Prodrugs of gamma-hydroxybutyric acid, compositions and uses thereof

CA 02999367 2018-03-21

WO 2017/050259 PCT/CN2016/099763

PRODRUGS OF GAMMA-HYDROXYBUTYRIC ACID, COMPOSITIONS AND USES THEREOF

FIELD OF THE INVENTION

[0001] The present disclosure generally relates to prodrugs of gamma-hydroxybutyric acid (GHB), as well as compositions and uses thereof.

BACKGROUND OF THE INVENTION

[0002] Narcolepsy is a chronic neurological disorder characterized by excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. EDS is usually present and appears first. Cataplexy occurs in approximately 70% of patients with narcolepsy while the other symptoms feature less frequently and in various combinations. The prevalence of narcolepsy in the United States and Europe ranges from 20 to 67 per 100,000

[0003] GHB is a naturally-occurring central nervous system (CNS) transmitter. The GHB sodium salt also called sodium oxybate, currently being marketed by Jazz Pharmaceuticals plc as Xyrem, is the first and only drug approved by the U.S. Food and Drug Administration (FDA) to treat cataplexy associated with narcolepsy. Sodium oxybate has been shown to be highly efficacious with a ~70% reduction of the total number of cataplexy episodes. In Europe, sodium oxybate is used medicinally for various purposes including narcolepsy, alcohol dependence, and opiate dependence. In November 2005, the FDA approved an expanded indication for sodium oxybate as a treatment for excessive daytime sleepiness (EDS). In addition, sodium oxybate has also been conducted in the clinical trial in the U.S. for fibromyalgia syndrome, a pain of fibromyalgia that is notoriously difficult to treat. Sodium oxybate also has potential to treat other CNS disorders such as insomnia, hallucinogenic dreams and sleep paralysis.

[0004] Despite its efficacious effect and advantageous position in treating EDS and cataplexy associated with narcolepsy, sodium oxybate displays a sub-optimal pharmacokinetics profile that makes it difficult to provide optimal therapeutic benefits. The deficiencies of sodium oxybate include: 1) variable oral bioavailability and unpredictable drug plasma concentrations resulting from its erratic absorption in patients; 2) short plasma half-life (ti/2 < 1 hr); 3) significant food effect (high fat meal may significantly delay and decrease absorption of sodium oxybate); 4) high bolus oral dosing caused unpleasant G1

- 1 84228409 disturbance; 5) poor patient compliance and inconvenient drug administration (due to the twice per night dosage regimen); 6) risk of hypernatremia (due to intake of large amount of sodium salt form compounds). Consequently, these deficiencies prevent sodium oxybate from providing the maximum therapeutic benefit that it can possibly achieve. Therefore, there remains a continuing need for compounds derived from GHB to overcome some or all of the above described deficiencies.

SUMMARY OF THE INVENTION

[0005] The present disclosure provides, inter alia, a compound of Formula I:

o

<img file="CA2999367C_D0001.tif" />

o

Formula (I) or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein the variables are defined below.

[0006] The present disclosure further provides a pharmaceutical composition comprising one or more compounds of the present disclosure.

[0007] The present disclosure also provides use of one or more compounds in the manufacture of a medicament for treating a disease, wherein the disease is narcolepsy, excessive daytime sleepiness, cataplexy, neurodegenerative disease, sleep disturbance syndrome, fibromyalgia, chronic fatigue, schizophrenia, binge eating disorder, Parkinson disease, tardive dyskinesia, or Alzheimer's disease.

[0008] The present disclosure further provides a method of treating a disease, comprising administering to a subject an effective amount of one or more compounds of the present disclosure, wherein the disease is narcolepsy, excessive daytime sleepiness, cataplexy, neurodegenerative disease, sleep disturbance syndrome, fibromyalgia, chronic fatigue, schizophrenia, Binge eating disorder, Parkinson disease, tardive dyskinesia, or Alzheimer's disease.

[0009] The present disclosure also provides a compound of the present disclosure for use in any of the methods described herein.

□ate Reçue/Date Received 2021-05-28

84228409

[0009a] In some embodiments, the present disclosure provides:

- a compound of Formula (IA):

^Rh o /N. /OH r&lt; γ o Rg O

Formula (IA) or a pharmaceutically acceptable salt thereof, wherein, R_g is hydrogen or C1-3 alkyl; and

Rh and Rf are independently hydrogen or C1.3 alkyl,

- a compound having the structure of Formula (ID): O

<img file="CA2999367C_D0002.tif" />

o o

Formula (ID) or a pharmaceutically acceptable salt thereof, wherein, R² is —(CR⁶R⁷ )m—, wherein, m is an integer from 1 to 6; and each of R⁶ and R⁷ is independently selected from hydrogen and Ci-3 alkyl; and R³ is selected from C5-8 aryl, C3-8 heterocycloalkyl, C5-8 heteroaryl, substituted C1-12 alkyl, substituted C5-8 aryl, substituted C3-8 heterocycloalkyl, and substituted C5-8 heteroaryl, wherein each of the one or more substituent groups is independently selected from halogen, Ci^ alkyl, Ci^ alkoxy, and —NR2, wherein each R is independently selected from hydrogen, C1-6 alkyl, and C1-6 alkylcarbonyl,

- a pharmaceutical composition comprising the compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,

- use of the compound as described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment of a disease, wherein the disease is narcolepsy, excessive daytime sleepiness, cataplexy, a neurodegenerative disease, sleep disturbance syndrome, fibromyalgia, chronic fatigue, schizophrenia, binge eating disorder, Parkinson’s disease, tardive dyskinesia, Alzheimer's disease, excessive daytime sleepiness associated with narcolepsy, or cataplexy associated with narcolepsy,

- use of the compound as described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein, in the manufacture of a medicament for the treatment of a disease, wherein the disease is alcohol dependence, -la-

Date Reçue/Date Received 2021-05-28

84228409 opiate dependence, fibromyalgia syndrome, pain associated with fibromyalgia, insomnia, hallucinogenic dreams, or sleep paralysis,

- use of the compound as described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described herein, for the treatment of a disease, wherein the disease is narcolepsy, excessive daytime sleepiness, cataplexy, a neurodegenerative disease, sleep disturbance syndrome, fibromyalgia, chronic fatigue, schizophrenia, binge eating disorder, Parkinson’s disease, tardive dyskinesia, Alzheimer's disease, excessive daytime sleepiness associated with narcolepsy, or cataplexy associated with narcolepsy, and

- use of the compound as described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of as described herein for the treatment of a disease, wherein the disease is alcohol dependence, opiate dependence, fibromyalgia syndrome, pain associated with fibromyalgia, insomnia, hallucinogenic dreams, or sleep paralysis.

DETAILED DESCRIPTION OF THE INVENTION

-2bDate Reçue/Date Received 2021-05-28

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Compound

[0010] In one aspect, the present disclosure provides a compound of Formula I: o

B O — O

Formula (I) or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein, ^Rh, X

B is^{Rf R}s , -(O)R¹, -R²(OCO)R³, substituted or unsubstituted C₅.i₀ aryl, Ci.u alkyl, C5.12 aralkyl, C2-12 alkenyl, Cé-i2 aralkenyl, C2-12 alkynyl, C3.8 cycloalkyl, 3-10 membered heterocyclic alkyl, or 5-10 membered heterocyclic aryl, wherein the one or more substituents are selected from the group consisting of C1-12 alkyl, amino, substituted amino, amino protecting group, -R⁴-S-R⁵, halogen, hydroxyl, cyano, mono-, di- or tri- halo-Ci-6 alkyl, C2.12 alkenyl, C2.12 alkynyl, C1.12 alkoxy, C5.10 aryl, C5.10 alkylaryl, C3.8 cycloalkyl, C1-12 alkyl sulfonyl, 3-8 membered heterocyclic alkyl, 3-10 membered heterocyclic aryl, C5.10 aryloxyl, C5.10 arylcarbonyl, Cm alkylcarbonyloxyl or Cm alkyloxycarbonyl;

wherein

R¹ and R³are independently C1.12 alkyl, C2-12 alkenyl, C5.12 aralkyl, C₆.i2 aralkenyl, C2.12 alkynyl, C5.10 aryl, C3.8 cycloalkyl, 3-10 membered heterocyclic alkyl, 5-10 membered m .

heterocyclic aryl, or , any of which can be optionally mono- or independently multi- substituted by -R⁴-S-R⁵, halogen, hydroxyl, cyano, amino, substituted amino, C1-12 alkyl, C2-12 alkenyl, C2.12 alkynyl, C5.10 aryl, Cm2 alkoxy, C3.8 cycloalkyl, 3-8 membered heterocyclic alkyl, or 3-10 membered heterocyclic aryl, Cm alkylsulfonyl, C5.10 aryloxyl, C5. 10 arylcarbonyl, Cm alkyloxycarbonyl, or Cpn alkylcarbonylamino;

R² is C1-6 alkylene or Cm alkyleneoxyl, any of which is optionally further substituted with Cm alkyl;

R⁴ is a bond. Cm alkylene, C5.10 arylene, or C5.12 arylenealkylene, any of which is optionally further substituted with C1-3 alkyl, and R⁵ is hydrogen or C1-12 alkyl,

Rg is hydrogen, Cm alkyl, phenyl, or phenylmethyl, any of which is optionally mono- or independently multi- substituted by halogen, hydroxyl, methylthio, Cm alkyl,

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PCT/CN2016/099763 or C5.8 aryl; and Rh and Rf are independently hydrogen, C1.6 alkyl, Ci-β alkylcarbonyl, Cp 6 alkoxylcarbonyl, C3.6 cycloalkoxylcarbonyl, or an amino protecting group;

or

R_t- and R_g together with C, Ο, N or S atom form a 4-8 membered heterocyclic alkyl o=( or , any of which is optionally mono- or independently multi- substituted by halogen, hydroxyl or C1.4 alkyl, and Rh is hydrogen, Ci^ alkyl or an amino protecting group.

[0011]

In some embodiments, B is C1.8 alkyl substituted with C2.6 alkyl, aryl or amino group and B is not linear alkyl. In some embodiments, B is C2-6 alkenyl substituted with Ci^ alkyl, aryl or amino group. In some embodiments, B is substituted or unsubstituted C3.8 cycloalkyl, wherein the substituent is selected from the group consisting of halogen, hydroxyl and Ci-6 alkyl. In some embodiments, B is substituted or unsubstituted 3-8 membered heterocyclic alkyl, wherein the substituent is selected from the group consisting of halogen, hydroxyl and Cp6 alkyl. In some embodiments, B is substituted or unsubstituted 5-8 membered heterocyclic aryl, wherein the substituent is selected from the group consisting of halogen, hydroxyl and Ci^ alkyl.

[0012] In some embodiments, B is -CHR^I3R¹⁴, wherein R¹³ and R¹⁴ are independently selected from the group consisting of hydrogen, C1.6 alkyl, C5-10 aryl and amino group, wherein R¹³ and R¹⁴ cannot be methyl at the same time. In some embodiments, R¹³ and R¹⁴ can be cyclized to form a C3.8 cycloalkyl. In some embodiments, R¹³ and R¹⁴together with a Ο, N or S atom form a 3-8 membered heterocyclic alkyl.

[0013] The present disclosure also provides a compound having the chemical structure shown in Formula (IA):

Formula (IA) or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R_g is hydrogen, Cpô alkyl, phenyl, or phenylmethyl, any of which is optionally mono- or independently multi-substituted by halogen, hydroxyl, methylthio, Cp4 alkyl, or C5.8 aryl; and

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Rh and Rf are independently hydrogen, Cm alkyl, Cm alkylcarbonyl, Cm alkoxylcarbonyl, cycloalkoxylcarbonyl or an amino protecting group.

[0014] In some embodiments, R_g is hydrogen or C1.3 alkyl. In some embodiments, at least one of Rh and Rf is hydrogen or C1.3 alkyl. In some embodiments, both Rh and Rf are hydrogen or C1.3 alkyl. In some embodiments, Rhis hydrogen or C1.3 alkyl and Rf is -COR’, and R⁵ is C].3 alkyl, C1.3 alkoxyl, or C5.6 cycloalkyloxyl. In some embodiments, when Rf or Rh is an amino protecting group, R_g is not isopropyl or benzyl.

[0015] The present disclosure also provides a compound having the chemical structure shown in Formula (IA):

Rf

Rh O

<img file="CA2999367C_D0003.tif" />

R

Formula (IA) or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

<img file="CA2999367C_D0004.tif" />

Rf and R_g together with C , O, or N atom form a 4-6 membered heterocyclic alkyl or , any of which is optionally mono- or independently multi- substituted by halogen, hydroxyl, Cm alkyl or an amino protecting group;

R_h is hydrogen, C1.3 alkyl or an amino protecting group.

[0016] The present disclosure also provides a compound having the chemical structure shown in Formula (TA-1 ):

O

<img file="CA2999367C_D0005.tif" />

Formula (IA-1) or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R_h is hydrogen, C1.3 alkyl or an amino protecting group.

[0017] The present disclosure also provides a compound having the chemical structure shown in Formula (IA-2):

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<img file="CA2999367C_D0006.tif" />

Formula (IA-2) or a pharmaceutically acceptable sait, ester, hydrate, or solvate thereof, wherein,

Ri is hydrogen, C1.4 alkyl or an amino protecting group.

[0018] The present disclosure also provides a compound having the chemical structure shown in Formula (IB):

<img file="CA2999367C_D0007.tif" />

Formula (IB) or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein, 0-,/^ &lt; II Ί . 0^-^/

R is Ci-8 alkyl, C5-8 aryl, C₅.12 aralkyl, 3-10 membered heterocyclic alkyl or , any of which is optionally mono- or independently multi- substituted by halogen, cyano, hydroxyl, C 1.12 alkyl or C1.4 alkoxy.

Ria |0019J In some embodiments, R¹ is iand wherein Ru and Ris are independently hydrogen, C1.12 alkyl, C1.4 alkoxy or halogen. In some embodiments, R¹ is ^1e S \__9 , and Ric is hydrogen, Ci-n alkyl or halogen.

[0020] The present disclosure also provides a compound having the chemical structure shown in Formula (IC):

R_e O

JLzÀ ο

Rc Ra

Rb

Formula (IC) or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

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R_a, Rb, Rc, R&lt;i and Re are independently hydrogen, halogen, Cpn alkyl, Cm2 alkoxy, cyano, Cpu alkyl sulfonyl, Ci-6 alkylcarbonyloxyl, C1.4 alkyloxycaibonyl, mono-, di- or trihalo-Ci-6 alkyl, Cs-ioaryloxyl or C5.10 aryl carbonyl; and when R_a, Rb, Re, Rd and R&lt; are all hydrogen, at least one of R_a, Rb, Re, Rd and Re is not protium.

[0021] In some embodiments, Rb, Re, Rd are all hydrogen, and Re and R_a are independently hydrogen, halogen, C1.3 alkyl, C1.3 alkoxy cyano, C1.3 alkylsulfonyl, C1.3 alkylcarbonyloxyl, C1.3 alkyloxycarbonyl, or mono-, di- or tri- halo-Ci-3 alkyl. In some enbodiments, one of Re and R_a is hydrogen. In some embodiments, not all of R_a, Rb, Re, Rd and R. are hydrogen at the same time.

[0022] The present disclosure also provides a compound having the chemical structure shown in Formula (ID):

o 0

Formula (ID) or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R² is -(CR⁶R⁷)m-, wherein m=l-6 and R⁶ and R⁷ are independently hydrogen or C1.3 alkyl;

R³ is C m2 alkyl, C5-8 aryl, 3-8 membered heterocyclic alkyl, or 5-8 membered heterocyclic aryl, which are each optionally mono- or independently multi- substituted by halogen, unsubstituted or substituted amino, C1.6 alkyl or Ci^ alkoxy; wherein when the amino is substituted it can be optionally mono- or independently multi- substituted by Ci-6 alkyl, or C1.6 alkylcarbonyl.

[0023] In some embodiment, R² is -CH2-. In some embodiment, R³ is methyl, ethyl, phenyl, which are each optionally mono- or independently multi- substituted by methoxyl, methyl or ethyl.

