Hz, 2H), 3.93- 3.75 (m, 1H), 3.75 -3.32 (m, 1H), 3.02-3.00 (brs, 4H), 2.60 (s, 3H), 2.28 (s, 3H), 1.37-1.35 (brs, 2H), 1.22 -l .20(brs, 11H), 0.85 (s, 6H). Example 308

Step 1 : To a stirred solution of 4-fluoro-2-methylphenol (1 g, 7.93 mmoL) in DMF (15 mL) was added CS2CO3 (5.17 g, 15.86 mmoL) in one-portion and stirred at 20 °C for 0.5 h. Then, 2-((tert-butoxycarbonyl)amino)ethyl methane sulfonate (1.898 g, 7.93 mmoL) was added and stirred at 120 °C for 16 hrs. LCMS showed the reaction was completed. The reaction mixture was filtered and the cake was washed with EtOAc (10 ml x 2). The filtrate was diluted with water (200 ml) and EtOAc (100), aqueous phase separated and the organic phase was washed with brine (200 ml x 3), dried over anhydrous Na2S04, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel

chromatography (5%~l0% EtO Ac/pet. ether) to give tert-butyl (2-(4-fluoro-2- methylphenoxy) ethyl)carbamate (1.2 g, 3.60 mmoL, 45.4 % yield) as a white solid. LCMS (M+H) = 292; Retention time (0.1% TFA): 1.646 min.

Step 2: To tert-butyl (2-(4-fluoro-2-methylphenoxy)ethyl)carbamate (0.6 g, 2.228 mmoL) was added 4M HC1 in dioxane (5.00 ml, 20 mmoL) at once and stirred at 15 °C for 12 hours. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with ether (10 ml), filtered and was washed with ether (10 ml), dried to give 2-(4-fluoro-2-methylphenoxy)ethan-l -amine (330 mg, 1.950 mmoL, 88 % yield) as a light yellow solid. (M+H) = 170; Retention time (0.1% TFA): 0.882 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (0.5 mL) was added 2-(4-fluoro-2-methylphenoxy)ethan-l -amine (53.8 mg, 0.318 mmol) and K₂CO₃ (44.0 mg, 0.318 mmol). The reaction mixture was stirred at 90 °C for 16 hours. LCMS showed presence of desired product. The reaction mixture was filtered and concentrated to obtain light yellow oil. The crude product purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A:

Water (10 mmol NH4HCO3); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin- l-yl)-6'-((2-(4-fluoro-2-methylphenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (20 mg, 0.032 mmol, 30.4 % yield) was obtained as a white solid. LCMS (M+H) = 621; Retention time (10 mM NH4HCO3): 2.572 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(4-fluoro-2-methylphenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (20 mg, 0.032 mmol) in methanol (5 mL) and water (1 mL) was added NaOH (25.8 mg, 0.644 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours. LCMS showed reaction was completed. The mixture was cooled and the pH was adjusted to ~7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(4-fluoro-2-methylphenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (6.4 mg, 10.79 pmol, 33.5 % yield) as white solid. LCMS (M+H) = 579; Retention time (10 mM NH4HC03) = 1.625 min. Ή NMR (400 MHz, MeOD) d 7.91 (s, 1H), 7.82-7.80 (m,

1H), 7.32 (dd, J = 8.7, 2.2 Hz, 1H), 6.80 - 6.68 (m, 3H), 6.63 (d, J = 8.7 Hz, 1H), 5.59 (s,

1H), 4.05 (t, J = 5.5 Hz, 2H), 3.73 - 3.60 (m, 2H), 3.18 - 2.81 (m, 2H), 2.60-2.58 (brs, 2H), 2.53 (s, 3H), 2.10 (s, 3H), 1.32 -l .30(brs, 2H), 1.25-1.18 (m, 2H), 1.07 (s, 9H), 0.78 (s, 6H).

Example 309

Step 1 : To a stirred solution of tert-butyl (2-(4-fluoro-2-methylphenoxy)ethyl) carbamate (600 mg, 2.228 mmoL) in DMF (5 mL) was added NaH (107 mg, 4.46 mmoL) in one-portion at 0 °C and stirred for 0.5 h. Then, Mel (0.279 mL, 4.46 mmoL) was added, warmed up to 25 °C and stirred for 0.5 hrs. LCMS showed reaction was completed. The reaction mixture was diluted with water (100 ml) and EtOAc (200 ml), aqueous phase separated and the organic phase was washed with brine (200 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% EtO Ac/pet. ether) to give tert-butyl (2-(4-fluoro-2- methylphenoxy)ethyl)(methyl)carbamate (430 mg, 0.817 mmoL, 36.7 % yield)as a colorless oil. LCMS (M+H) = 306; Retention time (0.1% TFA): l .5 lmin.

Step 2: To tert-butyl (2-(4-fluoro-2-methylphenoxy)ethyl)(methyl)carbamate (0.43 g, 1.518 mmoL) added 4M HC1 in dioxane (5.00 ml, 20 mmoL) at once and stirred at 15 °C for 12 hours. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with ether (10 ml), filtered and the cake was washed with ether (10 ml), dried to obtain 2-(4-fluoro-2-methylphenoxy)-N-methylethan-l -amine (255 mg, 1.392 mmoL, 92 % yield) as a white solid. LCMS (M+H) = 184; Retention time (0.1% TFA) = 0.903 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (0.5 mL) was added 2-(4-chloro-2-methylphenoxy)-N-methylethan-l -amine (21.17 mg, 0.106 mmol) and K2CO₃ (44.0 mg, 0.318 mmol). The reaction mixture was stirred at 120 °C for 16 hours. LCMS showed presence of desired product. The reaction mixture was filtered and concentrated to obtain light yellow oil. The crude product purified by Prep-HPLC

{Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HC03); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(4- (4,4-dimethylpiperidin- 1 -yl)-6'-((2-(4-fluoro-2-methylphenoxy)ethyl) (methyl)amino)-6- methyl-[3,3'-bipyridin]-5-yl)acetate (20 mg, 0.032 mmol, 29.7 % yield) was obtained as a white solid. LCMS (M+H) = 635; Retention time (10 mM NH4HC03): 2.855 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(4-fluoro-2-methylphenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (20 mg, 0.032 mmol) in methanol (5 mL) and water (1 mL) was added NaOH (25.2 mg, 0.630 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours. LCMS showed reaction was completed. The mixture was cooled and the pH was adjusted to ~7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(4-(4,4- dimethylpiperidin-l-yl)-6'-((2-(4-fhioro-2-methylphenoxy)ethyl)(methyl)-amino)-6-methyl- [3,3'-bipyridin]-5-yl)acetic acid (6.1 mg, 10.29 pmol, 32.7 % yield) as white solid. LCMS (M+H) = 593; Retention time (10 mM NH4HC03) = 1.72 min. Ή NMR (400 MHz, MeOD) d 7.93-7.92 (m, 2H), 7.40 (dd, J = 8.8, 2.3 Hz, 1H), 6.82 - 6.66 (m, 4H), 5.59 (s, 1H), 4.09 (t, J = 5.2 Hz, 2H), 3.96 (dd, J = 7.6, 5.1 Hz, 2H), 3.18-3.03 (m, 5H), 2.63-2.60 (brs, 2H), 2.53 (s, 3H), 2.04 (s, 3H), 1.25-1.19 (m, 4H), 1.08 (s, 9H), 0.77 (s, 6H).

Example 310

Step 1 : To a stirred solution of 2-chloro-4-methylphenol (1 g, 7.01 mmoL) in DMF (15 mL) was added CS2CO3 (4.57 g, 14.02 mmoL) one-portion at 20 °C and stirred for 0.5 h. Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.677 g, 7.01 mmoL) was added and stirred at 100 for 16 hrs. LCMS showed most of starting material consumed. The reaction mixture was filtered and the cake was washed with EtOAc (10 ml x 2). The filtrate was diluted with water (200 ml) and EtOAc (100), aqueous phase separated and the organic phase was washed with brine (200 ml x 3), dried over anhydrous Na2S04, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel

chromatography (5%~l0% EtOAc/pet. ether) to give tert-butyl (2-(2-chloro-4- methylphenoxy)ethyl)carbamate (1.2 g, 3.55 mmoL, 50.6 % yield). LCMS (M+H) = 308 & 310; Retention time (0.1% TFA): l .682min.

Step 2: To tert-butyl (2-(2-chloro-4-methylphenoxy)ethyl)carbamate (0.6 g, 2.100 mmoL) was added 4M HC1 in dioxane (5.00 ml, 20 mmoL) at once. The reaction mixture was stirred at 15 °C for 12 hours. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with ether (10 ml), filtered and the solid was washed with ether (10 ml), dried to give 2-(2-chloro-4-methylphenoxy)ethan-l -amine (280 mg, 1.508 mmoL, 71.8 % yield) as a yellow solid. LCMS (M+H) = 186 & 188, Retention time (0.1% TFA): 1.211 min.

Step 3: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (30 mg, 0.064 mmol) in NMP (0.5 mL) was added 2-(2-chloro-4-methylphenoxy)ethanamine (59.0 mg, 0.318 mmol) and K2CO₃ (61.5 mg, 0.445 mmol). The reaction mixture was stirred at 120 °C for 16 hours. LCMS showed presence of desired product. The reaction mixture was filtered and the filtrate was diluted with water (50 ml) and EtOAc (50 ml), the organic phase was separated, washed with brine (50 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to obtain 50 mg crude oil whic was used in the next step without further purification. LCMS (M+H) = 637; Retention time (10M NH4HCO3): 2.542 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-4- methylphenoxy)ethyl) amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (50 mg, 0.078 mmol) in ethanol (5 mL) and water ( 1 mL) was added NaOH (31.4 mg, 0.785 mmol) at once. The resulting mixture was stirred at 90 °C for about 16 hours. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid, Then, concentrated under vacuum and purified by Prep-HPLC. (Instrument: Gilson 281 ( PHG-009; Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 40-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00) to give (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-4- methylphenoxy)ethyl)amino) -4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (5.7 mg, 9.58 pmol, 12.21 % yield) as white solid. LCMS (M+H) = 595 & 597; Retention time (10M NH4HCO3): 1.370 min. Ή NMR (400 MHz, CDC13) d 8.16 (s, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 8.5, 2.2 Hz, 1H), 7.10 (dd, J = 11.2, 2.6 Hz, 2H), 6.75 (d, J = 8.5 Hz, 1H), 6.55 (d, J = 8.6 Hz, 1H), 6.03-6.01 (m, 1H), 5.08 (s, 1H), 4.17 (t, J = 5.1 Hz, 2H), 3.94- 3.76 (m, 2H), 3.72- 3.26 (m, 1H), 3.00-2.98 (brs, 1H), 2.60 (s, 3H), 2.21-2.20 (m, 5H), 1.36 (d, J = 11.0 Hz, 2H), 1.22 (s, 11H), 0.85 (s, 6H).

Example 311

Step 1 : To a stirred solution of tert-butyl (2-(2-chloro-4-methylphenoxy)ethyl) carbamate (600 mg, 2.100 mmol) in DMF (5 mL) was added NaH (101 mg, 4.20 mmol) one- portion at 0 °C and stirred for 0.5 h. Then, Mel (0.263 mL, 4.20 mmol) was added, warmed up to 25 °C and stirred for 0.5 hrs. TLC (pet. ether: EtOAc= 1 : 1) showed reaction was completed. The reaction mixture was diluted with water (100 ml) and EtOAc (200 ml), aqueous phase separated and the organic phase was washed with brine (200 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% EtOAc/pet. ether) to give tert-butyl (2-(2- chloro-4-methylphenoxy)ethyl)(methyl)carbamate (400 mg, 0.632 mmol, 30.1 % yield) as a colorless oil. LCMS (M+H) = 322; Retention time (0.1% TFA): l .9 l5min.

Step 3: To tert-butyl (2-(2-chloro-4-methylphenoxy)ethyl)(methyl)carbamate (0.4 g, 1.334 mmol) added HC1 (5.00 ml, 20 mmol) at once. The reaction mixture was stirred at 15 °C for 12 hours. TLC (pet. ether: EtOAc= 1 : 1) showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with ether (10 ml), filtered and the cake was washed with ether (10 ml), dried to obtain the desired product 2-(2-chloro-4- methylphenoxy)-N-methylethan-l -amine (280 mg, 0.715 mmol, 53.6 % yield) as a light yellow solid. LCMS (M+H) = 200; Retention time (0.1% TFA) = 0.984 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-chloro-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.102 mmol) in toluene (3 mL) was added 2-(2-chloro-4-methylphenoxy)-N-methylethan-l -amine (40.9 mg, 0.205 mmol), dicyclohexyl(2',6'-diisopropoxy-[l, r-biphenyl]-2-yl)phosphane (9.56 mg,

0.020 mmol), Pd2(dba)3 (9.38 mg, 10.24 pmol) and cesium carbonate (100 mg, 0.307 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 hours. LCMS showed reaction was completed. The reaction mixture was filtered and concentrated to obtain light yellow oil. The crude product purified by Prep-HPLC {Instrument: Gilson 281 (PHG- 009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 pm; Mobile Phase A: Water (10 mmol NH4HC03); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-4- methylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (20 mg, 0.031 mmol, 30.0 % yield) as a white solid. LCMS (M+H) = 651; Retention time (10 mM NH4HC03): 2.469 min.