[0024] The present disclosure also provides a compound having the chemical structure shown in Formula (ID-1):

<img file="CA2999367C_D0008.tif" />

R_3e Ο O

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Formula (ID-1) or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

Rîa, R3b, R30 Rid and Rs_e are independently hydrogen, halogen, C1.6 alkyl, or C1.6 alkoxy.

[0025] The present disclosure also provides a compound having the chemical structure shown in Formula (ID-2):

Λ,OH

NO

R⁹ O R⁸O

Formula (ID-2) or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R⁹ and R¹⁰ are independently hydrogen, C1-6 alkyl or C1-6 alkylcarbonyl; and R⁸ is hydrogen or C]^ alkyl.

[0026] The present disclosure also provides a compound having the chemical structure shown in Formula (DE):

O R¹² O _R11 0

Formula (EE) or a pharmaceutically acceptable salt, ester, hydrate, or solvate thereof, wherein,

R¹¹ is Ci-8 alkyl or C5-8 aryl, any of which is optionally mono- or independently multisubstituted by halogen, hydroxyl, C1.6 alkyl or C1.4 alkoxy;

R¹² is hydrogen or C_b6 alkyl.

[0027] In some embodiments, the molecular weight of each of the compounds disclosed herein is no more than 450 Da. In some embodiments, the molecular weight of each of the compounds disclosed herein is 150-450 Da, 150-300 Da, or 200-300 Da.

[0028] In some embodiments, the compound is selected from:

<td> 1 ⁰</td><td> 0</td><td> 0</td>

<td> A zOH</td><td></td><td></td>

<td> ίιΎ ° r</td><td> ίΐ°·ΐ</td><td> ίιΎ ° ί</td>

<td> o</td><td>⁰</td><td></td>

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<td> 0</td><td> Aô~r</td><td>^χο ο Α~Υ</td>

<td> \ ο J ο I</td><td> ο ίίη^ο π</td><td> CI ο Ô^ï</td>

<td> Ο Ck ,ΟΗ ΡΡθ^τ</td><td> ο xV'V ΧΧ ο</td><td> 0 NC. A ζΧ/χ,ΟΗ γγ°^ι Ο</td>

<td> ο ΡΡ°^^Ύ χΛ^ ο</td><td></td><td> ^0 CïVx ο</td>

<td> ο ΡΡ°^Ύ χ^α^ °</td><td> A^xr</td><td> ο Ό. Α_λχ\ /X &gt;ΟΗ χ^· ο ^,0</td>

<td> ο \χΛ„ΧΧζΟΗ Γ7 °^ϊ Ο</td><td> 0 ^ΧχχΑ^/Χ/Χ/ΟΗ ΡΡ^θ^Ύ ΧτΑ ⁰</td><td> 0 J T 0</td>

<td> I ο ο Ο =^</td><td> Α' 0 Άγ0χχχΑ_0Η0</td><td> δ Ί ο _^=ο</td>

<td> I ο r Ο</td><td> ο ρΛο---γ^ΟΗ°</td><td> I ο _rο “&gt; ο λ°</td>

<td> 0 Αχ-Ύ⁰ 0</td><td> ο ο J ο I</td><td> ο XX 1 0</td>

<td> ο η ίΓ ⁰ ° π ο</td><td> ΟΑχ^ 0</td><td> 0 ^_!:^^o_r^o/J 0 Cl</td>

<td> ο ρ^°_γ°/ χΑχ^ ο</td><td> ο ,-χΑχ·ΧΧ°Η ΡΡ^Ύ χχχθΑχ ο</td><td> ο ΡΡ°^Υ</td>

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<td> _ Ο Ο ' ί ° Γ</td><td> A J ο I</td><td> ο °=( ο L ο □:</td>

<td> 0 ° ϊ ΑχΑ ο</td><td> 1 ° A^AA--^./\/^0H[ΐΑ θ ^ ΓΓ</td><td> Ο Α_λχ~\/~\/ΟΗ [ΠΡθ^Ύ ^^QP_h °</td>

<td> ο Α°τ ΑΑΑ\ ο</td><td> ο ο ^°γΥ^_ο-^γ^ΟΗΑΑ Ο</td><td> 0 1 |Τ^ΟΪ Α_ΟΑ&gt; ο</td>

<td> ο |Ρ| ° Ί'</td><td> ο οχ^ν 0</td><td> ο ο .ο. /·\ A ^^-^οη 0</td>

<td> ο .,-0^ο</td><td> D Ο D^ Α^ Α_Λ^\ ,ΟΗ ο^'γ'Ό ^ο D</td><td> 0 /^sA°-^v^OHV-N Ο</td>

<td> Ο ζ^ΑΑ/^/'-^ΑΠ οΥ ° ϊι \Α 0</td><td> 0 s^i \^ 0</td><td> ft &lt; 1 0 VN_S Boc</td>

<td> 0 ^Β“Ζγ°'^ ^Η S</td><td> 0 Η₂Ν 0</td><td> ί/Α νη₂ ο LAX,o^A Ο</td>

<td> γ ° η₂ν Υ^'-^ΑΥ ο</td><td> 0 AUA ⁰</td><td> ο A Η₂Ν η^ '^-^ΟΗ 0</td>

<td> 1 Î η₂ν ^ζγ°'^^ζΛ_0Η0</td><td> 0 0 Ν 'Υθ'^Χ^'ΟΗ ^Η S</td><td> ο ο ο</td>

<td> ο ο 1 Ο</td><td> Ο Ο Α^Ν'Υ&lt;°'^χ-^/^Α^·_0Η¹ Ο</td><td> ο ο Α^· _Ν -^γ°χ^\Α^_ΟΗ^η S</td>

<td> ο γ ο ^Η S</td><td> Ο Ο /ν A Α. Ο Ν — OH ^Η S</td><td> 1 Ο 0 ^Ο^Ν'''^⁰^'''''·''^^^ ^Η J</td>

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<td> H ?</td><td> O</td><td> /.....\ ΙΖ ' &gt;° ο )</td><td> 0</td><td> Ο</td><td> Ο=</td><td> Η Π Ο</td><td> ο</td>

<td> o o</td><td> 0 ^OH</td><td colspan="2"> ί Ί ⁰</td><td> Ο 'ΌΗ</td><td> Ο-. C 0</td><td> ί 1 </td><td> ο</td>

<td> o</td><td> o</td><td> ο'Α ο</td><td></td><td> Ο</td><td></td><td> Ο</td><td> Χ^ΟΗ0</td>

<td> o Y o \</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> χ· *</td><td> ο VVy⁰' ο -S.</td><td> ο</td>

<td> o /</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> η₂ν</td><td> ο ο</td><td> 0</td>

<td> o H₂N Y° Yv'-' O 1</td><td> ^^ΟΠ Ο</td><td> ο ^ΛΝ-γ°^Η 5</td><td> ο</td><td> ο</td><td> ο</td><td> ·°γ^ογ°^ ¹ ο</td><td> ο '''''-'''ΌΗ</td>

<td> o ¹ o</td><td> Ο ^^ΌΗ</td><td> Ο 1</td><td> ο</td><td> Ο</td><td> Η₂Ν.</td><td> Ο I ο Λ JL Λ , ο ο ο</td><td> Ο</td>

[0029] Various features of the present disclosure that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0030] As used herein, the term “substituted”, when refers to a chemical group, means the chemical group has one or more hydrogen atoms that is/are removed and replaced by substituents. As used herein, the term “substituent” has the ordinary meaning known in the art and refers to a chemical moiety that is covalently attached to, or if appropriate fused to, a parent group. As used herein, the term “optionally substituted” means that the chemical group may have no substituents (i.e. unsubstituted) or may have one or more substituents (i.e. substituted). It is to be understood that substitution at a given atom is limited by valency.

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[0031] As used herein, the term “C_n._m” indicates a range of the carbon atoms numbers, wherein n and m are integers and the range of the carbon atoms numbers includes the endpoints (i.e. n and m) and each integer point in between. For examples, Ci^ indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms.

[0032] As used herein, the term “alkyl”, whether as part of another term or used independently, refers to a saturated hydrocarbon group that may be straight-chain or branched-chain. The term “C_n-m alkyl” refers to an alkyl having n to m carbon atoms. In some embodiments, the alkyl group contains 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Examples of alkyl group include, but are not limited to, chemical groups such as methyl, ethyl, «-propyl, isopropyl, «-butyl, /er/-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l-butyl, «-pentyl, 3-pentyl, «-hexyl, 1,2,2-trimethylpropyl, and the like.

[0033] As used herein, the term “alkenyl”, whether as part of another term or used independently, refers to an unsaturated hydrocarbon group that may be straight-chain or branched-chain having at least one carbon-carbon double bond. The term “C_n-_m alkenyl” refers to an alkenyl having n to m carbon atoms. In some embodiments, the alkenyl group contains 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the alkenyl group contains 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 carboncarbon double bond. Examples of alkenyl groups include, but are not limited to, chemical groups such as ethenyl, «-propenyl, isopropenyl, «-butenyl, sec-butenyl, and the like.

[0034] As used herein, the term “alkynyl”, whether as part of another term or used independently, refers to an unsaturated hydrocarbon group that may be straight-chain or branched-chain having at least one carbon-carbon triple bonds. The term “C_n._m alkynyl” refers to an alkynyl having n to m carbon atoms. In some embodiments, the alkynyl group contains 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the alkynyl group contains 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, chemical groups such as ethynyl, propyn-l-yl, propyn-2-yl, and the like.

[0035] As used herein, the term “alkylene”, whether as part of another term or used independently, refers to a bivalent saturated hydrocarbon moieties which is linear, or branched, and which connects two other parts of a molecule. The term “C_n._m alkylene” refers to an alkylene having n to m carbon atoms. In some embodiments, the alkylene group

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WO 2017/050259 PCT/CN2016/099763 contains 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylene groups include, but are not limited to, chemical groups such as methylene, ethylene, 1-methyl-methylene, propylidene, butylidene and the like.

[0036] As used herein, the term “aryl or “aromatic”, whether as part of another term or used independently, refers to a mono- or polycyclic carbocyclic ring system radicals with alternating double and single bonds between carbon atoms forming the rings. In some embodiments, the aryl ring systems have 5 to 10, 5 to 8, or 5 to 6 carbon atoms in one or more rings. In some embodiment, the aryl ring system have 2 or more rings fused together. Examples of aryl groups include, but are not limited to, chemical groups such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.

[0037] As used herein, the term “arylene”, whether as part of another term or used independently, refers to a divalent aryl ring or ring system which connects two other parts of a molecule, i.e. the two parts are bonded to the ring in two distinct ring positions. When the aryl ring of the arylene is a monocyclic ring system, the two parts are bonded to the same ring in two distinct ring positions. When the aryl ring of the arylene is a polycyclic ring system, the two parts can be bonded to the same ring or different rings in two distinct ring positions. Arylene may be substituted or unsubstituted. Unsubstituted arylene has no substituents other than the two parts of the molecule it connects. Substituted arylene has substituents in addition to the two parts of the molecule it connects.

[0038] As used herein, the term “aralkyl”, whether as part of another term or used independently, refers to a group of formula -alkyl-aryl The term “C_n._m aralkyl” refers to aralkyl with a total carbon number between n to m. In some embodiments, the alkyl moiety has 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. In some embodiments, the aralkyl group has 5-12, 5-10, 5-8, or 6-7 carbon atoms. Examples of aralkyl groups include, but are not limited to, various alkyl benzenes and alkyl naphthalenes.

[0039] As used herein, the term “arylenealkylene”, whether as part of another term or used independently, refers to a group of formula -alkylene-arylene, wherein the arylene and alkylene groups are as previously described, wherein the term “C_n._m arylenealkylene” refers to an arylenealkylene group with a total carbon number between n to m. In some embodiments, the alkylene portion of the arylenealkylene moiety has 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. In some embodiments, the arylene portion of the arylenealkylene moiety

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WO 2017/050259 PCT/CN2016/099763 has 6 to 12, 6 to 11, 6 to 10, 6 to 9, or 6 to 8 ring forming carbon atoms. In some embodiments, the arylenealkylene moiety has 7-12, 7-10, 7-9, or 7-8 carbon atoms.

[0040] As used herein, the terni “aralkenyl”, whether as part of another term or used independently, refers to a group of formula -alkenyl-aryl, wherein the term “C_n__m aralkenyl” refers to an aralkenyl group with a total carbon number between n to m. In some embodiments, the alkenyl moiety contains 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the aralkenyl group has 6-18, 6-12, 6-10, 6-8, or 6-7 carbon atoms. Examples of aralkenyl groups include, but are not limited to, chemical groups such as styryl, 3-(benzyl) prop-2-enyl, and 6-napthylhex-2-enyl.

[0041] As used herein, the term “cycloalkyl”, whether as part of another term or used independently, refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, the cycloalkyl is saturated cycloalkyl Cycloalkyl groups can have 3, 4, 5, 6, 7, 8 ring-forming carbons (Cj.?). Examples of cycloalkyl groups include, but are not limited to, chemical groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like. In some embodiments, a cycloalkyl used herein may be fused (i.e., having a bond in common with) with one or more aromatic rings, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. In some embodiments, a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.

[0042] As used herein, the term “cycloalkylene”, whether as part of another term or used independently, refers to a bivalent saturated or partially saturated non-aromatic cyclic hydrocarbons group, and which connects two other parts of a molecule. The term “C_n-m cycloalkylene” refers to a cycloalkylene having n to m carbon atoms. In some embodiments, the cycloalkylene group contains 3 to 12, 3 to 10,3 to 8, 3 to 7, 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Examples of cycloalkylene groups include, but are not limited to, chemical groups such as cyclopropylidene, cyclobutalidene and the like.

[0043] As used herein, the term “alkoxy”, whether as part of another term or used independently, refers to a group of formula -O-alkyl. The term “C_n._m alkoxy” means that the alkyl moiety of the alkoxy group has n to m carbon atoms. In some embodiments, the alkyl moiety has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxy groups include, but are

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WO 2017/050259 PCT/CN2016/099763 not limted to, chemical groups such as methoxy, ethoxy, propoxy (e.g., π-propoxy and isopropoxy), /-butoxy, and the like.

[0044] As used herein, the term “aryloxyl” refers to a group of formula -O-aryl, wherein the aryl group is as previously described. “C_n._ra aryloxyl” means that the aryl moiety of the aryloxyl group has n to m carbon atoms. In some embodiments, the aryl moiety has 5 to 10, 5 to 8, or 5 to 6 carbon atoms.

[0045] As used herein, the term “alkylamino”, whether as part of another term or used independently, refers to a group of formula -NH-alkyl. The term “C_n-_m alkylamino” means that the alkyl moiety of the alkylamino group has n to m carbon atoms. In some embodiments, the alkyl moiety has 1 to 6,1 to 4, or 1 to 3 carbon atoms.

[0046] As used herein, the term “arylcarbonyl”, whether as part of another term or used independently, refers to a group of formula -C(=O>aryl, wherein the aryl group is as previously described. “C_n._m arylcarbonyl” means that the aryl moiety of the arylcarbonyl group has n to m carbon atoms. In some embodiments, the aryl moiety has 5 to 10, 5 to 8, or 5 to 6 carbon atoms.

[0047] As used herein, the term “alkylcarbonyl”, whether as part of another term or used independently, refers to a group of formula -C(=O)-alkyl. The term “C_n._m alkylcarbonyl” means that the alkyl moiety of the alkylcarbonyl group has n to m carbon atoms. In some embodiments, the alkyl moiety has 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.

[0048] As used herein, the term “alkoxycarbonyl”, whether as part of another term or used independently, refers to a group of formula -C(=O)-O-alkyl. The term “C_n._malkoxy carbonyl” means that the alkyl moiety of the alkoxycarbonyl group has n to m carbon atoms. In some embodiments, the alkyl moiety has 1 to 6,1 to 4,1 to 3 or 1 to 2 carbon atoms.

[0049] As used herein, the term “cycloalkoxylcarbonyl”, whether as part of another term or used independently, refers to a group of formula -C(=O)-O-cycloalkyl, wherein the cycloalkyl group is as previously described. The term “C_n._mcycloalkyloxylcarbonyl” means that the cycloalkyl moiety of the cycloalkoxylcarbonyl group has n to m carbon atoms. In some embodiments, the cycloalkyl moiety has 3 to 8, 3 to 6, 3 to 5 or 3 to 4 carbon atoms.

[0050] As used herein, the term “alkylcarbonyloxyl”, whether as part of another term or used independently, refers to a group of formula -O-C(=O)-alkyl. The term “Cn.m alkylcarbonyloxyl” means that the alkyl moiety of the alkylcarbonyloxyl group has n to

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WO 2017/050259 PCT/CN2016/099763 m carbon atoms. In some embodiments, the alkyl moiety has 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.

[0051] As used herein, the term “n membered”, wherein n is an integer typically employed in combination with a ring system to describe the number of ring-forming atoms in the ring system. For example, piperidinyl is an example of a 6 membered heterocycloalkyl ring, pyrazolyl is an example of a 5 membered heteroaryl ring, pyridyl is an example of a 6 membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10 membered cycloalkyl group.

[0052] As used herein, the term “heterocyclic aryl” refers to aryl group wherein at least one ring atom in the aromatic ring is a heteroatom, and the remainder of the ring atoms being carbon atoms. The term “n-m membered heterocyclic aryl” refers to heterocyclic aryl having n to m ring-forming members. Example heteroatoms include, but are not limited to, oxygen, sulfur, nitrogen, phosphorus, and the like. In some embodiments, heterocyclic aryl can have 5 to 10, 5 to 8, or 5 to 6 ring-forming members. In some embodiments, heterocyclic aryl is 5 membered or 6 membered heterocyclic aryl. Examples of heterocyclic aryl include, but are not limited to, furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-Noxide, pyrimidyl, pyrazinyl, imidazolyl, indolyl and the like.

[0053] A 5 membered heterocyclic aryl is a heterocyclic aryl with a ring having five ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms can be independently selected from N, Ο, P, and S. Exemplary 5 membered heterocyclic aryl are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

[0054] A 6 membered heterocyclic aryl is a heterocyclic aryl with a ring having six ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms can be independently selected from N, Ο, P, and S. Exemplary 6 membered heterocyclic aryl are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

[0055] As used herein, the term “heterocyclic alkyl” refers to cycloalkyl group wherein at least one ring atom in the ring systems is a heteroatom, and the remainder of the ring atoms being carbon atoms. The term “n-m membered heterocyclic alkyl” refers to heterocyclic alkyl having n to m ring-forming members. In addition, the ring may also have one or more double bonds, but not have a completely conjugated system. In some

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WO 2017/050259 PCT/CN2016/099763 embodiments, the heterocyclic alkyl is saturated heterocyclic alkyl. Examples of heteroatoms include, but are not limited to, oxygen, sulfur, nitrogen, phosphorus, and the like. In some embodiments, heterocyclic alkyl has 3 to 8, 3 to 6, or 4 to 6 ring-forming carbons. Examples of heterocyclic alkyl include, but are not limited to, azetidine, aziridine, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

[0056] As used herein the terms “halo” and “halogen” refer to an atom selected from fluorine, chlorine, bromine and iodine.

[0057] As used herein, “mono-, di- or tri- halo-C_n-_m alkyl” refers to an alkyl group that is substituted by one, two or three halo, wherein the alkyl group has n to m carbon atoms and the halo as substituent may be same or different. Examples of mono-, di- or tri- halo-C_n-m alkyl include without limitation, trichloromethyl, chloromethyl, bischloromethyl, chlorobromomethyl.

[0058] As used herein the terms “cyano” refer to a group of formula -CN.

[0059] As used herein, the term “hydroxyl” refers to a group of formula -OH.

[0060] As used herein, the term “methylthio” refers to a group of formula -S-CHs.

[0061] As used herein, the term “alkylsulfonyl” refers to a group of formula sulfonyl-alkyl. The term “C_n._m alkylsulfonyl” refers to alkylsulfonyl wherein the alkyl moiety has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylsulfonyl groups include without limitation, methanesulfonyl, ethanesulfonyl, ter/-butanesulfonyl, and the like.

[0062] As used herein, the term “amino” refers to a group of formula -NH2.

[0063] As used herein, the term “substituted amino” refers to an amino that is monoor independently substituted by one or more substituents. Examples of substituents include, but are not limited to, halogen, hydroxyl, C1.4 alkyl, C5.8 aryl, Ci^alkoxyl, C3.8 cycloalkyl, 38 membered heterocyclic alkyl, or 3-8 membered heterocyclic aryl, C1.4 alkylsulfonyl, C5.10 aryloxyl, C5.10 arylcarbonyl or Ci.₆ alkyloxycarbonyl, amino protecting group, and the like.

[0064] As used herein, the term “amino protecting group” refers to a substituent that protects an amino functionality against undesirable reactions during synthetic procedures. Examples of amino protecting groups include, but are not limited to, carbamate-protecting groups, such as 2-trimethyl-silylethoxycarbonyl (Teoc), 1 -methyl-l-(4-bi-phenyl-yl)-ethoxycarbonyl (Bpoc), z-butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), 9-fluorenyl

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WO 2017/050259 PCT/CN2016/099763 methyloxycarbonyl (Fmoc), and benzyl-oxycarbonyl (Cbz); amide-protecting groups, such as formyl, acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl; sulfona-mide-protecting groups, such as 2-nitrobenzenesulfonyl; and imine- and cyclic imide-protecting groups, such as phthalimido and dithiasuccinoyl.

[0065] As used herein, the term “compound” is meant to include all stereoisomers (eg. enantiomers and diastereomers), geometric iosomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0066] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, carbon-carbon double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0067] In some embodiments, the compounds described herein have the (R)configuration. In some embodiments, the compounds described herein have the (S)configuration.

[0068] Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid, which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, Nmethylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

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[0069] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

[0070] Compounds of the present disclosure also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0071] Compounds of the present disclosure can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include protium, deuterium and tritium. In some embodiments, the isotope of hydrogen is protium and deuterium. In some embodiments, the hydrogens on the aromatic ring of the compounds include at least one deuterium. In some embodiments, the hydrogens on the aromatic ring of the compounds are all deuteriums.

[0072] In some embodiments, the compounds of the present disclosure can convert to GHB after oral administration. In some embodiments, the compounds of the present disclosure can enter into human circulatory system through a biological process after oral administration. In some embodiment, the compounds of the present disclosure convert to GHB in liver. In some embodiment, the compounds of the present disclosure convert to GHB in blood. In some embodiment, the GHB releasing efficiency of the compounds within 1 hour after contacting blood or liver is no less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. In some embodiment, the GHB releasing efficiency of the compounds within 2 hours after contacting blood or liver is no less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, or 20%.

[0073] In some embodiments, the compounds of the present disclosure have higher oral bioavailability than the oral bioavailablity of GHB sodium salt. Tn some embodiments, the oral bioavailability of the compounds of the present disclosure is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, or 4 times higher than the oral bioavailability of GHB sodium salt.

- 1984228409

In some embodiments, the compounds of the present disclosure have higher colonic absorption than the colonic absorption of GHB. In some embodiments, the colonic absorption of the compounds of the present disclosure is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2 5. 3, 4, 5, 6, 8, or 10 times higher than the colonic absorption of GHB. In some embodiment, the oral bioavailability of the compounds of the present disclosure is no less than 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0074] Not to be limited by the theory, the nature of compounds of the present disclosure enables the compounds to be formulated to a stable solid formulation, especially the sustained or controlled-release formulation. For example, some compounds of the present disclosure can be formulated into a drug with controlled absorption in GI tract. In some embodiment, the oral absorption of the compounds in the colon is no less than 40%, 50%, 60%, 70%, 80%, 90% or more of the total oral absorption.

Synthesis Method

[0075] Compounds of the present disclosure, including salts, esters, hydrates, or solvates thereof, can be prepared using any known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes.

[0076] The reactions for preparing compounds of the present disclosure can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by a skilled artisan.

[0077] Preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley &amp; Sons, Inc., New York (1999).

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84228409

[0078J Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e g., 'H or ^IJC), infrared spectroscopy, spectrophotometry (eg., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chern. 2004, 6(6), 874883) and normal phase silica chromatography. Exemplary synthetic schemes are listed below, the abbreviations for the reactants or for the chemical groups of the reactants included in the synthetic schemes are defined in the Examples.

[0079] For example, compounds of Formula I can be formed as shown in Scheme 1.

Scheme 1

<img file="CA2999367C_D0009.tif" />

[0080] Alternatively, compounds of Formula I can be formed as shown in Scheme 2.

Scheme 2

<img file="CA2999367C_D0010.tif" />

DCC, DMAP, DCM ) oxidation

2) HCI/EA (optionally)

<img file="CA2999367C_D0011.tif" />

[0081] For example, compounds of Formula IA can be formed as shown in Scheme 3 (X in the scheme refers to any substituent group).

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Scheme 3

<img file="CA2999367C_D0012.tif" />

Pd/C, H₂

MeOH

<img file="CA2999367C_D0013.tif" />

[0082] A representative compound of Formula IA can be formed as shown in Scheme

4.

Scheme 4

<img file="CA2999367C_D0014.tif" />

[0083] A representative compound of Formula IA can be formed as shown in Scheme

5.

Scheme 5

<img file="CA2999367C_D0015.tif" />

<img file="CA2999367C_D0016.tif" />

[0084] Alternatively, the compounds of Formula IA can be formed as shown in

Scheme 6 (wherein X in the scheme refers to any substituent group).

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Scheme 6

Ο

<img file="CA2999367C_D0017.tif" />

<img file="CA2999367C_D0018.tif" />

K₂CO₃, h₂o

<img file="CA2999367C_D0019.tif" />

<img file="CA2999367C_D0020.tif" />

DCC, DMAP, DCM

<img file="CA2999367C_D0021.tif" />

O oxidation

<img file="CA2999367C_D0022.tif" />

[0085] A representative compound of Formula LA can be formed as shown in Scheme

7.

Scheme 7

<img file="CA2999367C_D0023.tif" />

<img file="CA2999367C_D0024.tif" />

[0086] A representative compound of Formula IA can be formed as shown in Scheme

8.

Scheme 8

<img file="CA2999367C_D0025.tif" />

<img file="CA2999367C_D0026.tif" />

K₂CO₃, H₂O

<img file="CA2999367C_D0027.tif" />

<img file="CA2999367C_D0028.tif" />

HATU, DIPEA, DCM

<img file="CA2999367C_D0029.tif" />

[0087] A representative compound of Formula IA-2 can be formed as shown in

Scheme 9.

Scheme 9

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<img file="CA2999367C_D0030.tif" />

<img file="CA2999367C_D0031.tif" />

[0088] For example, compounds of Formula IB can be formed as shown in Scheme

10.

Scheme 10

<img file="CA2999367C_D0032.tif" />

<img file="CA2999367C_D0033.tif" />

R¹-OH, triphosgene

Et₃N, DCM

<img file="CA2999367C_D0034.tif" />

[0089] A representative compound of Formula IB can be formed as shown in Scheme

11.

Scheme 11

<img file="CA2999367C_D0035.tif" />

<img file="CA2999367C_D0036.tif" />

(Boc)₂O

DMAP, DCM

<img file="CA2999367C_D0037.tif" />

[0090] A representative compound of Formula IB can be formed as shown in Scheme

12.

Scheme 12

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<img file="CA2999367C_D0038.tif" />

[0091] For example, compounds of Formula ID can be formed as shown in Scheme

13.

Scheme 13

<img file="CA2999367C_D0039.tif" />

O ^α/α

Et₃N, DCM

<img file="CA2999367C_D0040.tif" />

O « η .. oxidation ^rY°-_rA_o-^^oh------o

O r³^oh

Et₃N, acetone

<img file="CA2999367C_D0041.tif" />

[0092] A representative compound of Formula ID-2 can be formed as shown in

Scheme 14.

Scheme 14

<img file="CA2999367C_D0042.tif" />

<img file="CA2999367C_D0043.tif" />

[0093] A representative compound of Formula ID-2 can be formed as shown in

Scheme 15.

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Scheme 15

<img file="CA2999367C_D0044.tif" />

<img file="CA2999367C_D0045.tif" />

Et₃N, Nai, DMF

<img file="CA2999367C_D0046.tif" />

HCI/EA

<img file="CA2999367C_D0047.tif" />

[0094]

A representative compound of Formula

TD-2 can be formed as shown in

Scheme 16.

<img file="CA2999367C_D0048.tif" />

[0095] For example, compounds of Formula IE can be formed as shown in Scheme

17.

Scheme 17

<img file="CA2999367C_D0049.tif" />

<img file="CA2999367C_D0050.tif" />

Pharmaceutical Composition

-2684228409

[0096] The present disclosure provides pharmaceutical composition comprising one or more compounds of the present disclosure, and a pharmaceutically acceptable carrier.

[0097] These pharmaceutical compositions can be prepared in a manner well known in the pharmaceutical art. In some embodiments, the compounds of the present disclosure may be admixed with pharmaceutically acceptable carrier for the preparation of pharmaceutical composition.

[0098] As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some embodiments, compounds, materials, compositions, and/or dosage forms that are pharmaceutically acceptable refer to those approved by a regulatory agency (such as U.S. Food and Drug Administration, China Food and Drug Administration or European Medicines Agency) or listed in generally recognized pharmacopoeia (such as U.S. Pharmacopoeia, China Pharmacopoeia or European Pharmacopoeia) for use in animals, and more particularly in humans.

[0099] As used herein, the term “pharmaceutically acceptable carrier” refers to any and all solvents, excipients, coatings, antibacterial and antifungal agents, flavoring agents, isotonic and absorption delaying agents, and the like that are pharmaceutically acceptable and can facilitate storage and administration of the compounds of the present disclosure to a subject. Pharmaceutically acceptable carrier that can be employed in present disclosure includes those generally known in the art, such as those described in “Remington Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991).

[00100] Examples of pharmaceutically acceptable carriers include, but are not limited to, solvents, liposomes, polymeric excipients and the like.

[00101] In certain embodiments, the pharmaceutically acceptable carrier is a solvent that can dissolve or disperse the compounds of the present disclosure. Illustrative examples of solvent include, without limitation, buffer saline, normal saline, phosphate buffer, citrate buffer, acetate buffer, bicarbonate buffer, sucrose solution, polysorbate solution, oil, ester, and alchohol.

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[00102] In certain embodiments, the pharmaceutically acceptable carriers are liposomes, and the compounds of the present disclosure can be encapsulated within the aqueous portion or lipid portion of the liposomes. Illustrative examples of liposomes include, without limitation, liposomes based on 3 /V-dimethylaminoethane) carbamoyl] cholesterol (DC-Chlo), liposomes based on A-(2,3-dioleoyloxy)propyl-/V,/VJVtrimethylammonium chloride (DOTMA), and liposomes based on l,2-dioleoyloxy-3trimethylammonium propane (DOTAP).

[00103] In certain embodiments, the pharmaceutically acceptable carriers are polymeric excipients such as, without limitation, microspheres, microcapsules, polymeric micelles and dendrimers. The compounds of the present disclosure may be encapsulated, adhered to, or coated on the polymer-based components by methods known in the art.

[00104] The form of pharmaceutical compositions depends on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered. The pharmaceutical compositions can be formulated for oral, nasal, rectal, percutaneous, intravenous, or intramuscular administration. In accordance to the desired route of administration, the pharmaceutical compositions can be formulated in the form of tablets, pills, powders, lozenges, sachets, cachets, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) or ointments.

[00105] For oral administration, powders, granules, pills, tablets, caplets, capsules, and gelcaps are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the present disclosure with at least one carrier such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides, methyl cellulose, hydroxypropylmethyl-cellulose, and/or polyvinylpyrrolidone. In some embodiments, solid dosage forms for oral administration can further comprise other carrier ingredients to aid in manufacture or administration with lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agents, or chelating agents such as EDTA, binders, thickeners, flavoring agents or perfuming agents. In certain embodiments, solid dosage forms for oral administration may additionally comprise dyestuffs or pigments for identification. Tablets and pills may be further treated with suitable coating materials known in the art, such as moisture protective, enteric, or sustained release coatings.