Step 5 : To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-4- methylphenoxy)ethyl) (methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (20 mg, 0.031 mmol) in methanol (5 mL) and water (1 mL) was added NaOH (24.56 mg, 0.614 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours. LCMS showed reaction was completed. The mixture was cooled and the pH was adjusted to ~7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep- HPLC {Instrument: Gilson 281 (PHG-009); Column Xtimate Prep C18 OBD, 21.2 x 250 mm, 10 mih; Mobile Phase A: Water (10 mmol NH4HCO3); B: MeCN; Gradient 36-68%B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give (S)-2-(tert-butoxy)-2-(6'-((2-(2- chloro-4-methylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl- [3,3'-bipyridin]-5-yl)acetic acid (3 mg, 4.92 pmol, 16.04 % yield) as white solid. LCMS (M+H) = 609; Retention time (10 mM NH4HC03) = 1.764 min. Ή NMR (400 MHz,

MeOD) d 7.97- 7.87 (m, 2H), 7.40 (dd, J = 8.8, 2.4 Hz, 1H), 7.06 (d, J = 1.7 Hz, 1H), 6.92 (dd, J = 8.4, 1.5 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 5.58 (s, 1H), 4.14 (t, J = 5.1 Hz, 2H), 4.03 - 3.87 (m, 2H), 3.21-3.13 (m, 5H), 2.61-2.60 (brs, 2H), 2.54 (s, 3H), 2.14 (s, 3H), 1.33-1.22 (m, 4H), 1.07 (s, 9H), 0.76 (s, 6H).

Example 312

Step 1 : To a solution of 2,4-dimethylphenol (1.5 g, 12.28 mmol) in DMF (15 mL) was added CS2CO3 (5.20 g, 15.96 mmol) at room temperature and stirred for 15 minutes. Then, 2- ((tert-butoxycarbonyl)amino)ethyl methanesulfonate (3.53 g, 14.73 mmol) was added and stirred at 100 °C for 16 hours. The mixture was cooled and diluted with water (30 mL), extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous NaiSO and the solvent was removed in vacuum to give the crude product as an oil. The crude was purified by column chromatography (Cl 8, Water (10 mmol/L NH4HCO3 a.q.): Methanol = 60%) to give tert-butyl (2-(2,4- dimethylphenoxy)ethyl)carbamate (1.5 g, 5.14 mmol, 41.9 % yield) as yellow solid. LCMS (M-100) = 165; Retention time (0.01% NH4HCO3) = 2.01 min.

Step 2: To a solution of HC1 (8 mL, 4M solution in l,4-dioxane) was added tert-butyl (2-(2,4-dimethylphenoxy)ethyl)carbamate (0.5 g, 1.884 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. LCMS showed reaction was completed. The mixture was concentrated, washed with ether and filtered to give 2-(2,4- dimethylphenoxy)ethan-l -amine hydrochloride (330 mg, 1.636 mmol, 87 % yield) as a white solid. The solid was used in the next step without further purification. LCMS (M+H) = 166; Retention time (0.01% NH4HCO3) = 1.451 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mL) was added 2-(2,4-dimethylphenoxy)ethanamine hydrochloride (86 mg, 0.424 mmol) and K2CO₃ (147 mg, 1.060 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours. LCMS showed reaction was completed. The mixture was filtered and the filtrate was purified by Prep-HPLC to give isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2,4- dimethylphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin- 1 -yl)-6-methyl- [3 ,3 '-bipyridin] -5 - yl)acetate (18 mg, 0.029 mmol, 27.5 % yield) as yellow solid. LCMS (M+H)= 617.7;

Retention time (0.01% NH4HCO3) = 2.706 min.

Step 4: To a solution of NaOH (11.67 mg, 0.292 mmol) in ethanol (3 mL) and H20 (0.500 mL) was added the isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2,4- dimethylphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin- 1 -yl)-6-methyl-[3 ,3 -bipyridin] -5 - yl)acetate (18 mg, 0.029 mmol). The mixture was stirred at 90 °C for additional 20 h. The LCMS showed the reaction was completed. The pH was adjusted to about 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC to give (S)-2-(tert- butoxy)-2-(6'-((2-(2,4-dimethylphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6- methyl-[3,3'-bipyridin]-5-yl)acetic acid (8.0 mg, 0.014 mmol, 47.7 % yield) was obtained. LCMS (M+H) = 575.2; Retention time (0.0l% NH₄HCO3) = 1.688 min. Ή NMR (400 MHz, MeOD) d 8.08 (s, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.44 (dd, J= 8.8, 2.3 Hz, 1H), 6.93 (d, J= 7.6 Hz, 2H), 6.78 (t, J= 8.5 Hz, 2H), 5.70 (s, 1H), 4.14 (m, 2H), 3.80 - 3.77 (m, 2H), 3.21- 3.17 (brs, 2H), 2.78-2.76 (brs, 2H), 2.66 (s, 3H), 2.23 (s, 3H), 2.17 (s, 3H), 1.55 - 1.36 (m, 4H), 1.20 (s, 9H), 0.91 (s, 6H).

Example 313

Step 1 : To a solution oftert-butyl (2-(2,4-dimethylphenoxy)ethyl)carbamate (500 mg, 1.884 mmol) in DMF (8 mL) was added the NaH (226 mg, 5.65 mmol). Then, iodomethane (401 mg, 2.83 mmol) was added and stirred for 0.5 h. LCMS showed reaction was completed. Then, the reaction mixture was diluted with ice water and extracted with EtOAc (3 x 20 mL). The combined organic layers washed with water (2 x 20 mL), dried over anhydrous NaiSOr and evaporated in vacuo to give tert-butyl (2-(2,4-dimethylphenoxy)ethyl)(methyl)carbamate (480 mg, 0.309 mmol, 16.41 % yield) as orange oil which was used in next step without purification. LCMS (M-100) = 179.0; Retention time (0.01% NH4HCO3) = 1.891 min.

Step 2: To a solution of HC1 (8 mL, 4M solution in l,4-dioxane) was added tert-butyl (2-(2,4-dimethylphenoxy)ethyl)(methyl)carbamate (480 mg, 1.718 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. LCMS showed reaction was completed. The mixture was concentrated, washed with ether and filtered to give 2-(2,4- dimethylphenoxy)-N-methylethan-l -amine hydrochloride (320 mg, 1.483 mmol, 86 % yield) as a white solid which was used in the next step without further purification. LCMS = 179.9 (M+H); Retention time (0.0l% NH4HCO3) = 1.27 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mL) was added 2-(2,4-dimethylphenoxy)-N-methylethan-l -amine hydrochloride (91 mg, 0.424 mmol) and K2CO3 (147 mg, 1.060 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours. LCMS showed reaction was completed. The mixture was filtered and the filtrate was purified by Prep-HPLC to give isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2,4- dimethylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (22 mg, 0.035 mmol, 32.9 % yield) as yellow solid. LCMS (M+H) = 631.7; Retention time (0.01% NH4HCO3) = 2.506 min.

Step 4: To a solution of sodium hydroxide (13.95 mg, 0.349 mmol) in ethanol (3 mL) and H2O (0.500 mL) was added the isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2,4- dimethylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (22 mg, 0.035 mmol). The mixture was stirred at 90 °C for 20 h. The LCMS showed the reaction was completed. The pH was adjusted to about 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPLC purification to give (S)- 2-(tert-butoxy)-2-(6'-((2-(2,4-dimethylphenoxy)ethyl)(methyl)amino)-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (12.3 mg, 0.021 mmol,

59.9 % yield) was obtained. LCMS (M+H) = 589.2; Retention time (0.0l% NH4HCO3) = 1.792 min. 'HNMR (400 MHz, MeOD) d 7.96 (s, 1H), 7.93 (d, J= 2.0 Hz, 1H), 7.42 (dd, J= 8.8, 2.4 Hz, 1H), 6.78 (dd, J= 12, 8.8 Hz, 3H), 6.64 (d, J= 8.0 Hz, 1H), 5.59 (s, 1H), 4.08 (t, J= 5.2 Hz, 2H), 3.98 - 3.93 (m, 2H), 3.21-3.19 (brs, 2H), 3.14 (s, 3H), 2.66 - 2.65 (m, 2H), 2.55 (s, 3H), 2.11 (s, 3H), 2.01 (s, 3H), 1.39- 1.23 (m, 4H), 1.09 (s, 9H), 0.78 (s, 6H).

Example 314

Step 1 : To a solution of 4-fluoro-2-methoxyphenol (1 g, 7.04 mmol) in DMF (15 mL) was added CS2CO3 (2.98 g, 9.15 mmol) at room temperature and stirred for 15 minutes.

Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (2.020 g, 8.44 mmol) was added and stirred at 100 °C for 16 hours. The reaction mixture cooled, filtered and filtrate was purified by Prep-HPLC to afford tert-butyl (2-(4-fluoro-2- methoxyphenoxy)ethyl)carbamate (l .6g, 5.61 mmol, 80 % yield) as yellow oil. LCMS (M+H) = 286; Retention time (0.0l% NH₄HCC>3) = 1.441 min.

Step 2: To a solution of tert-butyl (2-(4-fluoro-2-methoxyphenoxy)ethyl)carbamate (800 mg, 2.80 mmol) in DMF (15 mF) was added sodium hydride (81 mg, 3.36 mmol) at 0 °C and stirred for 15 minutes. Then, iodomethane (597 mg, 4.21 mmol) was added and stirred at 25 °C for 16 hours. Then, reaction mixture was diluted with ice water (10 ml) and extracted with ethyl acetate (20 ml x3). The combined organic layers were washed with water (20ml x 2), brine (20 ml), dried by NaiSOr and concentrated. The filtrate was purified by Prep-HPFC to give tert-butyl (2-(4-fluoro-2-methoxyphenoxy)ethyl)(methyl)carbamate (650 mg, 2.134 mmol, 76 % yield) as yellow oil. FCMS (M+H) = 300.1; Retention time (0.01% NH HC0₃) = 1.537 min.

Step 3 : To a solution of tert-butyl (2-(4-fluoro-2- methoxyphenoxy)ethyl)(methyl)carbamate (650 mg, 2.171 mmol) in DCM (10 mF) was added TFA (1.673 mF, 21.71 mmol) at 0 °C. The mixture was stirred at 0 °C for 6 hours. The reaction was concentrated and purified by Prep-HPFC to give 2-(4-fluoro-2- methoxyphenoxy)-N-methylethan-l -amine (403 mg, 1.918 mmol, 88 % yield) as yellow oil. LCMS (M+H) = 200.1; Retention time (0.01% TFA) = 1.222 min.

Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mL) was added 2-(4-fluoro-2-methoxyphenoxy)-N-methylethan-l -amine (100 mg, 0.424 mmol) and K2CO3 (147 mg, 1.060 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours. LCMS showed reaction was completed. The mixture was filtered and the filtrate was purified by HPLC to give isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'- ((2-(4-fluoro-2-methoxyphenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (20 mg, 0.031 mmol, 29.0 % yield) as yellow solid. LCMS (M+H) = 651.2; Retention time (0.01% NH4HCO3) = 2.59 min.

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(4-fluoro-2-methoxyphenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (20 mg, 0.031 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (24.58 mg, 0.615 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by Prep-HPLC to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(4-fluoro-2-methoxyphenoxy)ethyl)(methyl)amino)-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (11.4 mg, 0.019 mmol, 60.9 % yield) as white solid. LCMS = 609.2 (M+H); Retention time (0.01% NH4HCO3) = 1.60 min. Ή NMR (400 MHz, MeOD) d 8.04 (d. ./ =

3.6 Hz, 2H), 7.53 (dd, J= 2.4, 8.8 Hz, 1H), 6.93 (dd, J= 8.8, 1.2 Hz, 1H), 6.87 (d, J= 8.4 Hz, 1H), 6.80 (dd, J= 10.4, 2.8 Hz, 1H), 6.60 (td, J= 8.4, 2.8 Hz, 1H), 5.71 (s, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.22 (t, J= 5.2 Hz, 2H), 4.10-3.97 (m, 2H), 3.81 (s, 3H), 3.27 (s, 3H), 2.77-2.72 (brs, 2H), 2.65 (s, 3H), 1.36-1.34 (brs, 4H), 1.19 (s, 9H), 0.88 (s, 6H).

Example 315

Step 1 : To a solution of tert-butyl (2-(4-fluoro-2-methoxyphenoxy)ethyl)carbamate (800 mg, 2.80 mmol) in DCM (10 mL) was added TFA (2.160 mL, 28.0 mmol) at 0 °C and stirred for 6 hours. LCMS showed that the reaction was completed. The reaction was concentrated and purified by Prep-HPLC to afford aim product 2-(4-fluoro-2- methoxyphenoxy)ethan-l -amine (500 mg, 2.55 mmol, 91 % yield) as yellow oil. LCMS (M+H) = 186.1; Retention time (0.01% TFA) = 1.204 min.

Step 2: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mL) was added 2-(4-fluoro-2-methoxyphenoxy)ethan-l -amine (94 mg, 0.424 mmol) and K2CO3 (147 mg, 1.060 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours. LCMS showed reaction was completed. The mixture was filtered and the filtrate was purified by Prep-HPLC to give isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-((2-(4- fluoro-2-methoxyphenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (12 mg, 0.019 mmol, 17.77 % yield) as yellow solid. LCMS (M+H)= 637.3; Retention time (0.01% NH4HCO3) = 2.38min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-((2-(4-fluoro-2-methoxyphenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (12 mg, 0.019 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (15.07 mg, 0.377 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by Prep-HPLC to give (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-6'-((2-(4-fluoro- 2-methoxyphenoxy)ethyl)amino)-6-methyl-[3,3'-bipyridin]-5-yl)acetic acid (8.76 mg, 0.014 mmol, 76 % yield) as white solid. LCMS (M+H) = 595; Retention time (0.01% NHTK03) = 1.62 min. ¾ NMR (400 MHz, MeOD) d 8.08 (s, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.46 (dd, J= 2.4, 8.8 Hz, 1H), 7.00 (dd, J= 8.4, 5.2 Hz, 1H), 6.83 (dd, J= 10.0, 2.8 Hz, 1H), 6.77 (d, J= 8.8 Hz, 1H), 6.63 (td, J= 8.0, 2.8 Hz, 1H), 5.72(s,l H), 4.18 (t, J= 5.2 Hz, 2H), 3.86 (s, 3H), 3.80 - 3.71 (m, 2H), 3.32-3.28 (m, 2H), 2.79- 2.76 (brs, 2H), 2.66 (s, 3H), 1.47-1.45 (brs,

4H), 1.20 (s, 9H), 0.92 (s, 6H). Example 316

Step 1 : To a solution of 2-chloro-6-methylphenol (1.5 g, 10.52 mmol) in DMF (15 mL) was added CS2CO3 (4.46 g, 13.68 mmol) at room temperature and stirred for 15 minutes. Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (3.02 g, 12.62 mmol) was added and stirred at 100 °C for 16 hours. LCMS showed that the reaction was completed. The reaction was filtered and the filtrate was purified by Prep-HPLC to tert-butyl (2-(2-chloro-6- methylphenoxy)ethyl)carbamate (0.8 g, 2.52 mmol, 23.95 % yield) as yellow oil. LCMS (M+H) = 287; Retention time (0.0l% NH₄HCC>3) = 1.59 min.

Step 2: To a solution of HC1 (8 mL, 4M solution in l,4-dioxane) was added tert-butyl (2-(2-chloro-6-methylphenoxy)ethyl)carbamate (0.5 g, 1.750 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. LCMS showed reaction was completed. The mixture was concentrated and resulting solid washed with ether and filtered to give 2-(2-chloro-6-methylphenoxy)ethan-l -amine hydrochloride (250 mg, 1.126 mmol, 64.3 % yield) as a white solid which was used in the next step without further purification. LCMS (M+H) = 186.1; Retention time (0.0l% NH₄HCC>3) = 1.235 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-6'-fluoro-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.106 mmol) in NMP (2 mL) was added 2-(2-chloro-6-methylphenoxy)ethan-l -amine hydrochloride (94 mg, 0.424 mmol) and K2CO3 (147 mg, 1.060 mmol) at once. The reaction mixture was stirred at 120 °C for 36 hours. LCMS showed reaction was completed. The mixture was filtered and the filtrate was purified by Pre-HPLC to give isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-6- methylphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (20 mg, 0.031 mmol, 29.6 % yield) as yellow solid. LCMS (M+H) = 637.2;

Retention time (0.01% NHdTCCh) = 2.66 min, purity (100 %). Step 4: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-6- methylphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetate (10 mg, 0.016 mmol) in ethanol (2 mL) and water (0.4 mL) was added NaOH (12.55 mg, 0.314 mmol) at once. The resulting mixture was stirred at 90 °C for 10 hours. LCMS showed reaction was completed. The pH was adjusted to about 7 with acetic acid and purified by Prep-HPLC to give (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-6- methylphenoxy)ethyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5- yl)acetic acid (5.1 mg, 8.44 pmol, 53.8 % yield) as white solid. LCMS (M+H) = 595;

Retention time (0.0l% NH₄HCC>3) = 1.52 min. Ή NMR (400MHz. MeOD): d 8.07 (s, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.47 (dd, J= 8.6, 2.2 Hz, 1H), 7.23-7.21 (m, 1H), 7.15 (d, J=7.2 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 5.71 (s, 1H), 4.14-4.10 (m, 2H), 3.86- 3.78 (m, 2H), 3.33-3.30 (m, 2H), 3.77-3.73 (brs, 2H), 2.65 (s, 3H), 2.30 (s, 3H), 1.46-1.41 (m, 4H), 1.20 (s, 9H), 0.89 (s, 6H).

Example 317

Step 1 : To a solution of tert-butyl (2-(2-chloro-6-methylphenoxy)ethyl)carbamate (500 mg, 1.750 mmol) in DMF (8 mL) was added the NaH (210 mg, 5.25 mmol) followed iodomethane (373 mg, 2.62 mmol). After 0.5 h, LCMS showed reaction was completed. The reaction mixture was diluted with ice water and extracted with EtOAc(3 x 20 mL). The combined organic phases were washed with water (2 x 20 mL), dried over anhydrous NaiSOr and evaporated in vacuo to give tert-butyl (2-(2-chloro-6- methylphenoxy)ethyl)(methyl)carbamate (320 mg, 1.067 mmol, 61.0 % yield) as orange oil which was used in next step without purification. LCMS (M-99) =200; Retention time (0.01% NH4HCO3) = 1.745 min.

Step 2: To a solution of HC1 (8 mL, 4M solution in l,4-dioxane) was added tert-butyl (2-(2-chloro-6-methylphenoxy)ethyl)(methyl)carbamate (0.25 g, 0.834 mmol) at once. The reaction mixture was stirred at room temperature for 12 hours. LCMS showed reaction was completed. The mixture was concentrated, diluted with ether and filtered to give 2-(2-chloro- 6-methylphenoxy)-N-methylethan-l -amine hydrochloride (120 mg, 0.508 mmol, 60.9 % yield) as a white solid which was used in the next step without further purification. LCMS (M+H) = 166; Retention time (0.0l% NH₄HCC>3) = 1.451 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(6'-chloro-4-(4,4- dimethylpiperidin-l-yl)-6-methyl-[3,3'-bipyridin]-5-yl)acetate (50 mg, 0.102 mmol) in toluene (3 mL) was added 2-(2-chloro-6-methylphenoxy)-N-methylethan-l -amine hydrochloride (24.19 mg, 0.102 mmol), dicyclohexyl(2',6'-diisopropoxy-[l, r-biphenyl]-2- yl)phosphane (9.56 mg, 0.020 mmol), Pd2(dba)3 (9.38 mg, 10.24 pmol) and cesium carbonate (100 mg, 0.307 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 hours. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with DCM (50 ml), washed with water (50 ml x3), dried over NaiSOi and concentrated to afford a brown oil. The brown oil was purified by Prep-HPLC to afford isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-6- methylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (15 mg, 0.023 mmol, 22.48 % yield) as white solid. LCMS (M+H) = 651; Retention time = 4.624 min.

Step 4: To a solution ofNaOH (9.21 mg, 0.230 mmol) in ethanol (3 mL) and H20 (0.5 mL) was added the isopropyl (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-6- methylphenoxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin-l-yl)-6-methyl-[3,3'- bipyridin]-5-yl)acetate (15 mg, 0.023 mmol). The mixture was stirred at 90 °C for additional 20 h. The LCMS showed the reaction was completed. The pH was adjusted to about 7 with acetic acid. The mixture was filtered and the filtrate was directly subjected to Prep-HPLC purification to give (S)-2-(tert-butoxy)-2-(6'-((2-(2-chloro-6-methylphen- oxy)ethyl)(methyl)amino)-4-(4,4-dimethylpiperidin- 1 -yl)-6-methyl- [3 ,3 '-bipyridin] -5 - yl)acetic acid (2.9 mg, 4.76 pmol, 20.67 % yield) was obtained. LCMS (M+H) = 609.2, Retention time (0.0l% NH4HCO₃) = 1.751 min. Ή NMR (400MHz. MeOD): d 8.06 (s, 1H), 8.02(d, J= 2.0 Hz, 1H), 7.53 (dd, J=8.8, 2.4 Hz, 1H), 7.19 (dd, J= 1.2, 8.0 Hz, 1H), 7.11 (dd, .7=7.6, 0.4 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 5.67 (s, 1H), 4.14-4.10 (m, 4H), 3.30 (s, 3H), 3.29-3.25 (m, 2H), 2.72-2.70 (brs, 2H), 2.64 (s, 3H), 2.21 (s, 3H), 1.47- 1.37 (m, 4H), 1.17 (s, 9H), 0.82 (s, 6H). Example 318

Step 1 : To a solution of isopropyl (S)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy- 6'-methyl-[2,3'-bipyridin]-5'-yl)-2-isopropoxyacetate (40 mg, 0.088 mmol), (bromomethyl) cyclopropane (14.22 mg, 0.105 mmol) in DMF (l .5mL) was added cesium carbonate (86 mg, 0.263 mmol). The mixture was stirred for 6 h at 50 °C. The reaction was filtered and concentrated. The residue was purified by silica gel plate (EtOAc:pet. ether = 1 : 1) to afford isopropyl (S)-2-(5-(cyclopropylmethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)-2-isopropoxyacetate (44 mg, 0.086 mmol). LCMS (M+H) = 510. Retention time (10 mM NH4HCO3) = 2.41 min.

Step 2: To a solution of isopropyl (S)-2-(5-(cyclopropylmethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-isopropoxyacetate (44 mg, 0.086 mmol) in methanol (1.5 mL) was added sodium hydroxide (69.1 mg, 1.727 mmol) in water (0.5 mL). The mixture was refluxed for 6 h at 80 °C. The reaction mixture was filtered and purified by prep-HPLC to give (S)-2-(5-(cyclopropylmethoxy)-4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-2,3'-bipyridin-5'-yl)-2-isopropoxyacetic acid (18 mg, 0.038 mmol). LCMS (M+H) = 468. Retention time (10 mM NH4HCO3) = 1. 50 min. Ή NMR (400 MHz, MeOD): d 8.36 (d, J = 2.8Hz, 1H), 7.56-7.50 (m, 1H), 7.46 (d, J = 8.4Hz, 1H), 5.72 (s, 1H), 3.99 (d, J = 6.8Hz, 2H), 3.55-3.58 (m, 1H), 2.80-2.81 (m, 4H), 2.65 (s, 3H), 1.31-1.41 (m, 5H), 1.27 (d, J = 6.0Hz, 3H), 1.06 (d, J = 6Hz, 3H), 0.89 (s, 6H), 0.66-0.71 (m, 2H), 0.41-0.45 (m, 2H).

Example 319

Step 1 : To a solution of isopropyl (S)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy- 6'-methyl-[2,3'-bipyridin]-5'-yl)-2-isopropoxyacetate (40 mg, 0.088 mmol),

(bromomethyl)cyclobutane (15.70 mg, 0.105 mmol) in DMF (1.5 mL) was added cesium carbonate (86 mg, 0.263 mmol). The mixture was stirred for 6 h at 50 °C. The reaction was filtered and concentrated. The residue was purified by silica gel plate (EtOAc:pet. ether =

1 : 1) to afford isopropyl (S)-2-(5-(cyclobutylmethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl- [2,3 '-bipyridin] -5 '-yl)-2-isopropoxyacetate (31 mg, 0.056 mmol). LCMS (M+H) = 524. Retention time (10 mM NH4HCO3) = 2.66 min.

Step 2: To a solution of isopropyl (S)-2-(5-(cyclobutylmethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-isopropoxyacetate (31 mg, 0.059 mmol) in methanol (l .5mL) was added sodium hydroxide (47.3 mg, 1.184 mmol) water (0.5 mL) . The mixture was refluxed for 6 h at 80 °C. The reaction mixture filtered and purified by prep-HPLC to give (S)-2-(5-(cyclobutylmethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl- [2,3'-bipyridin]-5'-yl)-2-isopropoxyacetic acid (17 mg, 0.035 mmol). LCMS (M+H) = 481. Retention time (10 mM NH4HCO3) = 1. 59 min. Ή NMR (400 MHz, MeOD): d 8.36 (d, J = 2.8Hz, 1H), 8.19 (s, 1H), 7.56-7.53 (m, 1H), 7.47 (d, J = 8.0Hz, 1H), 5.72 (s, 1H), 4.11 (d, J = 6.8Hz, 2H), 3.57-3.61 (m, 1H), 2.83-2.88 (m, 5H), 2.65 (s, 3H), 1.97-2.21 (m, 6H), 1.38-1.41 (m, 4H), 1.28 (d, J = 6.0Hz, 3H), 1.07 (d, J = 6.0Hz, 3H), 0.9 (s, 6H).