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[00106] Fur ural administration, emulsions, syrups, elixirs, suspensions, slurries and solutions are acceptable as liquid dosage forms. These can be prepared, for example, by mixing one or more compounds of the present disclosure with sterile inactive solvent, such as but not limited to, water, alcohol, oil and a combination thereof. In some embodiments, the inactive diluent used in the liquid dosage form for oral administration comprise oil. such as but not limited to, peanut oil, sesame oil, cottonseed oil, com oil and olive oil. In some embodiments, the inactive diluent used in the liquid dosage form for oral administration comprise esters of fatty acids, such as but not limited to, ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. In some embodiments, the inactive diluent used in the liquid dosage form for oral administration comprise alcohols, such as but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. In some embodiment, liquid dosage forms for oral administration can further comprise surfactants, suspending agents, emulsifying agents, stabilizers, flavoring agents, chelating agents, preservatives, antioxidants, solubilizers (such as propylene glycol, glycerin, or sorbitol), dyes, or thickeners. In some embodiments, the liquid dosage form for oral administration can further comprise pH adjusting agent, such as but not limited to, sodium hydroxide, hydrochloric acid, or malic acid.

[00107] The pharmaceutical composition of the present disclosure can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. In some embodiments, the composition is formulated in a sustained released form. As used herein, the term “sustained released form” refers to release of the active agent from the pharmaceutical composition so that it becomes available for bio-absorption in the subject, primarily in the gastrointestinal tract of the subject, over a prolonged period of time (extended release), or at a certain location (controlled release). In some embodiments, the prolonged period of time can be about 1 hour to 24 hours, 2 hours to 12 hours, 3 hours to 8 hours, 4 hours to 6 hours, 1 to 2 days or more. In certain embodiments, the prolonged period of time is at least about 4 hours, at least about 8 hours, at least about 12 hours, or at least about 24 hours.

[00108] In some embodiments, the sustained release form of pharmaceutical compositions are tablets or pills, and the tablets or pills are coated or otherwise formulated to provide a dosage form affording the advantage of prolonged action. Factors affecting drug release are well known to the skilled artisan and have been described in the art (Bamba et al., Int. J. Pharm., 1979, 2, 307). For

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84228409 example, release rate of the active agent can not only be controlled by dissolution of the active agent in gastrointestinal fluid and subsequent diffusion out of the tablet or pills independent of pH, but can also be influenced by physical processes of disintegration and erosion of the tablet. In some embodiments, polymeric materials as described in “Medical Applications of Controlled Release,” Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); “Controlled Drug Bioavailability,” Drug Product Design and Performance, Smolen and Ball (eds), Wiley, New York (1984); Ranger and Peppas, 1983, J Macromol. Sci. Rev. Macromol Chern. 23:61; see also Levy el al., 1985, Science 228:190; During el al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105 can be used for sustainted release.

[00109J In some embodiments, polymeric materials are used for oral sustained release delivery. Examples of the polymeric materials include sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose. Other cellulose ethers have been described in Aiderman, Jnt. J. Pharm. Tech. &amp; Prod. Mfr., 1984, 5(3) 1-9. In some embodiments, enteric-coated preparations can be used for oral sustained release administration. Examples of the coating materials include polymers with a pHdependent solubility (ie., pH-controlled release), polymers with a slow pH-dependent rate of swelling, dissolution or erosion (i.e., time-controlled release), polymers that are degraded by enzymes (i.e., enzyme-controlled release) and polymers that form firm layers that are destroyed by an increase in pressure {i.e., pressure-controlled release). In some embodiments, osmotic delivery systems are used for oral sustained release administration as described in Verma el al., Drug Dev. Ind. Pharm., 2000, 26:695-708. In a preferred ambodiment, OROS™ osmotic devices are used for oral sustained release delivery devices as described in Theeuwes et al., United States Patent No. 3,845,770; Theeuwes et al., United States Patent No. 3,916,899. In some embodiments, a controlled-release system can be placed in proximity of the target of the compounds and/or composition of the present disclosure, thus requiring only a fraction of the systemic dose, see, e.g., Goodson, in “Medical Applications of Controlled Release,” supra, vol. 2, pp. 115-138 (1984). Other controlled-release systems as described in Langer, 1990, Science 249:1527-1533 may also be used.

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[00110] The compositions can be formulated in a unit dosage form, each dosage containing from about 0.5 to about 30 g, about 1 to about 20 g, about 2 to about 20 g, about 3 to about 20 g, about 4 to about 20 g, about 5 to about 20 g about 6 to about 20 g about 7 to about 20 g about 8 to about 20 g about 9 to about 20 g about 10 to about 20 g about 11 to about 20 g about 12 to about 20 g about 13 to about 20 g about 14 to about 20 g about 15 to about 20 g about 16 to about 20 g, about 17 to about 20 g about 18 to about 20 g 2 to about 18 g about 2 to about 16 g about 2 to about 14 g about 2 to about 12 g about 2 to about 10 g about 2 to about 9 g, about 2 to about 8 g, about 2 to about 6 g of the active ingredient. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetennined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.

Method for Treatment

[00111] The present disclosure provides, a method of treating a disease, comprising administering to a subject an effective amount of one or more compounds of the present disclosure.

[00112] In some embodiments, the disease is narcolepsy, excessive daytime sleepiness, cataplexy, neurodegenerative disease, sleep disturbance syndrome, fibromyalgia, chronic fatigue, schizophenia, binge eating disorder, Parkinson disease, tardive dyskinesia, or Alzheimer's disease. In some embodiments, the disease is excessive daytime sleepiness or cataplexy associated with narcolepsy.

[00113] Administration may be via oral, nasal, intravenous, subcutaneous, sublingual, or intramuscular administration.

[00114] The frequency of administration of the compounds will vary depending upon what is being administered, the amount of the therapeutic agent, the purpose of the administration, the state of the patient, the manner of administration, and the like. Determination of frequency of administration is well within the capability of those skilled in the art. In some embodiments, the administration is conducted no more than two time per day, no more than one time per day, no more than two times per three days, no more than one time per two days, no more than one time per three days, no more than one time per five days, no more than one time per one week, or no more than one time per two weeks.

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[00115] As used herein, the term “effective amount” means an amount of the therapeutic agent that is effective to provide a desired outcome. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. Generally, a therapeutically effective amount can vary with the subject’s history, age, condition, sex, as well as the severity and type of the medical condition in the subject, and administration of other agents that inhibit pathological processes in neurodegenerative disorders. In some embodiments, the effective amount of the therapeutic agent is from about 0.5 to about 30 g, about 1 to about 15 g, about 2 to about 15 g, about 3 to about 10 g, about 4 to about 10 g.

[00116] As used herein, the term treating or treatment of any disease or disorder refers to delaying onset of the disease or disorder; ameliorating at least one of the clinical symptoms relating to the disease or disorder; or both.

Pharmaceutical Use

[00117] The present disclosure also provides use of one or more compounds of the present disclosure in the manufacture of a medicament for treating a disease. In some embodiments, the disease is narcolepsy, excessive daytime sleepiness, cataplexy, neurodegenerative disease, sleep disturbance syndrome, fibromyalgia, chronic fatigue, schizophenia, binge eating disorder, Parkinson disease, tardive dyskinesia, or Alzheimer's disease. In some embodiments, the disease is excessive daytime sleepiness or cataplexy associated with narcolepsy.

[00118] The present disclosure also provides the compounds of the present disclosure for treating a disease. In some embodiments, the disease is narcolepsy, excessive daytime sleepiness, cataplexy, neurodegenerative disease, sleep disturbance syndrome, fibromyalgia, chronic fatigue, schizophenia, binge eating disorder, Parkinson disease, tardive dyskinesia, or Alzheimer's disease. In some embodiments, the disease is excessive daytime sleepiness or cataplexy associated with narcolepsy.

EXAMPLES

[00119] The following examples are presented to illustrate the present disclosure. They are not intended to be limiting in any manner.

EXAMPLE 1: Preparation and characterization of exemplary compounds

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[00120] Compounds encompassed in the present disclosure may be prepared via different schemes. Detailed preparation processes of 90 exemplary compounds via various schemes are described below and the characterization results are listed for each compound as well.

[00121] Unless stated otherwise, all reagents were purchased from commercial suppliers without further purification. Solvent drying by standard methods was employed when necessary. The plates used for thin-layer chromatography (TLC) were E. Merck silica gel 60F254 (0.24 nm thickness) precoated on aluminum plates, and then visualized under UV light (365 nm and 254 nm) or through staining with a 5% of dodecamolybdophosphoric acid in ethanol and subsequent heating. Column chromatography was performed using silica gel (200-400 mesh) from commercial suppliers. ’H NMR spectra were recorded on an Agilent 400-MR NMR spectrometer (400.00 MHz for 1H) at room temperature. Solvent signal was used as reference for *H NMR (CDC1₃, 7.26 ppm; CD3OD, 3.31 ppm; ak-DMSO, 2.50 ppm; D2O, 4.79 ppm). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, br.s. = broad singlet, dd = double doublet, td = triple doublet, dt = double triplet, dq = double quartet, m = multiplet. Other abbreviations used in the experimental details are as follows: Ar = aryl, Boc = ter/-butyloxy carbonyl, Bn = Benzyl, δ = chemical shift in parts per million downfield from tetramethyl silane, DCC = dicyclohexylcarbodiimide, DCM = dichloromethane, DTPEA = di isopropyl ethyl ami ne, DMAP = 4-(dimethylamino)pyridine, DMF = N,N ' -dimethylformamide, EA = ethyl acetate, Et = ethyl, HATU = l-[bis(dimethylamino)methylene]-l/f-l,2,3-triazolo[4,5-6]pyridinium 3oxid hexafluorophosphate, Hex.= hexanes, Hz = hertz, J = coupling constant (in NMR), Me = methyl, min = minute (s), NMR = nuclear magnetic resonance, Ph = phenyl, ppm = parts per million, /Pr = isopropyl, TBAF = tetrabutylammonium fluoride, tert = tertiary, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TLC = thin-layer chromatography.

<img file="CA2999367C_D0051.tif" />

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Example 1-1 [00123] Intermediate Compound 1 4-hydroxybutyl 2-methylbenzoate

<img file="CA2999367C_D0052.tif" />

[00124] A solution of 2-methylbenzoyl chloride (770 mg, 5 mmol) in DCM (2 mL) was added dropwise during 10 min to a stirred solution of butane-l,4-diol (450 mg, 5 mmol ) and EtjN (505 mg, 5 mmol) in DCM (8 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H2O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was then washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (470 mg, 45%) as a colorless oil. ¹H NMR was performed at 400MHz with CDClj as solvent to characterize the titled compound, results are as follows: δ = 7.91 (d, J= 8.0 Hz, 1 H), 7.40 (t, J= ΊΑ Hz, 1 H), 7.26 - 7.22 (m, 2 H), 4.34 (t, J = 6.8 Hz, 2 H), 3.73 (t, J = 6.4 Hz, 2 H), 2.60 (s, 3 Η), 1.90 -1.83 (m,2H), 1.77- 1.70 (m, 2 H).

[00125] Compound 1:4-(2-methylbenzoyloxy)butanoic acid

<img file="CA2999367C_D0053.tif" />

[00126] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 2methylbenzoate (400 mg, 1.92 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), then dried over anhydrous Na2SO4and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 3:1 to yield the titled compound (380 mg, 89%) as crystalline solids. ’Η NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.91 (d, J= 8.0 Hz, 1 H), 7.40 (ζ J = 7.8 Hz, 1 H), 7.28 - 7.22 (m, 2 H), 4.36 (t, J= 6.2 Hz, 2 H), 2.61 (s, 3 H), 2.55 (t, J= 7.4 Hz, 2 H), 2.15 - 2.08 (m, 2 H).

Example 1-2

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[00127] Intermediate Compound 2 \ 4-hydroxybutyl 3-methylbenzoate

O

<img file="CA2999367C_D0054.tif" />

[00128] A solution of 3-methylbenzoyl chloride (616 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and Et₃N (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H2O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was then washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (410 mg, 49%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.83 - 7.81 (m, 2 H), 7.35 - 7.28 (m, 2 H), 4.33 (t, J = 6.6 Hz, 2 H), 3.70 (t, J = 6.4 Hz, 2 H), 2.38 (s, 3 H), 2.07 (s, 1 Η), 1.89 - 1.82 (m, 2 Η), 1.75 1.68 (m, 2 H).

[00129] Compound 2:4-(3-methylbenzoyloxy)butanoic acid

O

<img file="CA2999367C_D0055.tif" />

[00130] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 3methylbenzoate (350 mg, 1.68 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SÛ4and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 3:1 to yield the titled compound (333 mg, 89%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows; Ô = 7.83 - 7.81 (m, 2 H), 7.36 - 7.28 (m, 2 H), 4.36 (t, J= 6.2 Hz, 2 H), 2.53 (t, J= 7.2 Hz, 2 H), 2.38 (s, 3 H), 2.14 - 2.07 (m, 2 H).

Example 1-3

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[00131] Intermediate Compound 3 4-hydroxybutyl 4-methylbenzoate

O

<img file="CA2999367C_D0056.tif" />

[00132] A solution of 4-methylbenzoyl chloride (616 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and Et₃N (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (470 mg, 56%) as a colorless oil. *H NMR was performed at 400MHz with CDCL as solvent to characterize the titled compound, results are as follows: δ = 7.91 (d, J = 8.4 Hz, 2 H), 7.20 (d, J= 8.4 Hz, 2 H), 4.32 (t, 6.6

Hz, 2 H), 3.69 (t, J = 6.6 Hz, 2 H), 2.38 (s, 3 H), 2.19 (br. s„ 1 H), 1.87 - 1.80 (m, 2 H), 1.741.67 (m, 2 H).

[00133] Compound 3:4-(4-methylbenzoyloxy)butanoic acid o

<img file="CA2999367C_D0057.tif" />

[00134] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 4methylbenzoate (400 mg, 1.92 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous NajSOjand concentrated. The residue was purified by a silica gel flash column with Hex/EA = 3:1 to yield the titled compound (364 mg, 85%) as crystalline solids. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.91 (d, J= 8.0 Hz, 2 H), 7.23 (d, 8.0 Hz, 2 H), 4.36 (t, J = 6.2 Hz, 2 H),

2.54 (t, J= ΊΑ Hz, 2 H), 2.40 (s, 3 H), 2.14 - 2.08 (m, 2 H).

Example 1-4

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[00135] Intermediate Compound 4’: 4-hydroxybutyl 4-fluorobenzoate

O

<img file="CA2999367C_D0058.tif" />

[00136] A solution of 4-fluorobenzoyl chloride (632 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-l,4-diol (450 mg, 5 mmol ) and EtjN (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H2O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na2SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (540 mg, 64%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.07 - 8.04 (m, 2 H), 7.11 (t, J= 8.6 Hz, 2 H), 4.36 (t, J= 6.4 Hz, 2 H), 3.73 (t, J = 6.4 Hz, 2 Η), 1.90 - 1.83 (m, 2 Η), 1.76 - 1.69 (m, 2 Η), 1 41 (br. s., 1 H).

[00137] Compound 4:4-(4-fluorobenzoyloxy)butanoic acid

O

<img file="CA2999367C_D0059.tif" />

[00138] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 4fluorobenzoate (500 mg, 2.36 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (356 mg, 67%) as crystalline solids. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.06 - 8.03 (m, 2 H), 7.11 (t, J = 8.6 Hz, 2 H), 4.38 (t, J= 6.4 Hz, 2 H), 2.54 (t, J = 7.2 Hz, 2 H), 2.15-2.07 (m, 2 H).

Example 1-5

[00139] Intermediate Compound S’: 4-hydroxybutyl 2,4,6-trimethylbenzoate

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<img file="CA2999367C_D0060.tif" />

[00140] A solution of 2,4,6-trimethylbenzoyl chloride (728 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane- 1,4-diol (450 mg, 5 mmol) and EtaN (505 mg, 5 mmol) in DCM (5 mL) at 0 °C was added a solution of 2,4,6trimethylbenzoyl chloride (728 mg, 4 mmol) in DCM (5 mL) dropwise during 10 min. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H2O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (600 mg, 64%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 6.85 (s, 2 H), 4.34 (t, J = 6.6 Hz, 2 H), 3.69 (t, J = 6.6 Hz, 2 H), 2.29 (s, 6 H), 2.28 (s, 3 Η), 1.88 - 1.80 (m, 2 H), 1.73 1.66 (m, 2 H), 1.49 (br. s„ 1 H).