Example 320

Step 1 : To a solution of isopropyl (S)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy- 6'-methyl-[2,3'-bipyridin]-5'-yl)-2-isopropoxyacetate (40 mg, 0.088 mmol), 2-(2- chlorophenoxy)ethyl methanesulfonate (33.0 mg, 0.132 mmol) in DMF (l .5mL) was added cesium carbonate (86 mg, 0.263 mmol). The mixture was stirred for 6 h at 50 °C. The reaction was filtered and concentrated. The residue was purified by silica gel plate

(DCM:MeOH = 15: 1) to afford isopropyl (S)-2-(5-(2-(2-chlorophenoxy) ethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-isopropoxyacetate (46 mg, 8.35 pmol). LCMS (M+H) = 610. Retention time (0. l%TFA) = 2.28 min.

Step 2: To a solution of (S)-isopropyl 2-(5-(2-(2-chlorophenoxy)ethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-2,3'-bipyridin-5'-yl)-2-isopropoxyacetate (46 mg, 0.075 mmol) in methanol (1.5 mL) was added sodium hydroxide (60.3 mg, 1.508 mmol) in water (0.5 mL). The mixture was refluxed for 6 h at 80 °C. The reaction mixture filtered and purified by prep-HPLC to give (S)-2-(5-(2-(2-chlorophenoxy)ethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-isopropoxyacetic acid (37.6 mg, 0.064 mmol, 85 % yield) as a white powder solid. LCMS (M+H) = 568. Retention time (10 mM NH4HCO3) = 1. 38 min. Ή NMR (400 MHz, MeOD): 5 8.46 (d, J = 2.8Hz, 1H), 8.20 (s, 1H), 7.67-7.60 (m, 1H), 7.49 (d, J = 8.4Hz, 1H), 7.37-7.30 (m, 1H), 7.27-7.33 (m, 1H), 7.16- 7.12 (m, 1H), 6.95-7.00 (m, 1H), 5.73 (s, 1H), 4.57-4.60 (m, 2H), 4.46-4.49 (m, 2H), 3.58- 3.61 (m, 1H), 2.82-2.85 (m, 4H), 2.65 (s, 3H), l .35-l .4l(m, 4H), 1.28 (d, J = 6.0Hz, 3H), 1.07 (d, J = 6.0Hz, 3H), 0.88 (s, 6H).

Example 321

Step 1 : To a stirred solution of 2-chloro-4-fluorophenol (1 g, 6.82 mmoL) in DMF (15 mL) was added CS2CO3 (4.45 g, 13.65 mmoL) one-portion at 20 °C. The reaction mixture was stirred at 20 °C for 0.5 h. Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.633 g, 6.82 mmoL) was added and heated at 100 °C for 16 hrs. LC/MS showed most of starting material consumed. The reaction mixture was filtered, the cake was washed with EtOAc (10 ml x 2), the filtrate was diluted with water (200 ml) and EtOAc (100), phases separated and the organic phase was washed with brine (200 ml x 3), dried over anhydrous Na2SC>4, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel column chromatography (5%~l0% EtO Ac/PE) to give tert-butyl (2-(2-chloro-4- fluorophenoxy)ethyl)carbamate (800 mg, 2.76 mmoL, 40.5 % yield). LCMS (M +H) = 312 & 314. Retention time (0.1% TFA): 1.639 min.

Step 2: To a stirred solution of tert-butyl (2-(2-chloro-4- fluorophenoxy)ethyl)carbamate (400 mg, 1.381 mmoL) in DMF (5 mL) was added NaH (66.3 mg, 2.76 mmoL) in one-portion at 0 °C. The reaction mixture was stirred for 0.5 h and Mel (0.086 mL, 1.381 mmoL) was added. The reaction was warmed to 25 °C and stirred for 0.5 h. LC/MS showed reaction completed. The reaction mixture was diluted with water (100 ml) and EtOAc (200 ml), phases separated and the organic phase was washed with brine (200 ml x 3), dried over anhydrous NaiSOi. filtered and concentrated to give a yellow oil. The crude product was purified by silical gel column chromatography (5%~l0% EtO Ac/PE) to give tert-butyl (2-(2-chloro-4-fluorophenoxy)ethyl)(methyl)carbamate (260 mg, 0.616 mmoL, 44.6 % yield) as a colorless oil. LC/MS (M+Na) = 326. Retention time (0.1% TFA): 1.725 min.

Step 3: To tert-butyl (2-(2-chloro-4-fluorophenoxy)ethyl)(methyl)carbamate (0.26 g, 0.856 mmoL) was added 4M HC1 in dioxane (5.00 ml, 20 mmoL) at once. The reaction mixture was stirred at 15 °C for 12 hours. LCMS showed reaction was completed. The solvent was removed in vacuo, the solid was diluted with ether (10 ml), filtered and the cake was washed with ether (10 ml), dried to give 2-(2-chloro-4-fluorophenoxy)-N-methylethan-l- amine HC1 (150 mg, 0.737 mmoL, 86 % yield) as a white solid. LCMS (M+H) = 204.

Retention time (0.1% TFA): 1.180 min.

Step 4: To a mixture of isopropyl (S)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5- (((trifluoromethyl)sulfonyl)oxy)-[2,3'-bipyridin]-5'-yl)-2-isopropoxyacetate (30 mg, 0.051 mmol),2-(2-chloro-4-fluorophenoxy)-N-methylethan-l -amine HC1 (15.59 mg, 0.077 mmol), Cs2C03 (49.9 mg, 0.153 mmol) and xantphos (5.91 mg, 10.21 pmol) in toluene (1.5 mL) was added Pd2(dba)3 (9.35 mg, 10.21 pmol) under nitrogen atmosphere. The mixture was stirred at 100 °C for 16 hr. LCMS showed the SM was consumed completely. The mixture was poured into water (5.0 mL) and extracted with EtOAc (5 mL). The organic layer was washed with brine (5 mL x 2), dried over Na2S04 filtered and concentrated to give residue. The residue was purified by prep-HPLC to obtain isopropyl (S)-2-(5-((2-(2-chloro-4- fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)-2-isopropoxyacetate (15 mg, 0.023 mmol, 45.8 % yield) as a white solid. LCMS (M+H) = 641. Retention time (10 mM NH4HC03): 1.58 min.

Step 5: To a solution of isopropyl (S)-2-(5-((2-(2-chloro-4- fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)-2-isopropoxyacetate (20 mg, 0.031 mmol) in methanol (5 mL) and water (1 mL) was added NaOH (24.95 mg, 0.624 mmol) at once. The resulting mixture was stirred at 90 °C for about 10 hours. Then, cooled, pH was adjusted to about 7 with acetic acid and purified by prep-HPLC to give (S)-2-(5-((2-(2-chloro-4- fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)-2-isopropoxyacetic acid (3.1 mg, 5.05 pmol, 16.19 % yield) as a white solid. LCMS (M+H) = 599, R.T. (10 mM NH4HC03): 1.627 min. ¾ NMR (400 MHz, MeOD): d 8.29 (d, J = 2.8 Hz, 1H), 8.16 (s, 1H), 7.43 (dd, J = 8.8, 3.0 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.20 (dd, J = 8.2, 2.9 Hz, 1H), 7.12 - 6.99 (m, 2H), 5.68 (s, 1H), 4.28 (t, J = 4.9 Hz, 2H), 3.97 (t, J = 4.9 Hz, 2H), 3.61 - 3.49 (m, 1H), 3.42-3.34 (brs, 2H), 3.21 (s, 3H), 2.90-2.76 (brs, 2H), 2.65 (s, 3H), 1.45-1.33 (m, 4H), 1.28 (d, J = 6.0 Hz, 3H), 1.07 (d, J = 6.2 Hz, 3H), 0.85 (s, 6H). Example 322

Step 1 : To a solution of isopropyl (S)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy- 6'-methyl-[2,3'-bipyridin]-5'-yl)-2-isopropoxyacetate (100 mg, 0.219 mmol) in DMF (1 mL) was added l-bromo-2-butanone (0.023 mL, 0.219 mmol) and Cs2C03 (215 mg, 0.658 mmol). The mixture was stirred at 50 °C for 2 h. The reaction mixture was filtered and the filtrate was diluted with water (10 ml) and EtOAc (10 ml). The organic phase was separated and washed with brine (10 ml x 3), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by Prep-TLC to give (S)-isopropyl 2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(2-oxobutoxy)-2,3'-bipyridin-5'-yl)-2-isopropoxyacetate (66 mg, 57% yield). LCMS (M + H) = 526. Retention time (10 mM NH4HC03) = 2.10 min.

Step 2: Isopropyl (S)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(2-oxobutoxy)- [2,3'-bipyridin]-5'-yl)-2-isopropoxyacetate (66 mg, 0.126 mmol) was added to DAST (1 mL, 7.56 mmol) at 0 °C. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with ice, filtered and the filtrate was diluted with DCM (10 ml). The organic phase was separated and washed with brine (10 ml x 3), dried over anhydrous Na2SC>4 and concentrated. The residue was purified by Prep-TLC to give (S)-isopropyl 2-(4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(2-oxobutoxy)-2,3'-bipyridin-5'-yl)-2- isopropoxyacetate (30 mg, 44% yield). LCMS (M + H) = 548. Retention time (0.1% TFA) = 2.27 min.

Step 3: To a solution of isopropyl (S)-2-(5-(2,2-difluorobutoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-isopropoxyacetate (30 mg, 0.055 mmol) dissolved in methanol (3 mL) and water (1 mL) was added sodium hydroxide (43.8 mg, 1.096 mmol). The mixture was stirred at 80 °C overnight. The mixture was cooled, acidified with HC1 to pH = 7. The crude was purified by Prep-HPLC to afford (S)-2-(5-(2,2- difluorobutoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-2,3'-bipyridin-5'-yl)-2- isopropoxyacetic acid (25 mg , yield 89%) as a white solid. LCMS (M + H) = 506. Retention time (10 mM NH4HC03) = 1.52 min. 1H NMR (400 MHz, MeOD): d 8.47 (d, J = 2.8 Hz, 1H), 8.19 (s, 1H), 7.78 - 7.37 (m, 2H), 5.72 (s, 1H), 4.41 (t, J = 12.0 Hz, 2H), 3.73 - 3.49 (m, 1H), 2.82 (d, J = 7.9 Hz, 4H), 2.65 (s, 3H), 2.20-2.10 (m, 2H), 1.56 - 1.22 (m, 7H), 1.17 - 0.99 (m, 6H), 0.90 (s, 6H).

Example 323

Step 1 : To a solution of isopropyl (S)-2-butoxy-2-(4'-(4,4-dimethylpiperidin-l-yl)-5- hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (30 mg, 0.064 mmol),

(bromomethyl)cyclopropane (12.94 mg, 0.096 mmol) in DMF (1.5 mL) was added cesium carbonate (62.4 mg, 0.192 mmol). The mixture was stirred for 6 h at 50 °C. Diluted with water (30 mL) and extracted with EtOAc (40 mL). The organic phase was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel plate (EtOAc:pet. ether = 1: 1) to afford isopropyl (S)-2-butoxy-2-(5- (cyclopropylmethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (22 mg, 5.89 pmol). LCMS (M+H) = 524. Retention time (0. l%TFA) =2.27 min.

Step 2: To a solution of isopropyl (S)-2-butoxy-2-(5-(cyclopropylmethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (30 mg, 0.057 mmol) in methanol (1.5 mL) was added sodium hydroxide (45.8 mg, 1.146 mmol) in water (0.5 mL) . The mixture was refluxed for 6 h at 80 °C, cooled, filtered and purified by prep-HPLC to give (S)-2-butoxy-2-(5-(cyclopropylmethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (6.0 mg, 0.012 mmol). LCMS (M+H) = 481. Retention time (10 mM NH4HCO3) = 1. 55 min. Ή NMR (400 MHz, MeOD): d 8.36 (d, J = 2.8Hz, 1H), 8.19 (s, 1H), 7.56-7.53 (m, 1H), 7.47 (d, J = 8.4Hz, 1H), 5.56 (s, 1H), 3.99 (d, J = 7.2Hz, 2H), 3.67- 3.74 (m, 1H), 3.32-3.34 (m, 1H), 2.83-2.98 (m, 4H), 2.64 (s, 3H), 1.28-1.64 (m, 9H), 0.87- 0.92 (m, 9H), 0.66-0.71 (m, 2H), 0.41-0.45 (m, 2H).