[00141] Compound 5:4-(2,4,6-trimethylbenzoyloxy)butanoic acid

<img file="CA2999367C_D0061.tif" />

[00142] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 2,4,6-trimethylbenzoate (500 mg, 2.12 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 5:1-3:1 to yield the titled compound (450 mg, 85%) as a white solid. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 6.85 (s, 2 H), 4.36 (t, J = 6.4 Hz, 2 H), 2.51 (t, J = 7.2 Hz, 2 H), 2.29 (s, 6 H), 2.28 (s, 3 H), 2.12 - 2.05 (m, 2 H).

Example 1-6

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[00143] Intermediate Compound 6’: 4-hydroxybutyl 2-methoxybenzoate

<img file="CA2999367C_D0062.tif" />

[00144] A solution of 2-methoxybenzoyl chloride (680 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and Et₃N (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H2O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous NaiSCU and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (370 mg, 41%) as a colorless oil. Ή NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.79 (dd, J= 1.6, 7.6 Hz, 1 H), 7.49 - 7.45 (m, 1 H), 7.00 - 6.97 (m, 2 H), 4.35 (t, J= 6.2 Hz, 2 H), 3.90 (s, 3 H), 3.77 - 3.68 (m, 2 Η), 1.91 - 1.83 (m, 2 H), 1.77 1.69 (m, 2 H), 1.56 (br. s , 1 H).

[00145] Compound 6:4-(2-methoxybenzoyloxy)butanoic acid

O

<img file="CA2999367C_D0063.tif" />

[00146] Jones reagent was added in portions toa stirred mixture of 4-hydroxybutyl 2methoxybenzoate (300 mg, 1.34 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO4and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (244 mg, 76%) as crystalline solids. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.78 (dd, J= 1.8, 7.8 Hz, 1 H), 7.49 - 7.45 (m, 1 H), 7.00 - 6.96 (m, 2 H), 4.36 (t, J= 6.0 Hz, 2 H), 3.90 (s, 3 H), 2.57 (t, J= 7.4 Hz, 2 H), 2.13 - 2.07 (m, 2 H).

Example 1-7

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[00147] Intermediate Compound 7’: 4-hydroxybutyl 3-methoxybenzoate

O

<img file="CA2999367C_D0064.tif" />

[00148] A solution of 3-methoxybenzoyl chloride (680 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and Et₃N (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H2O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous NaaSCU and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (420 mg, 47%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.63 (d, J= Ί.6 Hz, 1 H), 7.56 (s, 1 H), 7.34 (t, J = 8.0 Hz, 1 H), 7.10 (dd, J = 2.4, 8.0 Hz, 1 H), 4.36 (t, J = 6.4 Hz, 2 H), 3.85 (s, 3 H), 3.73 (t, J = 6.2 Hz, 2 H), 1.91-1.84 (m, 2 Η), 1.76 -1.69 (m, 2 H).

[00149] Compound 7:4-(3-methoxybenzoyloxy)butanoic acid

<img file="CA2999367C_D0065.tif" />

[00150] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 3methoxybenzoate (350 mg, 1.56 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 8:1-3:1 to yield the titled compound (287 mg, 77%) as crystalline solids. ⁿH NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.63 (d, J = 8.0 Hz, 1 H), 7.55 (s, 1 H), 7.35 (t, J= 7.8 Hz, 1 H), 7.10 (dd, J = 2.4, 8.0 Hz, 1 H), 4.39 (t, J= 6.4 Hz, 2 H), 3.86 (s, 3 H), 2.54 (t, J= 7.2 Hz, 2 H), 2.16 - 2.08 (m, 2 H).

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Example 1-8

[00151] Intermediate Compound 8’: 4-hydroxybutyl 4-methoxybenzoate

<img file="CA2999367C_D0066.tif" />

[00152] A solution of 4-methoxybenzoyl chloride (680 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and EtaN (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash columnwith Hex/EA = 10:1-5:1 to yield the titled compound (500 mg, 56%) as a colorless oil. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.99 (d, J = 9 2 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 4.33 (t, 6.6 Hz, 2 H), 3.86 (s, 3 H), 3.73 (s, 2 Η), 1.89 - 1.82 (m, 2 H), 1.76 - 1.69 (m, 2 H),

1.44 (br. s„ 1 H).

[00153] Compound 8:4-(4-methoxybenzoyloxy)butanoic acid

<img file="CA2999367C_D0067.tif" />

[00154] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 4methoxybenzoate (400 mg, 1.79 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of z’PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (370 mg, 87%) as a white solid. *Η NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.99 (d, J = 9.2 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 4.35 (t, J = 6.2 Hz, 2 H), 3.86 (s, 3 H), 2.54 (t, J= 7.2 Hz, 2 H), 2.13 - 2.08 (m, 2 H).

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Example 1-9

[00155] Intermediate Compound 9’: 4-hydroxybutyl 2-chlorobenzoate

Cl 0

<img file="CA2999367C_D0068.tif" />

[00156] A solution of 2-chlorobenzoyl chloride (2 g, 11.43 mmol) in DCM (10 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (3085 mg, 34.28 mmol ) and Et₃N (2308 mg, 22.85 mmol) in DCM (50 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 ~ 25 °C over 16 h. After that, the reaction mixture was diluted with H2O (30 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 8:1 to yield the titled compound (1.8 g, 69%) as colorless oil. NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.81 (dd, J= 1.4, 7.8 Hz, 1 H), 7.45 - 7.38 (m, 2 H), 7.34 - 7.28 (m, 1 H), 4.38 (t, J= 6.4 Hz, 2 H), 3.71 (t, J= 6.4 Hz, 2 H), 1.91 -1.84 (m, 2 H), 1.77 - 1.70 (m, 2 H).

[00157] Compound 9:4-(2-chlorobenzoyloxy)butanoic acid

Cl O

<img file="CA2999367C_D0069.tif" />

[00158] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 2chlorobenzoate ( 1.6 g, 7.02 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (20 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with brine (3 mL x 2), dried over Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 3:1 to yield the titled compound (1 g, 59%) as crystalline solids. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: Ô = 7.82 (dd, J = 1.2, 8.0 Hz, 1 H), 7.49 - 7.38 (m, 2 H), 7.34 - 7.29 (m, 1 H), 4.41 (t, J = 6.2 Hz, 2 H), 2.57 (t, J= 7.2 Hz, 2 H), 2.16 - 2.09 (m, 2 H).

Example 1-10

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[00159] Intermediate Compound 10 4-hydroxybutyl 3-chlorobenzoate

O

<img file="CA2999367C_D0070.tif" />

[00160] A solution of 3-chlorobenzoyl chloride (696 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-l,4-diol (450 mg, 5 mmol ) and EtjN (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H2O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na2SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (550 mg, 60%) as a colorless oil. *11 NMR was performed at 400MHz with CDCl? as solvent to characterize the titled compound, results are as follows: δ = 8.00 (s, 1 H), 7.92 (d, J = 7.6 Hz, 1 H), 7.52 (dd, J = 0.8, 8.4 Hz, 1 H), 7.38 (t, J= 7.8 Hz, 1 H), 4.36 (t, J= 6.4 Hz, 2 H), 3.73 (dd, J = 6.2, 10.6 Hz, 2 H), 1.91 1.84 (m, 2 H), 1.76 -1.69 (m, 3 H).

[00161] Compound 10: 4-(3-chlorobenzoyI oxy)butanoic acid

O

CK ζχΛ ζχ/χ ΌΗ xA O

[00162] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 3chlorobenzoate (500 mg, 2.19 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SÛ4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (420 mg, 79%) as a colorless oil. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.00 (s, 1 H), 7.92 (d, J= 7.6 Hz, 1 H), 7.55 - 7.52 (m, 1 H), 7.39 (t, J = 7.8 Hz, 1 H), 4.39 (t, J = 6.2 Hz, 2 H), 2.55 (t, J= 7.2 Hz, 2 H), 2.16 - 2.09 (m, 2 H).

Example 1-11

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[00163] Intemediate Compound 11 \ 4-hydroxybutyl 4-chlorobenzoate

Ο

<img file="CA2999367C_D0071.tif" />

[00164] A solution of 4-chlorobenzoyl chloride (2 g, 11.43 mmol) in DCM (10 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (3085 mg, 34.28 mmol ) and Et₃N (2308 mg, 22.85 mmol) in DCM (50 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 1 h. After that, the reaction mixture was diluted with H2O (30 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 7:1 to yield the titled compound (1.6 g, 62%) as crystalline solids. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.97 (d, J= 8.4 Hz, 2 H), 7.41 (d, J = 8.4 Hz, 2 H), 4.36 (t, J= 6.6 Hz, 2 H), 3.73 (t, J= 6.4 Hz, 2 H), 1.90 - 1.84 (m, 2 H), 1.75 - 1.69 (m, 2 H).

[00165] Compound 11: 4-(4-chlorobenzoyloxy)butanoic acid

<img file="CA2999367C_D0072.tif" />

[00166] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 4chlorobenzoate (1.5 g, 6.58 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 16 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (20 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with brine (3 mL x 2), dried over Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 3:1 to afford the title compound (600 mg, 38%) as crystalline solids. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.96 (d, J = 8.0 Hz, 2 H), 7.41 (d, J = 8.0 Hz, 2 H), 4.39 (t, J = 6.2 Hz, 2 H), 2.54 (t, J = 7.2 Hz, 2 H), 2.15 - 2.07 (m, 2 H).

Example 1-12

[00167] Intermediate Compound 12’: 4-hydroxybutyl3-cyanobenzoate

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Ο NC. /^ JX /·--. /\ ΌΗ ïj (001681 A solution of 3-cyanobenzoyl chloride (660 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-l,4-diol (450 mg, 5 mmol ) and EtsN (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (450 mg, 51%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCL as solvent to characterize the titled compound, results are as follows: δ = 8.31 (s, 1 H), 8.26 (d,./ = 8.0 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 7.58 (t, J = 8 0 Hz, 1 H), 4.39 (t, J = 6.4 Hz, 2 H), 3.73 (t, J = 6.4 Hz, 2 H), 1.92 - 1 85 (m, 2 H), 1.76- 1.69 (m, 2 H).

[00169J Compound 12: 4-(3-cyanobenzoyloxy)butanoic acid o NC. /OH

Ί|Ί 0

[00170] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 3cyanobenzoate (400 mg, 1.83 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (330 mg, 77%) as a white solid. 'H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.31 (s, 1 H), 8.26 (d, J= 8.0 Hz, 1 H), 7.85 (d, J= 7.6 Hz, 1 H), 7.59 (t, J= Ί» Hz, 1 H), 4.43 (t, J = 6.4 Hz, 2 H), 2.56 (t, 7.2 Hz, 2 H), 2.18 - 2.11 (m, 2 H).

Example 1-13

[00171] Intermediate Compound 13’: 4-hydroxybutyl 4-tert-butylbenzoate

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Ο

<img file="CA2999367C_D0073.tif" />

[00172] A solution of 4-Zerz-butylbenzoyl chloride (784 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg 5 mmol ) and Et₃N (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (530 mg, 53%) as a colorless oil.

NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.97 (d, J = 8.0 Hz, 2 H), 7.45 (d, J= 8.8 Hz, 2 H), 4.35 (t, J= 6.4 Hz, 2 H), 3.73 (t, J= 6.2 Hz, 2 H), 1.91 - 1.83 (m, 2 H), 1.76 - 1.71 (m, 2 H), 1.34 (s, 9 H).

[00173] Compound 13: 4-(4-tert-butylbenzoyloxy)butanoic acid

O

<img file="CA2999367C_D0074.tif" />

[00174] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 4/erZ-butylbenzoate (450 mg 1.8 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous NazSO4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (370 mg, 79%) as a white solid. *Η NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.96 (d, J = 8.4 Hz, 2 H), 7.45 (d, J = 8.8 Hz, 2 H), 4.37 (t, J = 6.2 Hz, 2 H), 2.55 (t, J = 7.4 Hz, 2 H), 2.15- 2.06 (m, 2 Η), 1.34 (s, 9 H).

Example 1-14

[00175] Intermediate Compound 14’: 4-hydroxybutyl 3-(trifluoromethyI) benzoate

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Ο F₃C. ^ΟΗ

Tj

[00176] A solution of 3-(trifluoromethyl)benzoyl chloride (832 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and Et₃N (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 12 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stinred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (670 mg, 64%) as a colorless oil. *H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 8 29 (s, 1 H), 8.23 (d, .1 = 8.0 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.59 (t, J = 7.8 Hz, 1 H), 4.40 (t, J = 6.4 Hz, 2 H), 3.74 (t, J = 6.6 Hz, 2 H), 1.93 - 1.86 (m, 2 H), 1.77 - 1.70 (m, 2 H), 1.42 (br. s., 1 H).

[00177] Compound 14: 4-(3-(trifluoromethyl)benzoyloxy)butanoic acid

O

F₃C. A 0 [00178] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 3(trifluoromethyl)benzoate (600 mg, 2.29 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of z'PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (400 mg, 63%) as a colorless oil. 'H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.29 (s, 1 H), 8.22 (d, J= 8.0 Hz, 1 H), 7.82 (d, J= Ί6 Hz, 1 H), 7.59 (t, J = 7.6 Hz, 1 H), 4.43 (t, J~ 6.4 Hz, 2 H), 2.55 (t, J= 7.4 Hz, 2 H), 2.18 - 2.12 (m, 2 H).

Example 1-15

[00179] Intermediate Compound 15 4-hydroxybutyl 3,4,5-trimethoxybenzoate

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<img file="CA2999367C_D0075.tif" />

[00180] A solution of 3,4,5-trimethoxybenzoyl chloride (920 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and Et₃N (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 12 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-4:1 to yield the titled compound (700 mg, 62%) as a colorless oil. ’H NMR was performed at 400MHz with CDCh as solvent to characterize the titled compound, results are as follows: δ = 7.29 (s, 2 H), 4.35 (t, J= 6.6 Hz, 2 H), 3.90 (s, 9 H), 3.77 - 3.69 (m, 2 H), 1.92 - 1.84 (m, 2 H), 1.75 - 1.68 (m, 2 H), 1.48 (br. s., 1 H).

[00181] Compound 15:4-(3,4,5-trimethoxybenzoyloxy)butanoic acid ^0

<img file="CA2999367C_D0076.tif" />

[00182] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 3,4,5-trimethoxybenzoate (600 mg, 2.11 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 8:1-3:1 to yield the titled compound (440 mg, 70%) as crystalline solids. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.28 (s, 2 H). 4.37 (t, ./= 6.4 Hz, 2 H), 3.90 (s, 9 H), 2.52 (t, ./= 7.2 Hz, 2 H), 2.15 - 2.08 (m, 2 H).

Example 1-16

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[00183] Intermediate Compound 16 4-hydroxybutyl 4-ethylbenzoate

O

<img file="CA2999367C_D0077.tif" />

[00184] A solution of 4-ethylbenzoyl chloride (500 mg, 2.98 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (534 mg, 5 93 mmol ) and EtjN (599 mg, 5.93 mmol) in DCM (10 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na2SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-6:1 to yield the titled compound (450 mg, 68%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.97 (s, 1 H), 7.94 (s, 1 H), 7.27 (s, 1 H), 7.25 (s, 1 H), 4.35 (t, J = 6.4 Hz, 2 H), 3.73 (t, J = 6.2 Hz, 2 H), 2.70 (q, J = 7.6 Hz, 2 Η), 1.90 - 1.83 (m, 2 H), 1 77 -1.70 (m, 2 Η), 1.34 (br. s, 1 Η), 1.25 (t, 7.6 Hz, 3 H).

[00185] Compound 16: 4-(4-ethylbenzoyloxy)butanoic acid

O

<img file="CA2999367C_D0078.tif" />

[00186] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 4ethylbenzoate (450 mg, 2.03 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (270 mg, 56%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.96 (s, 1 H), 7.94 (s, 1 H), 7.27 (s, 1 H), 7.25 (s, 1 H), 4.37 (t, J = 6.2 Hz, 2 H), 2.70 (q, J = 7.6 Hz, 2 H), 2.55 (t, J= 7.4 Hz, 2 H), 2.15 - 2.09 (m, 2 H), 1.25 (t, J= 7.6 Hz, 3 H).

Example 1-17

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[00187] Intermediate Compound 17*: 4-hydroxybutyl 2,3-dimethylbenzoate

<img file="CA2999367C_D0079.tif" />

[00188] A solution of 2,3-dimethylbenzoyl chloride (500 mg, 2.97 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane- 1,4-diol (534 mg, 5.93 mmol ) and EtjN (599 mg, 5.93 mmol) in DCM (10 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 3 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stinted for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 7:1 to yield the titled compound (390 mg, 59%) as a colorless oil. *H NMR was performed at 400MHz with CDCh as solvent to characterize the titled compound, results are as follows: δ = 7.61 (d, J = 7.6 Hz, 1 H), 7.28 (d,./ = 7.6 Hz, 1 H), 7.13 (t, J = 7.8 Hz, 1 H), 4.34 (t, J = 6.6 Hz, 2 H), 3.73 (t, J = 6.0 Hz, 2 H), 2.45 (s, 3 H), 2.32 (s, 3 H), 1.90 - 1.83 (m, 2 H), 1.78 - 1.69 (m, 2 H), 1.36 (br. s„ 1 H).

[00189] Compound 17: 4-(2,3-dimethylbenzoyloxy)butanoic acid

<img file="CA2999367C_D0080.tif" />

[00190] Jones reagent was added in portions toa stirred mixture of 4-hydroxybutyl 2,3-dimethylbenzoate (350 mg, 1.58 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SÛ4and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-6:1 to yield the titled compound (230 mg, 62%) as a white solid. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.61 (d, J = 7.6 Hz, 1 H), 7.28 (d, J= 7.2 Hz, 1 H), 7.13 (t, J= 7.6 Hz, 1 H), 4.35 (t, J= 6.2 Hz, 2 H), 2.54 (t, J= 7.2 Hz, 2 H), 2.45 (s, 3 H), 2.32 (s, 3 H), 2.15 - 2.08 (m, 2H).

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Example 1-18 [00191] Intermediate Compound 18’: 4-hydroxybutyl3,5-dimethoxybenz/oate

<img file="CA2999367C_D0081.tif" />

[00192] A solution of 3,5-dimethoxybenzoyl chloride (500 mg, 2.49 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and Et₃N (505 mg, 5 mmol) in DCM (10 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 3 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 7:1 to yield the titled compound (430 mg, 68%) as a colorless oil. ’H NMR was performed at 400MHz with CDCI₃as solvent to characterize the titled compound, results are as follows: δ = 7.18 (d, J = 2.4 Hz, 2 H), 6.65 (t, J= 2.0 Hz, 1 H), 4.36 (t, J= 6.4 Hz, 2 H), 3.83 (s, 6 H), 3.73 (t, J= 6.2 Hz, 2 H), 1.90 - 1.83 (m, 2 H), 1.76 1.69 (m, 2 H).

[00193] Compound 18: 4-(3,5-dimethoxybenzoyloxy)butanoic acid

<img file="CA2999367C_D0082.tif" />

[00194] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 3,5-dimethoxybenzoate (400 mg, 1.57 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄ and concentrated The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (200 mg, 47%) as a white solid.

NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound,

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Hz, 2 H), 3.82 (s, 6 H), 2.52 (t, 7.2 Hz, 2 H), 2.14 - 2.07 (m, 2 H).

Example 1-19 [00195] Intermediate Compound 19 4-hydroxybutyl 3,5-dimethylbenzoate

O

<img file="CA2999367C_D0083.tif" />

[00196] A solution of 3,5-dimethylbenzoyl chloride (500 mg, 2.96 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-l,4-diol (534 mg, 5.93 mmol ) and Et₃N (599 mg, 5.93 mmol) in DCM (10 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 16 h. After that, the reaction mixture was diluted with H2O (5 mL) and stinted for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous NazSO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 7:1 to yield the titled compound (400 mg, 61%) as a colorless oil. *H NMR was performed at 400MHz with CDClj as solvent to characterize the titled compound, results are as follows: δ = 7.65 (s, 2 H), 7.19 (s, 1 H), 4.35 (t, J= 6.4 Hz, 2 H), 3.73 (s, 2 H), 2.36 (s, 6 H), 1.90 - 1.83 (m, 2 H), 1.77 - 1.70 (m, 2 H).

[00197] Compound 19: 4-(3,5-dimethylbenzoyloxy)butanoic acid

O

<img file="CA2999367C_D0084.tif" />

[00198] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 3,5-dimethylbenzoate (400 mg, 1.8 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (300 mg, 70%) as a white solid. *Η NMR was performed at 400MHz with CDClj as solvent to characterize the titled compound, results are

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Example 1-20

[00199] Intermediate Compound 20 4-hydroxybutyl cinnamate

<img file="CA2999367C_D0085.tif" />

[00200] A solution of cinnamoyl chloride (664 mg. 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-l,4-diol (450 mg, 5 mmol ) and EtsN (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SÛ4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (455 mg, 52%) as a colorless oil. 'H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.69 (d, J= 16.0 Hz, 1 H), 7.54 - 7.52 (m, 2 H), 7.39 (t, J= 3.2 Hz, 3 H), 6.44 (d, J = 16.0 Hz, 1 H), 4.25 (t, J = 6.4 Hz, 2 H), 3.72 (t, J = 6.2 Hz, 2 H), 1.85 1.78 (m, 2 H), 1.73 - 1.66 (m, 2 H), 1.44 (br. s., 1 H).

[00201] Compound 20: (E)-4-(cinnamoyloxy)butanoic acid

<img file="CA2999367C_D0086.tif" />

[00202] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl cinnamate (400 mg, 1.81 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 3:1 to yield the titled compound (370 mg, 87%) as colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ

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Example 1-21

[00203] Intermediate Compound 21 4-hydroxybutyl 3-phenylpropanoate

<img file="CA2999367C_D0087.tif" />

[00204] A solution of 3-phenylpropanoyl chloride (672 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and Et.^N (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H2O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na2SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (370 mg, 42%) as a colorless oil.

NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.31 - 7.27 (m, 2 H), 7.21 - 7.19 (m, 3 H), 4.10 (ζ J= 6.6 Hz, 2 H), 3.65 (t, J= 6.4 Hz, 2 H), 2.95 (t, J= 7.8 Hz, 2 H), 2.63 (ζ J= 7.6 Hz, 2 H), 1.73 - 1.66 (m, 2 H), 1.60- 1.54 (m, 2 H), 1.33 (br. s., 1 H).

[00205] Compound 21: 4-(3-phenylpropanoyloxy)butanoic acid

<img file="CA2999367C_D0088.tif" />

[00206] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 3phenylpropanoate (300 mg, 1.35 mmol) and Celite (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of z’PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 3:1 to yield the titled compound (277 mg, 87%) as colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ

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Example 1-22

[00207] Intermediate Compound 22 4-hydroxybutylpivalate ο ^ΟΗ

[00208] A solution of pivaloyl chloride (1.2 g, 10 mmol) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (2.7 g, 30 mmol ) and Et₃N (2.02 g, 20 mmol) in DCM (30 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 ~ 25 °C over 1 h. After that, the reaction mixture was diluted with H₂O (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (15 mL). The combined organic phase was washed with brine (15 mL), dried over Na₂SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 20:1 -5:1 to yield the titled compound (1.5 g, 86%) as a colorless oil. ’H NMR was performed at 400MHz with CDCl₃as solvent to characterize the titled compound, results are as follows: δ = 4.09 (t, J = 6.0 Hz, 2 H), 3.68 (t, J =6.4 Hz, 2 H), 1.74 - 1.70 (m, 2 H), 1.65-1.61 (m,2H), 1.19(s,9H).

[00209] Compound 22: 4-(pivaloyloxy)butanoic acid

<img file="CA2999367C_D0089.tif" />

[00210] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl pivalate (10 g, 5.75 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (20 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (20 mL) and then filtered. The filtered cake was washed with EA (10 mL) and the combined filtrate was washed with brine (5 mL x 2), dried over Na₂SÛ4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (700 mg, 65%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCL as solvent to characterize the titled compound, results are as follows: δ = 4.11 (t, J = 6.4 Hz, 2 H), 2.46 (ζ J= 7.4 Hz, 2 H), 2.02-1.95 (m, 2 H), 1.19 (s, 9H).

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Example 1-23 [00211] Intermediate Compound23’: 4-hydroxybutyl2-ethylbutanoate

<img file="CA2999367C_D0090.tif" />

[00212] A solution of 2-ethylbutanoyl chloride (500 mg, 3.7 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-l,4-diol (669 mg, 7.43 mmol ) and Et₃N (750 mg, 7.43 mmol) in DCM (10 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 3 h. After that, the reaction mixture was diluted with H2O (5 mL) and stinted for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous NazSO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 6:1 to yield the titled compound (450 mg, 65%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.13 (t, J = 6.4 Hz, 2 H), 3.73 - 3.64 (m, 2 H), 2.23 - 2.16 (m, 1 H), 1.77 - 1.70 (m, 2 H), 1.68 - 1.58 (m, 4 H), 1.55 - 1.46 (m, 2 H), 0.89 (t, J = 7.4 Hz, 6 H)

[00213] Compound 23:4-(2-ethylbutanoyloxy)butanoic acid

S’ 0

<img file="CA2999367C_D0091.tif" />

o

[00214] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 2ethylbutanoate (450 mg, 2.39 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (300 mg, 62%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.14 (t, J= 6.2 Hz, 2 H), 2.46 (t, J= 7.6 Hz, 2 H), 2.24 - 2.17 (m, 1 H), 2.02 1.95 (m, 2 Η), 1.66 - 1.46 (m, 4 H), 0.89 (t, J = 7.4 Hz, 6 H).

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Example 1-24

[00215] Intermediate Compound24’: 4-hydroxybutyl 2-propylpentanoate

[00216] A solution of 2-propylpentanoyl chloride (1 g, 6.13 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-l,4-diol (1107 mg, 12.3 mmol ) and Et₃N (1242 mg, 12.3 mmol) in DCM (10 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 16 h After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (700 mg, 53%) as a colorless oil. *H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 4.11 (t, J= 6.6 Hz, 2 H), 3.69 (q, J= 5.8 Hz, 2 H), 2.39 - 2.32 (m, 1 Η), 1.77 - 1.69 (m, 2 H), 1.68 - 1.60 (m, 3 H), 1.58 - 1.53 (m, 1 H), 1.45 1.36 (m, 3 Η), 1.33 - 1.24 (m, 4 H), 0.89 (t, J= 7.2 Hz, 6 H).

[00217] Compound 24:4-(2-propylpentanoyloxy)butanoie acid

<img file="CA2999367C_D0092.tif" />

O

[00218] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 2propylpentanoate (500 mg, 2.31 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of z’PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SÛ4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (160 mg, 30%) as a colorless oil. *H NMR was performed at 400MHz with CDCI₃ as solvent to characterize the titled compound, results are as follows: δ = 4 12 (t, J= 6.0 Hz, 2 H), 2.46 (t, J= 7.6 Hz, 2 H), 2 41 - 2 31 (m, 1 H), 2.01

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1.95 (m, 2 H), 1.63 - 1.54 (m, 2 H), 1.45 - 1.37 (m, 2 H), 1.33 - 1.24 (m, 4 H), 0.89 (t, J = Ί.2

Hz, 6 H)

Example 1-25 [00219] Intermediate Compound 25 4-hydroxybutyl cyclopentanecarboxylate

<img file="CA2999367C_D0093.tif" />

[00220] A solution of cyclopentanecarbonyl chloride (528 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and Et^N (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stinred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na?SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (520 mg, 70%) as a colorless oil. NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.10 (t, J- 6.4 Hz, 2 H), 3.68 (t, J- 6.0 Hz, 2 H), 2.76 - 2.68 (m, 1 H), 1.92 -1.62 (m, 10 H), 1.60 - 1.53 (m, 2 H), 1.41 (br. s„ 1 H).

[00221] Compound 25: 4-(cyclopentanecarbonyloxy)butanoic acid

O

<img file="CA2999367C_D0094.tif" />

[00222] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl cyclopentanecarboxylate (450 mg, 2.42 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 3:1 to yield the titled compound (373 mg, 77%) as colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.12 (t, J = 6.2 Hz, 2 Η), 2.76 - 2.68 (m, 1 H), 2.45 (t, J = 7.2 Hz, 2 H), 2.01 - 1.94 (m, 2 H), 1.92 - 1.84 (m, 2 H), 1.82 - 1.65 (m, 4 H), 1.61 - 1.50 (m, 2 H).

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Example 1-26 [00223] Intermediate Compound26’: 4-hydroxybutyl cyclohexanecarboxylate

<img file="CA2999367C_D0095.tif" />

[00224] A solution of cyclohexanecarbonyl chloride (584 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and Et₃N (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H2O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na2SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-3:1 to yield the titled compound (440 mg, 55%) as a colorless oil. *H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 4.08 (ζ 6.2 Hz, 2 H), 3.66 (t, J= 6.2 Hz, 2 H), 2.32 - 2.24 (m, 1 H), 1.88 (d,J= 13.2 Hz, 2 H), 1.76 - 1.58 (m, 8 H), 1.48 - 1.37 (m, 2 H), 1.31 - 1.15 (m, 3 H).

[00225] Compound 26:4-(cyclohexanecarbonyloxy)butanoic acid

<img file="CA2999367C_D0096.tif" />

[00226] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl cyclohexanecarboxylate (400 mg, 2 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 ^CC for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 3:1 to yield the titled compound (350 mg, 82%) as colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.11 (t, J = 6.4 Hz, 2 H), 2.45 (t, J = 7.4 Hz, 2 H), 2.29 (tt, J = 3.6, 11.3 Hz, 1 H), 2.01 1.94 (m, 2 H), 1.91 - 1.87 (m, 2 H), 1.76 - 1.69 (m, 2 H), 1.65 - 1.62 (m, 1 H), 1.48 - 1.38 (m, 2H), 1.33 - 1.19 (m, 3 H).

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Example 1-27

[00227J Intermediate Compound27’: 4-hydroxybutyl 2-acetoxyacetate

O \ .0, A /\.OH

Y Q o

[00228] A solution of 2-chloro-2-oxoethyl acetate (544 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and EtjN (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL) The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica ge! flash column with Hex/EA = 8:1-5:1 to yield the titled compound (500 mg, 66%) as a colorless oil *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: 5 = 4.60 (s, 2 H), 4.22 (t, J= 6.4 Hz, 2 H), 3.68 (dd, J= 5.8, 10.6 Hz, 2 H), 2.16 (s, 3 H), 1.81 - 1.72 (m, 2 H), 1.68 - 1.60 (m, 2 Η), 1.39 (br. s., 1 H).

[00229] Compound 27: 4-(2-acetoxyacetoxy)butanoic acid O \ .OH

H 0 y 0 0

[00230] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 2acetoxyacetate (400 mg 2.11 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 8:1-3:1 to yield the titled compound (370 mg, 86%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.60 (s, 2 H), 4.24 (t, J = 6.2 Hz, 2 H), 2.46 (t, J = 7.4 Hz, 2 H), 2.16 (s, 3 H), 2.04 - 1.97 (m, 2 H).

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Example 1-28

[00231] Intermediate Compound28’: ethyl (4-hydroxybutyl) carbonate

<img file="CA2999367C_D0097.tif" />

[00232] A solution of ethyl carbonochloridate (1 g, 9.17 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (1659 mg, 18.43 mmol ) and EtjN (1861 mg, 18.43 mmol) in DCM (10 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 16 h. After that, the reaction mixture was diluted with H2O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na2SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (700 mg, 47%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.22 - 4.16 (m, 4 H), 3.68 (q, J = 5.8 Hz, 2 H), 1.81 - 1.74 (m, 2 Η), 1.69 - 1.62 (m, 2 Η), 1.38 (t,./ = 5.0 Hz, 1 Η), 1.31 (t, J = 7.0 Hz, 3 H).

[00233] Compound 28: 4-(ethoxycarbonyloxy)butanoic acid

O

<img file="CA2999367C_D0098.tif" />

O

[00234] Jones reagent was added in portions to a stirred mixture of ethyl (4hydroxybutyl) carbonate (500 mg, 3.09 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (70 mg, 13%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: 5 = 4.22 - 4.17 (m, 4 H), 2.50 (t, J= 7.2 Hz, 2 H), 2.05 - 1.98 (m, 2 H), 1.31 (t, J =7.2 Hz, 3 H).