Example 324

(bromomethyl)cyclobutane (14.28 mg, 0.096 mmol) in DMF (l .5mL) was added cesium carbonate (62.4 mg, 0.192 mmol). The mixture was stirred for 6 h at 50 °C. Diluted with water (30 mL) and extracted with EtOAc (40 mL). The organic phase was washed with brine (20 mL x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel plate (EtOAc:pet. ether = 1: 1) to afford isopropyl (S)-2-butoxy-2-(5- (cyclobutylmethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.013 mmol). LCMS (M+H) = 537. Retention time (0. l%TFA) =2.37 min.

Step 2: To a solution of isopropyl (S)-2-butoxy-2-(5-(cyclobutylmethoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (35 mg, 0.065 mmol) in methanol (1.5 mL) was added sodium hydroxide (52.1 mg, 1.302 mmol) in water (0.5 mL) . The mixture was refluxed for 6 h at 80 °C, cooled, filtered and purified by prep-HPLC to give (S)-2-butoxy-2-(5-(cyclobutylmethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (15.7 mg, 0.032 mmol). LCMS (M+H) = 496. Retention time (10 mM NH4HCO3) = 1. 65 min. ¹H NMR (400 MHz, MeOD): d 8.36 (d, J = 2.8Hz, 1H), 8.17 (s, 1H), 7.56-7.53 (m, 1H), 7.46 (d, J = 8.8Hz, 1H), 5.56 (s, 1H), 4.61 (m, 3H), 4.11 (d, J = 6.8Hz, 2H), 3.67-3.70 (m, 1H), 2.79-2.88 (m, 4H), 2.64 (s, 3H), 1.97-2.21 (m, 6H), 1.32-1.62 (m, 9H), 0.86-0.91 (m, 9H).

Example 325

Step 1 : To a solution of isopropyl (S)-2-butoxy-2-(4'-(4,4-dimethylpiperidin-l-yl)-5- hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (30 mg, 0.064 mmol), 2-(2- chlorophenoxy)ethyl methanesulfonate (24.02 mg, 0.096 mmol) in DMF (l .5mL) was added cesium carbonate (62.4 mg, 0.192 mmol). The mixture was stirred for 6 h at 50 °C. Diluted with water (30 mL) and extracted with EtOAc (40 mL). The organic phase was washed brine (20 mL x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel plate (EtOAc:pet. ether = 1.5: 1) to afford isopropyl (S)-2-butoxy-2-(5-(2-(2- chlorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (35 mg, 0.013 mmol). LCMS (M+H) = 624. Retention time (0. l%TFA) =2.33 min. Step 2: To a solution of isopropyl (S)-2-butoxy-2-(5-(2-(2-chlorophenoxy)ethoxy)-4'- (4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (35 mg, 0.056 mmol) in methanol (1.5 mL) was added sodium hydroxide (44.9 mg, 1.121 mmol) in water (0.5 mL). The mixture was refluxedfor 6 h at 80°C, cooled, filtered and purified by prep-HPLC to give (S)-2-butoxy-2-(5-(2-(2-chlorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl- [2,3'-bipyridin]-5'-yl)acetic acid (15.4 mg, 0.026 mmol). LCMS (M+H) = 582. Retention time (10 mM NH4HCO3) = 1. 64 min. ¾ NMR (400 MHz, MeOD): d 8.45 (d, J = 2.8Hz, 1H),

8.18 (s, 1H), 7.67-7.63 (m, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.37-7.34 (m, 1H), 7.27-7.32 (m,

1H), 7.16-7.12 (m, 1H), 6.95-6.99 (m, 1H), 5.56 (s, 1H), 4.57-4.50 (m, 2H), 4.46-4.40 (m, 2H), 3.65-3.68 (m, 1H), 3.28-3.30 (m, 1H), 2.81-2.83 (m, 4H), 2.64 (s, 3H), 1.31-1.60 (m, 8H), 0.86-0.91 (m, 9H).

Example 326

Step 1 : To a stirred solution of 2-chloro-4-fluorophenol (1 g, 6.82 mmoL) in DMF (15 mL) was added CS2CO3 (4.45 g, 13.65 mmoL) one-portion at 20 °C. The reaction mixture was stirred at 20 °C for 0.5 h. Then, 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.633 g, 6.82 mmoL) was added and heated at 100 °C for 16 hrs. LCMS showed most of starting material consumed. The reaction mixture was filtered and the cake was washed with EtOAc (10 ml x 2). The filtrate was diluted with water (200 ml) and EtOAc (100), organic layer separated, washed with brine (200 ml x 3), dried over anhydrous NaiSOi. filtered and concentrated to give a yellow oil. The crude product was purified by silical gel column chromatography (5%~10% EA/PE) to give tert-butyl (2-(2-chloro-4- fluorophenoxy)ethyl)carbamate (800 mg, 2.76 mmoL, 40.5 % yield). LCMS (M + H) = 312 & 314. Retention time (0.1% TFA): 1.639 min.

Step 2: To a stirred solution of tert-butyl (2-(2-chloro-4- fluorophenoxy)ethyl)carbamate (400 mg, 1.381 mmoL) in DMF (5 mL) was added NaH (66.3 mg, 2.76 mmoL) in one-portion at 0 °C and stirred for 0.5 h. Then Mel (0.086 mL,

1.381 mmoL) was added and warm up to 25 °C. LCMS after 30 min showed reaction was completed. The reaction mixture was diluted with water (100 ml) and EA (200 ml), organic layer separated, washed with brine (200 ml x 3), dried over anhydrous NaiSOr. filtered and concentrated to give yellow oil. The crude product was purified by silical gel column chromatography (5%~10% EA/PE) to give tert-butyl (2-(2-chloro-4- fluorophenoxy)ethyl)(methyl)carbamate (260 mg, 0.616 mmoL, 44.6 % yield) as a colorless oil. LCMS (M+Na) = 326. Retention time (0.1% TFA): l .725min.

Step 3: To tert-butyl (2-(2-chloro-4-fluorophenoxy)ethyl)(methyl)carbamate (0.26 g, 0.856 mmoL) was added 4M HC1 in dioxane (5.00 ml, 20 mmoL) at once. The reaction mixture was stirred at 15 °C for 12 hours. LCMS showed reaction was completed. The solvent was removed in vacuo, the resulting solid was diluted with ether (10 ml), filtered and the cake was washed with ether (10 ml) and dried to give 2-(2-chloro-4-fluorophenoxy)-N- methylethan-l -amine HC1 (150 mg, 0.737 mmoL, 86 % yield) as a white solid. LCMS (M+H) = 204. Retention time (0.1% TFA): 1.180 min.

Step 4: To a mixture of (S)-isopropyl 2-butoxy-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(trifhioromethylsulfonyloxy)-2,3'-bipyridin-5'-yl)acetate (30 mg, 0.051 mmol), 2- (2-chloro-4-fluorophenoxy)-N-methylethan-l -amine HC1 (15.59 mg, 0.097 mmol), CS2CO3 (49.9 mg, 0.153 mmol) and xantphos (5.91 mg, 10.21 pmol) in toluene (1.5 mL) was added Pd2(dba)3 (9.35 mg, 10.21 pmol) under nitrogen atmosphere. The mixture was stirred at 100 °C for 16 hr. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with EtOAc (5 mL). The organic layer was washed with brine (5 mL x 2), dried over Na2S04 filtered and concentrated to give residue. The residue was purified by prep-HPLC to obtain of isopropyl (S)-2-butoxy-2-(5-((2-(2-chloro-4- fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (20 mg, 32 % yield). LCMS (M+H) = 656. Retention time (10 Mmol NH4HCO3): 1.58 min.

Step 5: To a solution of isopropyl (S)-2-butoxy-2-(5-((2-(2-chloro-4- fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (20 mg, 0.031 mmol) in ethanol (3 mL) and water (1.00 mL) was added NaOH (6.10 mg, 0.153 mmol). The reaction mixture was stirred at 90 °C for 16 hours. Then, the reaction mixture was cooled, pH was adjusted to ~7 and concentrated to give a crude solid. The crude was purified by Prep-HPLC to afford (S)-2-butoxy-2-(5-((2-(2-chloro- 4-fluorophenoxy)ethyl)(methyl)amino)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)acetic acid (2 mg, 3.26 pmol, 10.69 % yield) as a white solid. LCMS (M + H) = 613, Retention time (10 mM NH4HCO3) = 1.68 min. ¾ NMR (400 MHz, MeOD): d 8.26 (d, J = 2.9 Hz, 1H), 8.13 (s, 1H), 7.42 (dd, J = 8.8, 3.0 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.20 (dd, J = 8.2, 3.0 Hz, 1H), 7.09 (dd, J = 9.1, 4.9 Hz, 1H), 7.06 - 6.98 (m, 1H), 5.53 (s, 1H), 4.28 (t, J = 4.9 Hz, 2H), 3.96 (t, J = 4.9 Hz, 2H), 3.61 (dt, J = 9.4, 6.3 Hz, 1H), 3.28 - 3.22 (m, 1H), 3.21 (s, 3H), 2.85-2.70 (br, s, 2H), 2.63 (s, 3H), 2.21 (t, J = 7.6 Hz, 1H), 2.05 (d, J = 5.2 Hz, 1H), 1.55 (ddd, J = 20.4, 14.6, 6.9 Hz, 4H), 1.35-1.25 (m, 4H), 0.90 - 0.79 (m, 9H).

Example 327

Step 1 : To a solution of isopropyl (S)-2-butoxy-2-(4'-(4,4-dimethylpiperidin-l-yl)-5- hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (100 mg, 0.213 mmol) dissolved in DMF (1 mL) was added l-bromo-2-butanone (0.022 mL, 0.213 mmol) and Cs2C03 (208 mg, 0.639 mmol).The mixture was stirred at 50 °C for 2 h. The reaction mixture was filtered and the filtrate was diluted with water (10 ml) and EA (10 ml). The organic phase was separated and washed with brine (10 ml x 3), dried over anhydrous Na2S04 and concentrated. The residue was purified by Prep-TLC to give (S)-isopropyl 2-butoxy-2-(4'-(4,4-dimethylpiperidin-l-yl)- 6'-methyl-5-(2-oxobutoxy)-2,3'-bipyridin-5'-yl)acetate (100 mg, 87% yield). LCMS (M + H) = 540. Retention time(0. l% TF A) =2.18 min.

Step 2: Isopropyl (S)-2-butoxy-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(2- oxobutoxy)-[2,3'-bipyridin]-5'-yl)acetate (66 mg, 0.122 mmol) was added to DAST (1 mL, 7.56 mmol) at 0 °C. The mixture was stirred overnight at room temperature. The reaction mixture was was quenched with ice, filtered and the filtrate was diluted with DCM (10 ml). The organic phase was separated and washed with brine (10 ml x 3), dried over anhydrous NaiSOy and concentrated. The residue was purified by Prep-TLC to give (S)-isopropyl 2- butoxy-2-(5-(2,2-difluorobutoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-2,3'-bipyridin-5'- yl)acetate (20 mg, 30% yield). LCMS (M + H) = 562. Retention time (0.1% TFA) = 2.49 min. Step 3: To a solution of isopropyl (S)-2-butoxy-2-(5-(2,2-difluorobutoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.036 mmol) in methanol (3 mF) and water (1 mF) was added sodium hydroxide (28.5 mg, 0.712 mmol). The mixture was stirred at 80 °C overnight, cooled and the pH was adjusted to 7 with HC1. The crude was purified by Prep-HPFC to afford (S)-2-butoxy-2-(5-(2,2-difluorobutoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (6.8 mg, 0.013 mmol,

36.3 % yield) as a white solid. FCMS (M + H) = 520. Retention time(l0 mM NH4HCO3) =1.60 min. Ή NMR (400 MHz, MeOD): d 8.46 (d, J = 2.8 Hz, 1H), 8.19 (s, 1H), 7.69 - 7.42 (m, 2H), 5.57 (s, 1H), 4.41 (t, J = 12.0 Hz, 2H), 3.77 - 3.60 (m, 1H), 3.05-2.83 (brs, 4H), 2.64 (s, 3H), 2.20-2.13 (m, 2H), 1.71 - 1.23 (m, 9H), 1.12 (t, J = 7.5 Hz, 3H), 0.97 - 0.76 (m, 9H).

Example 328

Step 1 : To a solution of triphenyl(propyl)phosphonium bromide (3.94 g, 10.21 mmol) in THF (20 mL) was added n-butyllithium (4.43 mL, 11.07 mmol) at -30 °C under an atmosphere of N2. The mixture was stirred at room temperature for 1 h, and then cooled to - 15 °C prior to the addition of 3-(benzyloxy)cyclobutan-l-one (1.5 g, 8.51 mmol) in 10 ml of THF. The resulting mixture was stirred at 25 °C for 16 h. Sat. NH4CI (10 ml) was added to the mixture. The mixture was extracted with EtOAc (30 ml x 2), the combined organic layers were washed with brine and dried over NaiSOr. concentrated in vacuum to afford crude product, which was purified by silica gel chromatography to give ((3- propylidenecyclobutoxy)methyl)benzene (300 mg, 1.468 mmol, 17.25 % yield). FCMS (M+H) = 203, Retention time (0.0 l%TFA) = 2.07 min.