Example 1-29

[00235] Intermediate Compound 29 4-hydroxybutyl isopropyl carbonate

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<img file="CA2999367C_D0099.tif" />

<img file="CA2999367C_D0100.tif" />

[00236] A solution of isopropyl carbonochloridate (10 ml, 1.0 M/L, 10 mmol) in DCM (10 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (1800 mg, 20 mmol ) and Et₃N (2020 mg, 20 mmol) in DCM (20 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 16 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (1.58 g, 90%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.90 - 4.84 (m, 1 H), 4.16 (t, J = 6.6 Hz, 2 H), 3.68 (t, J = 6.2 Hz, 2 H), 1.80 - 1.73 (m, 2 H), 1.69 - 1.62 (m, 2 H), 1.29 (d, 5.6 Hz, 6 H).

[00237] Compound 29:4-(isopropoxycarbonyloxy)butanoic acid I ⁰u ~ r

O

[00238] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl isopropyl carbonate (800 mg, 4.55 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO4and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (260 mg, 30%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.90 - 4.84 (m, 1 H), 4.18 (t, J = 6.2 Hz, 2 H), 2.50 (t, J= 7.2 Hz, 2 H), 2.05 1.97 (m, 2 H), 1.30 (d, J = 6.0 Hz, 6 H).

Example 1-30

[00239] Intermediate Compound30’: 4-hydroxybutyl isobutyl carbonate

<img file="CA2999367C_D0101.tif" />

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[00240] A solution of isobutyl carbonochloridate (544 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and Et₃N (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H2O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-6:1 to yield the titled compound (250 mg, 33%) as a colorless oil. *H NMR was performed at 400MHz with CDCh as solvent to characterize the titled compound, results are as follows: δ = 4 18 (t, J= 6.4 Hz, 2 H), 3.91 (d, J = 6.8 Hz, 2 H), 3.69 (dd, J= 5.4, 11.0 Hz, 2 H), 1.81 - 1.75 (m, 3 H), 1.70 - 1.62 (m, 2 H), 0.96 (s, 3 H), 0.94 (s, 3 H).

[00241] Compound 30: 4-(isobutoxycarbonyloxy)butanoic acid

I 0

[00242] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl isobutyl carbonate (200 mg, 1.1 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous NazSCUand concentrated. The residue was purified by a silica gel flash column with Hex/EA = 8:1-3:1 to yield the titled compound (110 mg, 51%) as a colorless oil. *H NMR was performed at 400MHz with CDCh as solvent to characterize the titled compound, results are as follows: δ = 4.20 (t, J= 6.4 Hz, 2 H), 3.92 (d, J~ 6.8 Hz, 2 H), 2.49 (t, 7.2 Hz, 2 H),

2.06 - 1.93 (m, 3 H), 0.96 (s, 3 H), 0.94 (s, 3 H).

Example 1-31

[00243] Intermediate Compound 31 ’: benzyl (4-hydroxybutyl) carbonate

<img file="CA2999367C_D0102.tif" />

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[00244] A solution of benzyl carbonochloridate (1 g, 5.86 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane- 1,4-diol (1055 mg, 11.72 mmol ) and Et₃N (1184 mg, 11.72 mmol) in DCM (10 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 3 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 7:1 to yield the titled compound (292 mg, 22%) as a colorless oil. ’H NMR was performed at 400MHz with CDCL as solvent to characterize the titled compound, results are as follows: δ = 7.40 - 7.32 (m, 5 H), 5.16 (s, 2 H), 4.20 (t, J= 6.6 Hz, 2 H), 3.68 (q, J= 6.0 Hz, 2 H), 1.81 - 1.74 (m, 2 H), 1.68 - 1.62 (m, 2 H), 1.29 (t, J= 5.4 Hz, 1 H).

[00245] Compound 31:4-(benzyloxycarbonyloxy)butanoic acid o

<img file="CA2999367C_D0103.tif" />

[00246] Jones reagent was added in portions to a stinred mixture of benzyl (4hydroxybutyl) carbonate (290 mg, 1.29 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SÛ4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (188 mg, 61%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.38 - 7.33 (m, 5 H), 5.16 (s, 2 H), 4.21 (t, J= 6.2 Hz, 2 H), 2.47 (t, J= 1.2 Hz, 2 H), 2.03 - 1.97 (m, 2 H).

Example 1-32

[00247] Intermediate Compound 32 4-hydroxybutylphenyl carbonate

<img file="CA2999367C_D0104.tif" />

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[00248] A solution of phenyl carbonochloridate (624 mg, 4 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (450 mg, 5 mmol ) and Et₃N (505 mg, 5 mmol) in DCM (5 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C for over 1 h. After that, the reaction mixture was diluted with H2O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (333 mg, 40%) as a colorless oil. *H NMR was performed at 400MHz with CDCh as solvent to characterize the titled compound, results are as follows: δ = 7.39 (t, J= 7.8 Hz, 2 H), 7.26 - 7 23 (m, 1 H), 7.18 (d, J= 8.0 Hz, 2 H), 4.30 (t, J = 6.6 Hz, 2 H), 3.72 (dd, J = 6.2, 11.2 Hz, 2 H), 1.89 - 1.82 (m, 2 H), 1.75 - 1.68 (m, 2 H), 1.35 (t, J= 5.2 Hz, 1 H).

[00249] Compound 32:4-(phenoxycarbonyloxy)butanoic acid

<img file="CA2999367C_D0105.tif" />

[00250] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl phenyl carbonate (300 mg, 1.55 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-2:1 to yield the titled compound (210 mg, 65%) as a white solid. *11 NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.39 (t, J = 8.0 Hz, 2 H), 7.25 (t, J = 7.2 Ηζ,Ι H), 7.18 (d, J = 8.0 Hz, 2 H), 4.32 (t, J= 6.2 Hz, 2 H), 2.55 (t, ΊΑ Hz, 2 H), 2.13 - 2.06 (m, 2 H).

Example 1-33

[00251] Intermediate Compound 33 4-chlorophenyl (4-hydroxybutyl) carbonate

<img file="CA2999367C_D0106.tif" />

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[00252] A solution of 4-chlorophenyl carbonochloridate (500 mg, 2.62 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane- 1,4-diol (707 mg, 7.86 mmol ) and Et₃N (529 mg, 5.24 mmol) in DCM (10 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 16 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 6:1 to yield the titled compound (420 mg, 66%) as a colorless oil. *H NMR was performed at 400MHz with CDCL as solvent to characterize the titled compound, results are as follows: δ = 7.35 (d, J = 9.2 Hz, 2 H), 7.13 (d, J = 9.2 Hz, 2 H), 4.30 (t, J= 6.4 Hz, 2 H), 3.72 (t, J= 6.2 Hz, 2 H), 1.89 - 1.82 (m, 2 H), 1.74 - 1.67 (m, 2 H).

[00253] Compound 33:4-((4-chlorophenoxy)carbonyloxy)butanoic acid o

<img file="CA2999367C_D0107.tif" />

[00254] Jones reagent was added in portions to a stirred mixture of 4-chlorophenyl (4hydroxybutyl) carbonate (400 mg, 1.64 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (220 mg, 52%) as a white solid. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.35 (d, J = 9.2 Hz, 2 H), 7.13 (d, J = 8.8 Hz, 2 H), 4.32 (t, J = 6.2 Hz, 2 H), 2.55 (t, J= 7.4 Hz, 2 H), 2.13 - 2.06 (m, 2 H).

Example 1-34

[00255] Intermediate Compound34’: 4-hydroxybutylp-tolyl carbonate

<img file="CA2999367C_D0108.tif" />

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[00256] A solution of p-tolyl carbonochloridate (500 mg, 2.94 mmol) in DCM (5 mL) was added dropwise during 10 min to a stirred solution of butane-1,4-diol (794 mg, 8.82 mmol ) and Et₃N (594 mg, 5.88 mmol) in DCM (10 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 16 h. After that, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 6:1 to yield the titled compound (600 mg, 91%) as a colorless oil. *H NMR was performed at 400MHz with CDCL as solvent to characterize the titled compound, results are as follows: δ = 7.17 (d, J = 8.4 Hz, 2 H), 7.05 (d, J = 8.4 Hz, 2 H), 4.29 (t, J = 6.8 Hz, 2 H), 3.72 (t, J = 6.2 Hz, 2 H), 2.34 (s, 3 H), 1.89- 1.82 (m, 2 H), 1.74 -1.67 (m, 2 H).

[00257] Compound 34:4-(p-tolyloxycarbonyloxy)butanoic acid o

<img file="CA2999367C_D0109.tif" />

[00258] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl ptolyl carbonate (500 mg, 2.23 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SÛ4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (170 mg, 32%) as a white solid. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: Ô = 7.17 (d, J = 8.4 Hz, 2 H), 7.05 (d, J= 8.0 Hz, 2 H), 4.31 (t, J= 6.2 Hz, 2 H), 2.55 (t, J = 7.2 Hz, 2 H), 2.34 (s, 3 H), 2.12 - 2.07 (m, 2 H).

[00259] Scheme 2

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Ο

<img file="CA2999367C_D0110.tif" />

DCC, DMAP, DCM ) oxidation

2) HCI/EA (optionally)

<img file="CA2999367C_D0111.tif" />

Example 1-35

[00260] Intermediate Compound 35 *: 4-hydroxybutyl 4-butoxybenzoate

<img file="CA2999367C_D0112.tif" />

[00261] 4-butoxybenzoic acid (882 mg, 4.55 mmol), DCC (1030 mg, 5 mmol) and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (450 mg, 5 mmol) in DCM (15 mL). The reaction was stirred at 25 °C for 3 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (500 mg, 41%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.97 (d, J = 8.4 Hz, 2 H), 6.90 (d, J= 9.2 Hz, 2 H), 4.33 (t, J= 6.2 Hz, 2 H), 4.01 (t, J= 6.6 Hz, 2 H), 3.73 (t, J= 6.4 Hz, 2 H), 1.89 - 1.71 (m, 6 H), 1.61 (br. s., 1 H), 1.54 - 1.45 (m, 2 H), 0.98 (t, J= 7.2 Hz, 3 H).

[00262]

Compound 35: 4-(4-butoxybenzoyloxy)butanoic acid

<img file="CA2999367C_D0113.tif" />

[00263] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 4butoxybenzoate (450 mg, 1.69 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 ^ÔC for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of z’PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous NazSChand concentrated. The residue was purified by a silica gel flash column with Hex/EA

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1.53 - 1.46 (m, 2 H), 0.98 (t, J = 7.4 Hz, 3 H).

Example 1-36

[00264] Intermediate Compound36’: 4-hydroxybutyl 4-isopropylbenzoate

O

<img file="CA2999367C_D0114.tif" />

[00265] 4-isopropylbenzoic acid (745 mg, 4.54 mmol), DCC (1030 mg, 5 mmol) and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (450 mg, 5 mmol) in DCM (15 mL). The reaction was stirred at 25 °C for 3 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (400 mg, 37%) as a colorless oil. ’Η NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.96 (d, J= 8.0 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 4.35 (t, J= 6.4 Hz, 2 H), 3.76 - 3.69 (m, 2 H), 2.99 - 2.93 (m, 1 H), 1.90 1.83 (m, 2 H), 1.76 -1.69 (m, 2 H), 1.40 (br. s, 1 H), 1.27 (s, 3 H), 1.26 (s, 3 H).

[00266] Compound 36:4-(4-isopropylbenzoyloxy) butanoic acid

<img file="CA2999367C_D0115.tif" />

[00267] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 4isopropylbenzoate (350 mg, 1.48 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous

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Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (200 mg, 54%) as a colorless oil. ’H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: Ô = 7.95 (d, J = 8.0 Hz, 2 H), 7.29 (d, J = 8.4 Hz, 2 H), 4.37 (t, J = 6.2 Hz, 2 H), 2.99 - 2.92 (m, 1 H), 2.54 (t, J = ΊΑ Hz, 2 H), 2.15 - 2.08 (m, 2 H), 1.27 (s, 3 H), 1.25 (s, 3 H).

Example 1-37

[00268] Intermediate Compound 3 7’: 4-hydroxybutyl 3-(methylsulfonyl)benzoate

<img file="CA2999367C_D0116.tif" />

[00269] 3-(methylsulfonyl) benzoic acid (505 mg, 2.53 mmol), DCC (572 mg, 2 78 mmol) and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (250 mg, 2.78 mmol) in DCM (15 mL). The reaction was stirred at 25 °C for 3 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 2:1 to yield the titled compound (150 mg, 22%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.60 (s, 1 H), 8.33 (d, J = 8.0 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.69 (f J = 7.8 Hz, 1 H), 4.42 (t, J = 6.6 Hz, 2 H), 3.74 (q, J= 6.0 Hz, 2 H), 3.10 (s, 3 Η), 1.94 - 1.87 (m, 2 Η), 1.76 - 1.70 (m, 2 Η), 1.36 (t, J=5.0Hz, 1 H).

[00270] Compound37: 4-(3-(methylsulfonyl)benzoyloxy)butanoic acid

<img file="CA2999367C_D0117.tif" />

[00271] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 3(methylsulfonyl)benzoate (150 mg, 0.55 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of (PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over

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Example 1-38

[00272]

Intermediate Compound38': 4-hydroxybutyl nicotinate

<img file="CA2999367C_D0118.tif" />

[00273] Nicotinic acid (615 mg, 5 mmol), DCC (1133 mg, 5.5 mmol) and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (900 mg, 10 mmol) in DCM (15 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with saturated aqueous NH₄C1 (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 1:1 to yield the titled compound (450 mg, 46%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 9.22 (d, 1.6 Hz, 1 H), 8.78 (dd, J= 1.6,4.8 Hz,

H), 8.30 (td, 1.6, 8.0 Hz, 1 H), 7.40 (dd, J = 5.0, 7.8 Hz, 1 H), 4.41 (t, 6.6 Hz, 2 H),

3.74 (t, J= 6.2 Hz, 2 H), 1.93 - 1.86 (m, 2 H), 1.77 - 1.70 (m, 2 H), 1.46 (br. s„ 1 H).

[00274]

Compound 38:4-(nicotinoyloxy)butanoic acid

<img file="CA2999367C_D0119.tif" />

[00275] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl nicotinate (450 mg, 2.31 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄ and

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Example 1-39

[00276] Intemediate Compound 39 4-hydroxybutyl isonicotinate o

<img file="CA2999367C_D0120.tif" />

[00277] Isonicotinic acid (1.23 g, 10 mmol), DCC (2.27 g, 11 mmol) and DMAP (122 mg) was added to a stirred solution of butane-l,4-diol (2.7 g, 30 mmol) in DCM (30 mL). The reaction was stirred at 25 °C for 8 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (15 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-2:1 to yield the titled compound (1 g, 51%) as a pale yellow oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.76 (d, J= 8.4 Hz, 2 H), 7.84 (d, J = 5.6 Hz, 2 H), 4.39 (t, J= 6.4 Hz, 2 H), 3.72 (t, 6.2 Hz, 2 H), 1.92-1.85 (m, 2 H), 1.75-1.70 (m, 2 H).

[00278] Compound 39:4-(isonicotinoyloxy)butanoic acid

O

[00279] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl isonicotinate (900 mg, 4.62 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (30 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (50 mL) and then filtered. The filtered cake was washed with EA (50 mL) and the combined filtrate was washed with brine (5 mL x 2), dried over Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 2:1 to yield the titled compound (70 mg, 7%) as a white solid. ^!H NMR was performed at 400MHz with CDCI3 as solvent to

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Example 1-40

[00280] Intermediate Compound40’: 4-hydroxybutyl 3-methoxy-4-methylbenzoate

O

<img file="CA2999367C_D0121.tif" />

[00281] 3-methoxy-4-methylbenzoic acid (500 mg, 3 mmol), DCC (683 mg, 3.32 mmol) and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (542 mg, 6 mmol) in DCM (15 mL). The reaction was stirred at 25 °C for 3 h. After that, the reaction mixture was diluted with saturated aqueous NH₄CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (450 mg, 63%) as a colorless oil. 'H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.55 (d, J= 7.6 Hz, 1 H), 7.48 (s, 1 H), 7.18 (d, J= 8.0 Hz, 1 H), 4.36 (t, J= 6.4 Hz, 2 H), 3.88 (s, 3 H), 3.73 (t, J = 6.2 Hz, 2 H), 2.26 (s, 3 H), 1.91 - 1.84 (m, 2 H), 1.76 - 1.70 (m, 2 H).