Step 2: To a solution of ((3-propylidenecyclobutoxy)methyl)benzene (300 mg, 1.483 mmol) in methanol (8 mF) was added Pd/C (100 mg) and the mixture was stirred at room temperature for 16 h. The resulting mixture was filtered and concentrated to give 3- propylcyclobutan-l-ol (50 mg, 0.394 mmol, 26.6 % yield). ¹HNMR (400 MHz, CDCb): d 4.21 - 4.01 (m, 1H), 2.55 - 2.34 (m, 1H), 2.10-2.02 (m, 2H), 1.51 - 1.18 (m, 4H), 0.91-0.84 (m, 3H).

Step 3: To a solution of 3-propylcyclobutan-l-ol (50 mg, 0.438 mmol) and EtOAc (0.183 mL, 1.314 mmol) in DCM (8.0 mL) was added methanesulfonyl chloride (0.051 mL, 0.657 mmol). The mixture was stirred at 25 °C for 1 h and diluted with ThO (50 ml) and DCM (30 ml). Organic layer was separated and washed with ThO (20 mL *3), dried and concentrated to give 3-propylcyclobutyl methanesulfonate (120 mg, 0.624 mmol, 143 % yield) as yellow oil, used in the next step as crude.

Step 4: A solution of 3-propylcyclobutyl methanesulfonate (40.9 mg, 0.213 mmol), Cesium Carbonate (173 mg, 0.532 mmol) and isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.106 mmol) in N,N-dimethylformamide (5 mL) was stirred overnight at 85 °C. LhO (50 ml) and EtOAc (50 ml) were added. Organic layer was separated and washed with LhO (20 mL *3), dried and concentrated. The residue was purified by silica gel column (pet. ether: EtOAc =

2: 1) to afford isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(3- propylcyclobutoxy)-[2,3'-bipyridin]-5'-yl)acetate (15 mg, 0.026 mmol, 24.40 % yield).

LCMS (M+H) = 566, Retention time (10 mM NH4HCO3) = 2.62 min.

Step 5: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(3-propylcyclobutoxy)-[2,3'-bipyridin]-5'-yl)acetate (15 mg, 0.027 mmol) in methanol (3 mL) was added sodium hydroxide (21.21 mg, 0.530 mmol) in LhO (1 mL). Then the reaction mixture was stirred at 80 °C overnight. LCMS showed that starting material was consumed completely. The mixture was acidified with HC1 to pH = 7. The crude was purified by Prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5- (3-propylcyclobutoxy)-[2,3'-bipyridin]-5'-yl)acetic acid (5.8 mg, 0.011 mmol, 41.8 % yield) as a white solid. LCMS (M+H) = 524, Retention time (10 mM NH4HC03) = 1.60 min.

1HNMR (400 MHz, MeOD):5 8.30-8.27 (m, 1H), 8.17 (s, 1H), 7.49 - 7.33 (m, 2H), 5.83 (s, 1H), 5.01 - 4.95 (m, 1H), 3.21 - 2.69 (m, 4H), 2.65 (s, 3H), 2.45 - 2.19 (m, 5H), 1.60 - 1.28 (m, 8H), 1.21 (s, 9H), 1.05 - 0.80 (m, 9H).

Example 329

Stepl: To a solution of 2-methylcyclobutan-l-ol (50 mg, 0.580 mmol),

methanesulfonyl chloride (0.068 mL, 0.871 mmol) in dichloromethane (4.0 mL) was added EtOAc (0.243 mL, 1.741 mmol). The mixture was stirred overnight at 25 °C. TLC showed that the reaction was completed. The reaction mixture was diluted with LhO (50 ml) and DCM (30 ml), organic layer was separated, washed with LhO (20 mL x 3), dried and concentrated to afford 2-methylcyclobutyl methanesulfonate (69 mg, 0.378 mmol, 65.1 % yield) as yellow oil, used in the next step as crude.

Step 2: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (70 mg, 0.149 mmol), cesium carbonate (146 mg, 0.447 mmol) in N,N-dimethylformamide (5.0 mL) was added 2- methylcyclobutyl methanesulfonate (49.0 mg, 0.298 mmol). The mixture was stirred overnight at 80 °C. LCMS showed that the reaction was completed. The reaction mixture was diluted with LhO (50 mL), EtOAc (30 mL) and organic layer was separated, washed with LhO (20 mL *3), dried and concentrated. The residue was purified by silica gel column (DCM/MeOH = 20: 1) to afford isopropyl (2S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(2-methylcyclobutoxy)-[2,3'-bipyridin]-5'-yl)acetate (21 mg, 0.035 mmol, 23.39 % yield) as yellow oil. LCMS (M+H) = 538.1, Retention time (10 mM NH4HCO3) = 2.24 min.

Step 3: To a solution of isopropyl (2S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(2-methylcyclobutoxy)-[2,3'-bipyridin]-5'-yl)acetate (12 mg, 0.022 mmol) in methanol (1.5 mL) was added sodium hydroxide (17.85 mg, 0.446 mmol) in water (0.5 mL) and stirred at reflux for 6 h. The mixture was acidified with HC1 to pH = 7 and purified by Prep-HPLC to give (2S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(2- methylcyclobutoxy)-[2,3'-bipyridin]-5'-yl)acetic acid (5.2 mg, 10.49 pmol, 47.0 % yield) as a white solid. LCMS (M+H) = 496, Retention time (10 mM NH4HCO3) = 1.60 min. ¹HNMR (400 MHz, MeOD):5 8.48 - 8.26 (m, 1H), 8.17 (s, 1H), 7.72 - 7.30 (m, 2H), 5.82 (s, 1H),

5.75 - 5.39 (m, 1H), 3.20-2.81 (m, 4H), 2.60 (s, 3H), 2.52-2.45 (m, 2H), 2.10-1.90 (m, 1H), 1.74 - 1.65 (m, 1.7H), 1.44-1.45 (brs, 4H), 1.25-1.23 (m, 1.3H), 1.21 (s, 9H), 0.91 (s, 6H). Example 330

Step 1 : A solution of 3-ethylcyclobutan-l-one (100 mg, 1.019 mmol) in BLL.THF (1019 pl, 1.019 mmol) was stirred at room temperature for 3 h. TLC (pet. ether: EtOAc =

5: 1) showed the starting material was consumed completely. The mixture was quenched with MeOH (30 mL), poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NaiSOr. filtered, concentrated and purified by flash silica gel column (pet. ether = 100%) to give 3- ethylcyclobutan-l-ol (85 mg, 0.849 mmol, 83 % yield) as colorless oil.

Step 2: A solution of 3-ethylcyclobutan-l-ol (70 mg, 0.699 mmol) and DIPEA (0.366 mL, 2.097 mmol) in dichloromethane (3 mL) was added methanesulfonyl chloride (0.054 mL, 0.699 mmol) drop wise at 0 °C. The mixture was stirred at room temperature for 3 h. TLC (pet. ether: EtOAc = 5: 1) showed the starting material was consumed completely. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over NaiSOi. filtered and concentrated, filtered through silica and washed with (pet. ether: EtOAc = 5: 1) to give 3- ethylcyclobutyl methanesulfonate (100 mg, 0.561 mmol, 80 % yield) as brown oil.

Step 3: A mixture of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)- 5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (25 mg, 0.053 mmol) and CS2CO3 (52.0 mg, 0.160 mmol) in N,N-dimethylformamide (3 mL) was added 3-ethylcyclobutyl methanesulfonate (18.98 mg, 0.106 mmol). The mixture was stirred at 80 °C for 3 h. LCMS showed the starting material was consumed completely. The reaction mixture was diluted with water (20 ml) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried, filtered, concentrated and purified by Prep-TLC to obtained isopropyl (S)-2-(tert- butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-(3-ethylcyclobutoxy)-6'-methyl-[2,3'-bipyridin]- 5'-yl)acetate (28 mg, 0.049 mmol, 92 % yield) as yellow solid. LCMS (M+H) = 552.3, Retention time (10 mM NH4HCO3) = 2.51 min. Step 4: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-(3-ethylcyclobutoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (27 mg, 0.049 mmol) in methanol (5 mL) was added sodium hydroxide (39.1 mg, 0.979 mmol). The mixture was stirred at 80 °C for 24 h. LCMS showed product detected. The reaction mixture was adjusted with HC1 (1.0 N) to pH = 5-6 and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over NaiSOr. filtered and concentrated. The residue was purified by HPLC to (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-(3- ethylcyclobutoxy)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetic acid (6.1 mg, 0.012 mmol, 24.46 % yield). LCMS (M+H) = 510, Retention time (10 mM NHiHCOi) = 1.69 min. 'HNMR (400 MHz, MeOD) d 8.27 - 8.10 (m, 1H), 8.03 (s, 1H), 7.33-7.20 (m, 2H), 5.69 (s, 1H), 4.60 (s, 1H), 3.10- 2.59 (m, 4H), 2.53-2.54 (brs, 4H), 2.18-2.10 (m, 4H), 1.63-1.60 (m, 1H), 1.51 - 1.31 (m, 6H), 1.08 (s, 9H), 0.88 - 0.68 (m, 9H).

Example 331

Step 1: To a solution of (S)-isopropyl 2-tert-butoxy-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-hydroxy-6'-methyl-2,3'-bipyridin-5'-yl)acetate (90 mg, 0.192 mmol) and cyclopentanol (66.0 mg, 0.767 mmol), triphenylphosphine (151 mg, 0.575 mmol) in THE (3 mL) was added DIAD (0.093 mL, 0.479 mmol) at room temperature. The mixture was stirred at room temperature overnight under N2. LCMS showed presence of the desired product. To the mixture was added 10 mL of water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over NaiSOi. filtered and concentrated. The residue was purified by silica gel plate to obtained (S)-isopropyl 2-tert-butoxy-2-(5- (cyclopentyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-2,3'-bipyridin-5'-yl)acetate (70 mg, 0.130 mmol, 67.9 % yield) as yellow solid. LCMS (M+H) = 538, Retention time (10 mM NH4HCO3) = 2.31 min.

Step 2: To a solution of (S)-isopropyl-2-(tert-butoxy)-2-(5-(cyclopentyloxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (70 mg, 0.130 mmol) in methanol (5 mL) was added sodium hydroxide (104 mg, 2.60 mmol) .The mixture was stirred at 80 °C for 24 h. The pH of reaction mixture was adjusted with HC1 (1.0 N) to 5-6, added 10 ml of water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na2S04, filtered, concentrated and purified by Prep-HPLC to give (S)-2-tert-butoxy-2-(5-(cyclopentyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-2,3'- bipyridin-5'-yl)acetic acid (9 mg, 0.018 mmol, 13.95 % yield) as white solid. LCMS (M+H) = 510, Retention time (10 mM NHiHCCh) = 1.44 min. ¹HNMR (400 MHz, MeOD):5 8.32 (d, J = 2.7 Hz, 1H), 8.18 (s, 1H), 7.66 - 7.34 (m, 2H), 5.82 (s, 1H), 4.99-4.95 (m, 1H), 2.82-2.83 (brs, 4H), 2.66 (s, 3H), 2.49 - 2.29 (m, 1H), 2.18 - 1.55 (m, 12H), 1.44-1.45 (brs, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 332

Step 1 : To a solution of (S)-isopropyl 2-tert-butoxy-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-hydroxy-6'-methyl-2,3'-bipyridin-5'-yl)acetate (100 mg, 0.213 mmol) and (3,3- dimethylcyclobutyl)methanol (97 mg, 0.852 mmol) in THF (3 mL) was added DIAD (0.104 mL, 0.532 mmol) and triphenylphosphine (168 mg, 0.639 mmol) at room temperature. The mixture was stirred at room temperature overnight under N2. LCMS showed presence of the desired product. The reaction mixture was diluted with 10 mL of water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered, concentrated and purified by silica gel plate (pet. etherEtOAc = 3:2) to obtained (S)-isopropyl 2-tert-butoxy-2-(5-((3,3-dimethylcyclobutyl)methoxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-2,3'-bipyridin-5'-yl)acetate (110 mg, 0.194 mmol, 91 % yield). LCMS (M+H) = 566, Retention time (10 mM NH4HCO3) = 2.54 min.

Step 2: To a solution of (S)-isopropyl-2-(tert-butoxy)-2-(5-((3,3- dimethylcyclobutyl)methoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (70 mg, 0.124 mmol) in methanol (5 mL) was added NaOH (99 mg, 2.474 mmol). The mixture was stirred at 80 °C overnight. The reaction mixture was adjusted with HC1 (1 N) to pH = 5-6, diluted with 10 ml of water and extracted with EtOAc (15 mL x 3).The combined organic layers were washed with brine, dried over Na2S04, filtered, concentrated and purified by Prep-HPLC to give (S)-2-tert-butoxy-2-(5-((3,3- dimethylcyclobutyl)methoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-2,3'-bipyridin-5'- yl)acetic acid (11.0 mg, 0.021 mmol, 16.98 % yield). LCMS (M+H) = 524, Retention time (10 mM NH4HCO3) = 1.58 min. ^!HNMR (400 MHz, MeOD):5 8.24 (d, J = 2.7 Hz, 1H), 8.05 (s, 1H), 7.63 - 7.25 (m, 2H), 5.70 (s, 1H), 3.98 (d, J = 6.4 Hz, 2H), 3.30-2.65 (brs, 4H), 2.54 (s, 3H), 1.95 - 1.76 (m, 2H), 1.74 - 1.57 (m, 2H), 1.33-1.30 (brs, 4H), 1.10 (d, J = 9.7 Hz, 12H), 1.02 (s, 3H), 0.80 (s, 6H).

Example 333

Step 1 : To a solution of (S)-isopropyl 2-tert-butoxy-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-hydroxy-6'-methyl-2,3'-bipyridin-5'-yl)acetate (70 mg, 0.149 mmol) and cyclohexanol (59.7 mg, 0.596 mmol), triphenylphosphine (117 mg, 0.447 mmol) in tetrahydrofuran (3 mL) was added DIAD (0.072 mL, 0.373 mmol). The mixture was stirred at room temperature overnight under N2. LCMS showed presence of the desired product. The reaction mixture was diluted with 10 mL of water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na2S04, filtered, concentrated and purified by silica gel plate (pet. ether: EtOAc = 3:2) to afford (S)-isopropyl 2-tert-butoxy-2- (5-(cyclohexyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-2,3'-bipyridin-5'-yl)acetate (68 mg, 0.123 mmol, 83 % yield) as yellow solid. LCMS (M+H) = 552.3, Retention time (10 mM NH4HCO3) = 2.44 min.

Step 2: To a solution of (S)-isopropyl)-2-(tert-butoxy)-2-(5-(cyclohexyloxy)-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (68 mg, 0.123 mmol) in methanol (5 mL) was added NaOH (99 mg, 2.465 mmol). The mixture was stirred at 80 °C for overnight. The reaction mixture was adjusted with HC1 (1 N) to pH = 5-6, diluted with 10 ml of water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over NaiSOi. filtered, concentrated and purified by Prep-HPLC to give (S)-2-tert-butoxy-2-(5-(cyclohexyloxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-2,3'- bipyridin-5'-yl)acetic acid ( 24.6mg, 0.048 mmol, 39.2 % yield) as white solid. LCMS (M+H) = 510, Retention time (10 mM NH4HCO3) = 1.51 min. TfNMR ^OO MHz, MeOD):5 8.22 (d, J = 2.8 Hz, 1H), 8.06 (s, 1H), 7.51 - 7.26 (m, 2H), 5.71 (s, 1H), 4.49 - 4.33 (m, 1H), 2.69- 2.70 (brs, 4H), 2.53 (s, 3H), 1.92-1.93 (brs, 2H), 1.72-1.73 (brs, 2H), 1.60-1.20 (m, 10H),

1.09 (s, 9H), 0.79 (s, 6H). Example 334

Step 1 : To a solution of (S)-isopropyl 2-tert-butoxy-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-hydroxy-6'-methyl-2,3'-bipyridin-5'-yl)acetate (70 mg, 0.149 mmol) and tetrahydro-2H- pyran-4-ol (60.9 mg, 0.596 mmol), triphenylphosphine (117 mg, 0.447 mmol) in THF (3 mL) was added DIAD (0.072 mL, 0.373 mmol). The mixture was stirred at room temperature overnight under N2. LCMS showed presence of the desired product. To the mixture was added 10 mL of water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered, concentrated and purified by silica gel plate (pet. ether :EtOAc = 3:2) to give (S)-isopropyl 2-tert-butoxy-2-(4'-(4,4- dimethylpiperidin- 1 -yl)-6'-methyl-5 -(tetrahydro-2H-pyran-4-yloxy)-2,3 '-bipyridin-5 yl)acetate (79 mg, 0.143 mmol, 96 % yield) as yellow solid. LCMS (M+H) = 512.7,

Retention time (10 mM NH4HC03) = 1.28 min.

Step 2: To a solution of (S)-isopropyl- 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-((tetrahydro-2H-pyran-4-yl)oxy)-[2,3'-bipyridin]-5'-yl)acetate (79 mg, 0.143 mmol) in methanol (5 mL) was added NaOH (114 mg, 2.85 mmol). The mixture was stirred at 80 °C overnight. The reaction mixture was adjusted with HC1 (1 N) to pH = 5-6, diluted with 10 ml of water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over NaiSOi. filtered, concentrated and purified by Pre-HPLC give (S)-2-tert-butoxy-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(tetrahydro-2H-pyran- 4-yloxy)-2,3'-bipyridin-5'-yl)acetic acid (13.8 mg, 0.027 mmol, 18.67 % yield) as white solid. LCMS (M+H) = 512, Retention time (10 mM NH4HCO3) = 1.28 min. ' HNMR (400 MHz, MeOD) d 8.28 (d, J = 2.8 Hz, 1H), 8.06 (s, 1H), 7.50 (dd, J = 8.6, 2.9 Hz, 1H), 7.36 (d, J =

8.6 Hz, 1H), 5.72 (s, 1H), 4.68 - 4.58 (m, 1H), 4.02 - 3.71 (m, 2H), 3.59-3.50 (m, 2H), 2.6- 2.70 (brs, 4H), 2.53 (s, 3H), 2.02-1.95 (m, 2H), 1.72-1.65 (m, 2H), 1.30-1.31 (brs, 4H), 1.09 (s, 9H), 0.79 (s, 6H).

Example 335

Step 1 : To a solution of (S)-isopropyl 2-tert-butoxy-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-hydroxy-6'-methyl-2,3'-bipyridin-5'-yl)acetate (70 mg, 0.149 mmol) and 3- methylcyclobutan-l-ol (25.7 mg, 0.298 mmol) in THF (3 mL) was added DIAD (0.072 mL, 0.373 mmol) and triphenylphosphine (117 mg, 0.447 mmol). The mixture was stirred at room temperature overnight under N2. LCMS showed presence of the desired product. The reaction mixture was diluted with 10 mL of water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over NaiSCh, filtered, concentrated and purified by silica gel plate (pet. ether: EtOAc =3:2) to give (S)-isopropyl 2-tert-butoxy-2- (4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(3-methylcyclobutoxy)-2,3'-bipyridin-5'- yl)acetate (90 mg, 0.167 mmol, 112 % yield) as yellow solid. LCMS (M+H) = 538.0, Retention time (10 mM NH4HCO3) = 2.32 min.

Step 2: To a solution of (S)-isopropyl-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(3-methylcyclobutoxy)-[2,3'-bipyridin]-5'-yl)acetate (90 mg, 0.167 mmol) in methanol (5 mL) was added NaOH (134 mg, 3.35 mmol).The mixture was stirred at 80 °C for 48 h. The reaction mixture was adjusted with HC1 (1 N) to pH = 5-6, diluted with 10 ml of water and extracted with EtOAc (l5mL x 3). The combined organic layers were washed with brine, dried over NaiSOi. filtered, concentrated and purified by Prep-HPLC to give (S)-2- (tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(3-methylcyclobutoxy)-[2,3'- bipyridin]-5'-yl)acetic acid (22.7 mg, 0.046 mmol, 27.4 % yield). LCMS (M+H) = 496, Retention time (10 mM NH4HCO3) = 1.47 min. ¹HNMR (400 MHz, MeOD) d 8.18-8.14 (m, 1H), 8.05 (s, 1H), 7.41 - 7.25 (m, 2H), 5.71 (s, 1H), 5.00- 4.88 (m, 1H), 3.20-2.66 (m, 4H), 2.53 (s, 3H), 2.47 - 2.06 (m, 4H), 1.32-1.33 (brs, 4H), 1.14 - 0.98 (m, 12H), 0.79 (s, 6H).

Example 336

Step 1 : To a solution of cyclobutanol (500 mg, 6.93 mmol), methane sulfonyl chloride (0.810 mL, 10.40 mmol) in DCM (5.0 mL) was added TEA (2.90 mL, 20.80 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 h. TLC showed that the reaction was completed. The reaction mixture was diluted with EhO (50 ml) and DCM (30 ml), organic layer was separated, washed with EhO (20 mL *3), dried and concentrated. The residue was purified by silica gel column (pet. ether/EtOAc = 10: 1) to afford cyclobutyl methane sulfonate (350 mg, 1.864 mmol, 26.9 % yield) as yellow oil.

Step 2: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (100 mg, 0.213 mmol), cesium carbonate (208 mg, 0.639 mmol) in DMF (7 mL) was added cyclobutyl methanesulfonate (64.0 mg, 0.426 mmol). The mixture was stirred overnight at 80 °C. LCMS showed that the starting material was consumed completely. The reaction mixture was diluted with ThO (50 ml) and EtOAc (30 mL). Organic layer was separated and washed with ThO (20 ml 3). dried and concentrated. The residue was purified by silica gel column (DCM/MeOH = 20: 1) to afford isopropyl (S)-2-(tert-butoxy)-2-(5-cyclobutoxy-4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-[2,3'-bipyridin]-5'-yl)acetate (44 mg, 0.047 mmol, 22.11 % yield) as a yellow oil. LCMS (M+H) = 524.4, Retention time (0.05 % TFA) = 1.69 min.

Step 3: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(5-cyclobutoxy-4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (40 mg, 0.076 mmol) in methanol (1.5 mL) was added sodium hydroxide (61.1 mg, 1.528 mmol) in water (0.5 mL). The mixture was stirred at reflux for 6 h. The mixture was adjusted with HC1 (1 N) to pH = 5~6 and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine and concentrated to give residue. The residue was purified by Prep-HPLC to give (S)-2- (tert-butoxy)-2-(5-cyclobutoxy-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetic acid (18 mg, 0.036 mmol, 46.7 % yield) as a white solid. LCMS (M+H) = 482, Retention time (10 mM NH4HCO3) = 1.58 min. 'HNMR (400 MHz, MeOD): d 8.29 (t, J =

1.7 Hz, 1H), 8.17 (s, 1H), 7.46 (d, J = 1.6 Hz, 2H), 5.82 (s, 1H), 4.89 - 4.73 (m, 1H), 2.81- 2.82 (brs, 4H), 2.65 (s, 3H), 2.60-2.55 (m, 2H), 2.22-2.20 (m, 2H), 2.01 - 1.69 (m, 2H), 1.60 - 1.26 (m, 4H), 1.21 (s, 9H), 0.91 (s, 6H).

Example 337

Step 1: To a solution of 3 -methylcyclobutane-l -carboxylic acid (270 mg, 2.365 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.311 mL, 3.55 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 1 h. Then (S)-l-(4- bromophenyl) ethan-l-ol (571 mg, 2.84 mmol) was added. The mixture was stirred at room temperature for 3 h. LCMS showed the starting material was consumed completely. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered, concentrated and purified by prep-TLC (pet. ether: EtOAc = 10: 1) to give (S)-l-(4- bromophenyl)ethyl 3-methylcyclobutane-l-carboxylate (190 mg, 0.639 mmol, 27.0 % yield) as colorless oil. LCMS (M+H) = 297, Retention time (0.05 % TFA) = 2.37 min.

Step 2: To a solution of (R)-l-(4-bromophenyl)ethyl 3-methylcyclobutane-l- carboxylate (280 mg, 0.942 mmol), diphenylmethanimine (222 mg, 1.225 mmol), xantphos (54.5 mg, 0.094 mmol) and Pd2(dba)₃ (43.1 mg, 0.047 mmol) in l,4-dioxane (3 mL) was added cesium carbonate (921 mg, 2.83 mmol). The mixture was stirred at 100 °C under N2 overnight. LCMS showed the starting material was consumed completely. The mixture was filtered, concentrated and purified by Prep-TLC (pet. ether: EtOAc = 10: 1) to give (R)-l-(4- ((diphenylmethylene)amino)phenyl)ethyl 3-methylcyclobutane-l-carboxylate (200 mg, 0.454 mmol, 48.2 % yield) as yellow oil. LCMS (M+H) = 398.2, Retention time (10 mM

NH4HCO3) = 2.08 min.

Step 3: The (S)-l-(4-((diphenylmethylene)amino)phenyl)ethyl 3-methylcyclobutane- l-carboxylate (1. lg, 2.77 mmol) was separated by SFC to obtained product (S)-l-(4- ((diphenylmethylene)amino)phenyl)ethyl (lr,3S)-3-methylcyclobutane-l-carboxylate (800 mg, 2.012 mmol, 72.7 % yield) and (S)-l-(4-((diphenylmethylene)amino)phenyl)ethyl (ls,3R)-3-methylcyclobutane-l-carboxylate (230 mg, 0.579 mmol, 20.91 % yield) as yellow oil. ( The assignment of stereochemistry of the products were tentative)

Step 4: A solution of (S)-l-(4-((diphenylmethylene)amino)phenyl)ethyl (ls,3R)-3- methylcyclobutane-l-carboxylate (160 mg, 0.402 mmol) in THF (2 mL) was added L1AIH4 (1.207 mL, 1.207 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 2 h. TLC (pet. ether: EtOAc = 10: 1) showed the starting material was consumed completely. The mixture was quenched with NaOH (20 %, l.2mL) filtered and concentrated to give the crude product ((ls, 3s)-3-methylcyclobutyl)methanol (30 mg, 0.300 mmol, 74.4 % yield) as yellow oil.

Step 5: To a solution of ((ls,3s)-3-methylcyclobutyl)methanol (10.66 mg, 0.106 mmol) and TEA (44.5 mΐ, 0.319 mmol) in DMF was added MsCl (12.44 mΐ, 0.160 mmol).

The mixture was stirred at room temperature for 2 h. Then isopropyl (S)-2-(tert-butoxy)-2- (4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate (50 mg, 0.106 mmol) and CS2CO3 (104 mg, 0.319 mmol) was added. The mixture was stirred at 80 °C for another 12 h. LCMS showed presence of the desired product. The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL), washed with brine (30 mL x 3), dried over Na2SC>4, filtered, concentrated and purified by Prep-TLC (pet. ether: EtOAc = 5: 1) to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(((ls,3R)-3- methylcyclobutyl)methoxy)-[2,3'-bipyridin]-5'-yl)acetate (35 mg, 0.036 mmol, 34.1 % yield) as yellow solid. LCMS (M+H) = 551.2, Retention time (0.05 % TFA) = 2.69 min.

Step 6: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((ls,3R)-3-methylcyclobutyl)methoxy)-[2,3'-bipyridin]-5'-yl)acetate (40 mg, 0.072 mmol) in MeOH (2 mL) was added NaOH (58.0 mg, 1.450 mmol) in water (2.000 mL). The mixture was stirred at 90 °C overnight. LCMS showed the starting material was consumed completely. The mixture was adjusted with 1N HC1 to pH = 6~7, extracted with EtOAc (20 mL x 3), the organic layers were washed with brine (20 mL), dried over Na2SC>4, filtered, concentrated and purified by Prep-HPLC to give (S)-2-(tert-butoxy)-2-(4'-(4,4- dimethylpiperidin-l-yl)-6'-methyl-5-(((ls,3R)-3-methylcyclobutyl)methoxy)-[2,3'-bipyridin]- 5'-yl)acetic acid (11.3 mg, 0.022 mmol, 30.6 % yield) as white solid. LCMS (M+H) = 510.3, Retention time (10 mM NH4HCO3) = 1.64 min. 'HNMR (400 MHz, DMSO):5 8.36 (d, J =

3.2 Hz, 1H), 7.99 (s, 1H), 7.48-7.46 (m, 1H), 7.37 (d, J = 8.8 Hz, 1H), 5.50 (s, 1H), 4.04 - 3.98 (m, 2H), 3.35 - 2.95 (m, 4H), 2.60 - 2.50 (m, 1H), 2.46 (s, 3 H), 2.32 - 2.22 (m, 3 H), 2.19 - 2.05 (m, 2 H), 1.47 - 1.22 (m, 4H), 1.04 (s, 9H), 1.02 (s, 3H), 0.87 - 0.77 (m, 6H).

Example 338

Step 7: To a solution of (S)-l-(4-((diphenylmethylene)amino)phenyl)ethyl (lr,3S)-3- methylcyclobutane-l-carboxylate (160 mg, 0.402 mmol) in THF (25 mL) was added L1AIH4 (1.2 mL, 1.200 mmol) drop-wise at 0 °C. The mixture was stirred at room temperature for 2 h. TLC (pet. ether: EtOAc = 10: 1) showed the starting material was consumed completely. The mixture was quenched with NaOH (20 %, l.2mL), filtered and concentrated to obtained crude product ((lr, 3r)-3-methylcyclobutyl)methanol (20 mg, 0.200 mmol, 49.6 % yield) as yellow oil.

Step 8: To a solution of ((lr, 3r)-3-methylcyclobutyl) methanol (10.66 mg, 0.106 mmol) and TEA (0.015 mL, 0.106 mmol) in N,N-dimethylformamide (3 mL) was added MsCl (8.30 mΐ, 0.106 mmol). The mixture was stirred at room temperature for 2 h. Then isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-5-hydroxy-6'-methyl-[2,3'- bipyridin]-5'-yl)acetate (50 mg, 0.106 mmol) and CS2CO3 (34.7 mg, 0.106 mmol) were added. The mixture was stirred at 80 °C for another 12 h. LCMS showed the presence of product. The mixture was poured into water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over NaiSOr.

filtered, concentrated and purified by Prep-TLC (pet. ether: EtOAc = 10: 1) to give isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(((lr,3S)-3- methylcyclobutyl)methoxy)-[2,3'-bipyridin]-5'-yl)acetate (20 mg, 0.017 mmol, 15.73 % yield) as yellow oil. LCMS (M+H) = 552.4, Retention time (10 mM NH4HCO3) = 2.65 min.

Step 9: To a solution of isopropyl (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l- yl)-6'-methyl-5-(((lr,3S)-3-methylcyclobutyl)methoxy)-[2,3'-bipyridin]-5'-yl)acetate (5 mg, 9.06 pmol) in MeOH (2 mL) was added NaOH (7.25 mg, 0.181 mmol) in water (2 mL) . The mixture was stirred at 90 °C overnight. LCMS showed the starting material was consumed completely. The mixture was acidified with 1N HC1 to pH = 6~7, extracted with EtOAc (20 mL x 3), the combined organic layers were washed with brine (20 mL), dried over NaiSOi filtered and concentrated to give residue. The residue was purified by Prep-HPLC to give (S)- 2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-5-(((lr,3S)-3-methylcyclobutyl) methoxy)-[2,3'-bipyridin]-5'-yl)acetic acid (1 mg, 1.962 pmol, 21.65 % yield) as white solid. LCMS (M+H) = 510.3, Retention time (10 mM NH4HCO3) = 1.64 min. 'HNMR (400 MHz, MeOD) d 8.35 (d, J = 3.2 Hz, 1H), 8.13 (s, 1H), 7.56-7.53 (m, 1H), 7.46 (d, J = 8.8 Hz, 1H), 5.79 (s, 1H), 4.16 - 4.14 (m, 2H), 2.90-2.76 (m, 4H), 2.63 (s, 3 H), 2.13-2.02 (m, 4H), 21.84- 1.78 (m, 2 H), 1.45- 1.40 (m, 4 H), 1.23 (s, 9H), 1.12 (s, 3H), 0.87 - 0.77 (m, 6H).

Biological Methods

Inhibition of HIV replication: A recombinant NL-RLuc proviral clone was constructed in which a section of the nef gene form NL4-3 was replaced with the Renilla Luciferase gene. This virus is fully infectious and can undergo multiple cycles of replication in cell culture. In addition, the luciferous reporter provides a simple and easy method for quantitating the extent of virus growth and consequently, the antiviral activity of test compounds. The plasmid pNLRLuc contains the proviral NL-Rluc DND cloned into pUCl8 at the PvuW site. The NL-RLuc virus was prepared by transfection of 293T cells with the plasmid pNLRLuc. Transfections were performed using the LipofectAMINE PLUS kit form Invitrogen (Carlsbad, CA) according to the manufacturer and the virus generated was titered in MT-2 cells. For susceptibility analyses, the titrated virus was used to infect MT-2 cells in the presence of compound, and after 5 days of incubation, cells were processed and quantitated for virus growth by the amount of expressed luciferase. Assay media was RPMI 1640 supplemented with 10% heat inactivated fetal bovine serum (FBS), 100 units/ml penicillin G/100 units/ml streptomycin, 10 mM HEPES buffer pH 7.55 and 2 mM L- glutamine. The results form at least 2 experiments were used to calculate the ECso values. Luciferase was quantitated using the Dual Luciferase kit form Promega (Madison, WI). Susceptibility of viruses to compounds was determined by incubation in the presence of serial dilutions of the compound. The 50% effective concentration (ECso) was calculated by using the exponential form of the median effect equation where (Fa) = l/[l+ (EDso/drug conc.)^m] (Johnson VA, Byington RT. Infectivity Assay. In Techniques in HIV Research ed. Aldovini A, Walker BD. 71-76. New York: Stockton Press.1990). Results are summarized in Table 1.

Table 1.

ND: Not determined

It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative Examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the Examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing Examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

CLAIMS We claim:

1. A compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is hydrogen, halogen, or Ci-₃alkyl;

R³ is Ci-ioalkyl;

R⁴ is H, halogen, or Ci-ioalkyl;

X is O, S, or N(R⁶);

Q is a bond, Ci-ioalkyl, C₃-8Cyeloalkyl, optionally substituted with 1 to 3 subtituents independently selected from OH, halogen, C₃-8cycloalkyl;

R⁵ is H, halo, pyrrolidinyl, piperidinyl, imidazolyl, morpholinyl, oxetanyl, thiomorpholinyl, pyrazolyl, pyridinyl, 2-oxopyridinyl, indenyl, dihydropyridinyl, pyrimidinyl,

tetrahydrofuranyl, tetrahydropyranyl, phenylpyrazolyl, tetrahydronaphthalenyl, tetrahydro- lH-cyclopropa[3,4]cyclopenta[ 1 ,2-c]pyrazolyl, tetrahydro- 1H- cyclopropa[3,4]cyclopenta[l,2-c]pyrazolyl, Ci-6alkyl-0-, C3-8Cyeloalkyl, Ar-O-, Ar-Ci-4alkyl- 0-, C2-8alkenyl, C3-8Cyeloalkenyl, Ci-3alkyl-(0-Ci-3alkyl)i-5-0-, C3-8Cyeloalkyl-0-,

(R⁶)(R⁷)N-, or (R⁶)(R⁷)(R⁸)Si and R⁵ is optionally substituted with 1-4 substituents independently selected from HO, halogen, Ci-salkyl, Ci-salkylO-, CN, CONH2, and CO2H;

Ar is pyridinyl, pyrimidinyl, or phenyl;

each R⁶ and R⁷ is independently hydrogen, or Ci-₆alkyl; and

R⁸ is Ci-₆alkyl.

2 A compound or salt according to Claim 1 wherein R¹ is H.

3. A compound or salt according to Claim 1 or Claim 2 wherein R³ is Ci-6alkyl .

4. A compound or salt according to any of Claims 1-3 wherein R⁴ is H or Ci-3alkkyl.

5. A compound or salt according to any of Claims 1-4 wherein R² is pyridinyl, pyrimidinyl, or phenyl and is optionally substituted with 1 or 2 substituents independently selected from halogen and Nth.

6. A compound or salt according to any of Claims 1-5 wherein X is O, S, or N(R⁶).

7. A compound or salt according to any of Claims 1-6 wherein Q is a bond, Ci-6alkyl, or

C4-6cycloalkyl and is optionally substituted with 1 to 3 substituents independently selected from OH, halogen, and C3-6Cycloalkyl.

8. A compound or salt according to any of Claims 1-7 wherein R⁵ is H, pyrrolidinyl, piperidinyl, imidazolyl, morpholinyl, oxetanyl, thiomorpholinyl, pyrazolyl, pyridinyl, 2- oxopyridinyl, indenyl, dihydropyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenylpyrazolyl, tetrahydronaphthalenyl, tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2- c]pyrazolyl, tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazolyl, Ci-4alkyl-0-, C3- 7Cyeloalkyl, phenyl-O-, phenyl-Ci-3alkyl-0-, C2-4alkenyl, C5-6Cycloalkenyl, Ci-3alkyl-(0-Ci- 3alkyl)i-3-0-, C4-6Cycloalkyl-0-, (R⁶)(R⁷)N, Si(CH3)3, and is optionally substituted with 1 to 3 substituents independently selected from OH, halogen, Ci-3alkyl, Ci-3alkylO-, and CO2H.

9. A pharmaceutical composition comprising a compound or salt according to any of Claims 1-8.

10. The composition of claim 9 further comprising at least one other agent used for treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, CAPSID inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.

11. A method for treating HIV infection comprising administering a composition according to Claim 9 to a patient in need thereof.

12. The method of claim 11 further comprising administering at least one other agent used for treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, CAPSID inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors.

13. A compound or pharmaceutically acceptable salt thereof according to any of Claims 1-8 for use in therapy

14. A compound or pharmaceutically acceptable salt thereof according to any of Claims 1-8 for use in treating HIV infection.

15. A compound or pharmaceutically acceptable salt thereof according to any of Claims 1-8 for use in the manufacture of a medicament for the treatment of HIV infection.