[00282] Compound 40:4-(3-methoxy-4-methylbenzoyloxy)butanoic acid

<img file="CA2999367C_D0122.tif" />

[00283] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 3m et h oxy-4-me thy I benzoate (450 mg, 1.89 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 4:1 to yield the titled compound (280 mg, 59%) as crystalline solids.

NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.54 (d, J = 7.6 Hz, 1 H), 7.47 (s, 1 H), 7.18 (d, J = 7.6 Hz, 1 H),

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4.37 (t, J = 6.2 Hz, 2 H), 3.88 (s, 3 H), 2.54 (t, J = Ί A Hz, 2 H), 2.26 (s, 3 H), 2.15 - 2.09 (m,

H).

Example 1-41

[00284] Intermediate Compound 41 4-hydroxybutyl 2,6-dimethylbenzoate

<img file="CA2999367C_D0123.tif" />

[00285] 2,6-dimethylbenzoic acid (500 mg, 3.33 mmol), DCC (755 mg, 3.67 mmol) and DMAP (50 mg) was added to a stirred solution of butane-l,4-diol (600 mg, 6.67 mmol) in DCM (15 mL). The reaction was stirred at 25 °C for 3 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (100 mg, 14%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.18 (t,./ = 7.6 Hz, 1 H), 7.03 (d, J= 8.0 Hz, 2 H), 4.37 (t, J= 6.6 Hz, 2 H), 3.71 (t, J= 6.4 Hz, 2 H), 2.32 (s, 6 Η), 1.89 - 1.82 (m,2H), 1.74 - 1.67 (m, 2 H).

[00286] Compound 41:4-(2,6-dimethylbenzoyloxy)butanoic acid .OH o

[00287] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 2,6-dimethylbenzoate (100 mg, 0.45 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (50 mg, 47%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.19 (t, J = 7.4 Hz, 1 H), 7.03 (d, J= 7.6 Hz, 2 H), 4.39 (t, J= 6.4 Hz, 2 H), 2.52 (t, J= ΊΑ Hz, 2 H), 2.32 (s, 6 H), 2.13 - 2.07 (m, 2 H).

<img file="CA2999367C_D0124.tif" />

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Example 1-42

[00288] Intermediate Compound 42 *: 4-hydroxybutyl 2-phenoxybenzoate

O

<img file="CA2999367C_D0125.tif" />

[00289] 2-phenoxybenzoic acid (1070 mg, 5 mmol), DCC (1133 mg, 5.5 mmol) and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (900 mg, 10 mmol) in DCM (30 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 8:1 to yield the titled compound (700 mg, 49%) as a colorless oil. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.93 (dd, J = 1.6, 8.0 Hz, 1 H), 7.50 - 7.45 (m, 1 H), 7.32 (t, J = 7.8 Hz, 2 H), 7.21 (t, J = 7.6 Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 7.00 (d,J= 8 0 Hz, 1 H), 6 94 (d, 7.6 Hz, 2 H), 4.26 (t, J= 6.2 Hz, 2 H), 3.58 (s, 2 H),

1.72 - 1.65 (m, 2 Η), 1.58 - 1.51 (m, 2 H).

[00290] Compound 42:4-(2-phenoxybenzoyloxy)butanoic acid

<img file="CA2999367C_D0126.tif" />

[00291] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 2phenoxybenzoate (700 mg, 2.45 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (400 mg, 54%) as a white solid. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: Ô = 7.92 (dd, J= 1.6, 7.6 Hz, 1 H), 7.50 - 7.46 (m, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.20 (t, J =

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7.6 Hz, 1 H), 7.07 (t, J= 7.4 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 2 H), 4.27 (t, J= 6.2 Hz, 2 H), 2.36 (t, J= 1.2 Hz, 2 H), 1.96 - 1.90 (m, 2 H).

Example 1-43

[00292] Intermediate Compound 43 V 4-hydroxybutyl 2,4-dimethylbenzoate

O

<img file="CA2999367C_D0127.tif" />

[00293] 2,4-dimethylbenzoic acid (750 mg, 5 mmol), DCC (1133 mg, 5.5 mmo!) and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (900 mg, 10 mmol) in DCM (30 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 8:1 to yield the titled compound (700 mg, 63%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.82 (d, J = 1.6 Hz, 1 H), 7.05 7.03 (m, 2 H), 4.32 (t, J= 6.6 Hz, 2 H), 3 73 (s, 2 H), 2.57 (s, 3 H), 2.35 (s, 3 H), 1.89 - 1.82 (m,2H), 1.76- 1.69 (m, 2 H).

[00294] Compound 43:4-(2,4-dimethylbenzoyloxy)butanoic acid

O

<img file="CA2999367C_D0128.tif" />

[00295] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 2,4-dimethylbenzoate (700 mg, 3.15 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the tided compound (550 mg, 74%) as a white solid. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: ô = 7.82 (d, J= 7.6 Hz, 1 H), 7.05 - 7.03 (m, 2 H), 4.34 (t, J= 6.2 Hz, 2 H), 2.57 (s, 3 H), 2.54 (t, J = 7.4 Hz, 2 H), 2.35 (s, 3 H), 2.14 - 2.08 (m, 2 H).

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Example 1-44

[00296] Intermediate Compound 44’: 4-hydroxybutyl 2,3-dimethoxybenzoate

<img file="CA2999367C_D0129.tif" />

[00297] 2,3-dimethoxybenzoic acid (910 mg, 5 mmol), DCC (1133 mg, 5.5 mmol) and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (900 mg, 10 mmol) in DCM (30 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 8:1 to yield the titled compound (600 mg, 47%) as a colorless oil. ‘H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.32 (dd, J = 1.6, 7.2 Hz, 1 H), 7.11 - 7.04 (m, 2 H), 4.36 (t, J = 6 4 Hz, 2 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3 74 - 3.70 (m, 2 H), 1.90 - 1.84 (m, 2 Η), 1.77 - 1.70 (m, 2 H), 1.40 (t, 4.8 Hz, 1 H).

[00298] Compound 44: 4-(2,3-dimethoxybenzoyloxy)butanoic acid

<img file="CA2999367C_D0130.tif" />

[00299] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl

23-dimethoxybenzoate (600 mg, 2.36 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (250 mg, 39%) as a white solid. *H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 7.31 (dd, J = 2.0, 7.2 Hz, 1 H), 7.11 - 7.05 (m, 2 H), 4.38 (t, J= 6.2 Hz, 2

H), 3.91 (s, 3 H), 3.89 (s, 3 H), 2.57 (t, J = ΊΑ Hz, 2 H), 2.15 - 2.08 (m, 2 H).

Example 1-45

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[00300] Intermediate Compound45’: 4-hydroxybutyl 4-isopropoxybenzoate

O

<img file="CA2999367C_D0131.tif" />

[00301] 4-isopropoxybenzoic acid (900 mg, 5 mmol), DCC (1133 mg, 5.5 mmol) and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (900 mg, 10 mmol) in DCM (30 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 6:1 to yield the titled compound (800 mg, 63%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.97 (d, 8.8 Hz, 2 H), 6.88 (d,

J = 9.2 Hz, 2 H), 4.66 - 4.60 (m, 1 H), 4.33 (t, J = 6.4 Hz, 2 H), 3.73 (q, J = 6.0 Hz, 2 H), 1.89 - 1.82 (m, 2 H), 1.76 - 1.69 (m, 2 H), 1.37 (s, 3 H), 1.35 (s, 3 H).

[00302] Compound 45: 4-(4-isopropoxybenzoyloxy)butanoic acid

O

<img file="CA2999367C_D0132.tif" />

[00303] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 4isopropoxybenzoate (800 mg, 3.17 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (380 mg, 45%) as a colorless oil. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.96 (d, J= 8.8 Hz, 2 H), 6.88 (d, J= 8.8 Hz, 2 H), 4.66 - 4.60 (m, 1 H), 4.35 (t, J= 6.2 Hz, 2 H), 2.54 (t, ./= 7.2 Hz, 2 H), 2.15 - 2.08 (m, 2 H), 1.37 (s, 3 H), 1.35 (s, 3 H).

Example 1-46

[00304] Intermediate Compound 46’: 4-hydroxybutyl 2-ethylbenzoate

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Ο

<img file="CA2999367C_D0133.tif" />

[00305] 2,6-dimethylbenzoic acid (500 mg, 3.33 mmol), DCC (755 mg, 3.67 mmol) and DMAP (50 mg) was added to a stirred solution of butane-l,4-diol (600 mg, 6.67 mmol) in DCM (30 mL). The reaction was stirred at 25 °C for 3 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 8:1 to yield the titled compound (480 mg, 65%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.84 (d, J= 8.0 Hz, 1 H), 7.43 (t,

ΊΑ Hz, 1 H), 7.28 - 7.22 (m, 2 H), 4.34 (t, J= 6.6 Hz, 2 H), 3.73 (t, J= 6 0 Hz, 2 H), 2.98 (q, J= 7.6 Hz, 2 H), 1.91 - 1.84 (m,2H), 1.77 - 1 70(m, 2H), 1.24 (t, J = 7.4Hz, 3 H).

[00306] Compound 46:4-(2-ethylbenzoyloxy)butanoic acid o

<img file="CA2999367C_D0134.tif" />

[00307] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 2ethylbenzoate (480 mg, 2.16 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 6:1 to yield the titled compound (290 mg, 57%) as a white solid. NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.84 (d, J= 8.0 Hz, 1 H), 7.43 (d, J= 7.2 Hz, 1 H), 7.29 - 7.22 (m, 2 H), 4.36 (t, J= 6.2 Hz, 2 H), 2.98 (q, J= 7.6 Hz, 2 H), 2.55 (t, J= 7.2 Hz, 2 H), 2.15 - 2.08 (m, 2 Η), 1.24 (t, J= 7.6 Hz, 3 H).

Example 1-47

[00308] Intermediate Compound 47’: 4-hydroxybutyl 4-benzoylbenzoate

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Ο

<img file="CA2999367C_D0135.tif" />

Ο

[00309] 4-benzoylbenzoic acid (500 mg, 2.21 mmol), DCC (501 mg, 2.44 mmol) and DMAP (5 mg) was added to a stirred solution of butane-1,4-diol (398 mg, 4.42 mmol) in DCM (30 mL). The reaction was stirred at 25 °C for 3 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 6:1 to yield the titled compound (400 mg, 61%) as a white solid. ’H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 8.15 (d, J = 8.4 Hz, 2 H), 7.85 7.80 (m, 4 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.50 (t, J= 7.6 Hz, 2 H), 4.41 (t, J= 6.4 Hz, 2 H), 3.75 (t, J =6.4 Hz, 2 H), 1.94 - 1.87 (m, 2 H), 1.79 - 1.72 (m, 2 H).

[00310] Compound 47: 4-(4-benzoylbenzoyloxy)butanoic acid

O

<img file="CA2999367C_D0136.tif" />

O

[00311] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 4benzoylbenzoate (400 mg, 1.34 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (280 mg, 67%) as a white solid. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: Ô = 8.14 (d, J = 8.4 Hz, 2 H), 7.85 - 7.80 (m, 4 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.50 (ζ J = 7.6 Hz, 2 H), 4.44 (t, J= 6.2 Hz, 2 H), 2.57 (t, J = Ί2 Hz, 2 H), 2.19 - 2.12 (m, 2 H).

Example 1-48

[00312] Intemediate Compound 48’: 4-hydroxybutyl methyl phthalate

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Ο

<img file="CA2999367C_D0137.tif" />

Ο

[00313] 2-(methoxycarbonyl)benzoic acid (900 mg, 5 mmol), DCC (1.13 g, 5.5 mmol) and DMAP (60 mg) was added to a stirred solution of butane-1,4-diol (1.35 g, 15 mmol) in DCM (30 mL). The reaction was stirred at 25 °C for 3 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (15 mL). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-2:1 to yield the titled compound (1 g, 79%) as a colorless oil. ^]H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.72 - 7.68 (m, 2 H), 7.55 - 7.51 (m, 2 H), 4.34 (t, J = 6.6 Hz, 2 H), 3.89 (s, 3H), 3.68 (t, J= 6.4 Hz, 2 H), 1.83 - 1.77 (m, 3 H), 1.70 - 1.65 (m, 2 H).

[00314] Compound 48: 4-(2-(methoxycarbonyl)benzoyloxy)butanoic acid

O

<img file="CA2999367C_D0138.tif" />

[00315] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl methyl phthalate (900 mg, 3.57 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (20 mL) at 0 °C The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (10 mL) and the combined filtrate was washed with brine (3 mL x 2), dried over Na₂SO4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-1:1 to yield the titled compound (800 mg, 84%) as a colorless oil. NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.74 - 7.70 (m, 2 H), 7.55 - 7.53 (m, 2 H), 4.37 (t, J = 6.2 Hz, 2 H), 3.91 (s, 3 H), 2.51 (t, J = 7.2 Hz, 2 H), 2.10 - 2.03 (m, 2 H).

Example 1-49

[00316] Intemediate Compound49’: 4-hydroxybutyl methyl terephthalate

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Ο

<img file="CA2999367C_D0139.tif" />

Ο

[00317] 4-(methoxycarbonyl)benzoic acid (1 g, 5.56 mmol), DCC (1258 mg, 6.11 mmol) and DMAP (10 mg) was added to a stirred solution of butane-1,4-diol (1.5 g, 16.67 mmol) in DCM (20 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with brine (10 mL), dried over Na₂SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 7:1 to yield the titled compound (750 mg, 54%) as crystalline solids. *Η NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.10 (s, 4 H), 4.39 (t, J = 6.6 Hz, 2 H), 3.95 (s, 3 H), 3.74 (t, J = 6.4 Hz, 2 H), 1.92 - 1.87 (m, 2 H), 1.77 - 1 72 (m, 2 H).

[00318] Compound 49: 4-(4-(methoxycarbonyl)benzoyloxy)butanoic acid o

<img file="CA2999367C_D0140.tif" />

[00319] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl methyl terephthalate (700 mg, 2.78 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of z’PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with brine (2 mL x 2), dried over Na₂SO4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 7:1 to yield the titled compound (400 mg, 54%) as crystalline solids. NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: Ô = 8.09 (s, 4 H), 4.41 (t, J = 6.2 Hz, 2 H), 3.95 (s, 3 H), 2.55 (t, J= 7.2 Hz, 2 H), 2.18 - 2.11 (m, 2 H).

Example 1-50

[00320] Intermediate Compound 50’: 4-hydroxybutyl (²Hs)benzoate

D O

<img file="CA2999367C_D0141.tif" />

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[00321] (¾) benzoic acid (300 mg 2.36 mmol), DCC (535 mg 2.6 mmol) and

DMAP (10 mg) was added to a stirred solution of butane-l,4-diol (425 mg, 4.72 mmol) in DCM (20 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na2SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (320 mg, 68%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.37 (t, J = 6.4 Hz, 2 H), 3.74 (t, J= 6.4Hz, 1 H), 1.91 - 1.84(m, 2H), 1.78-1.71 (m,2H).

[00322] Compound 50:4-((²Hs)phenylcarbonyloxy)butanoic acid

D O

<img file="CA2999367C_D0142.tif" />

D

[00323] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl ( Hs)benzoate (300 mg, 1.51 mmol) and Celite (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (220 mg, 69%) as a white solid. 'H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.39 (t, 6.2 Hz, 2 H), 2.56 (t, J= 7.4 Hz, 2 H), 2.17 - 2.10 (m, 2 H).

Example 1-51

[00324] Intermediate Compound 51 ’: 4-hydroxybutyl thiazole-2-carboxylate

<img file="CA2999367C_D0143.tif" />

[00325] Thiazole-2-carboxylic acid (500 mg, 3.88 mmol), DCC (879 mg, 4.27 mmol) and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (1.05 g, 11.66 mmol) in DCM (10 mL). The reaction was stirred at 25 °C for 8 h. After that, the reaction mixture

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[00326] Compound 51:4-(thiazole-2-carbonyloxy)butanoic acid

<img file="CA2999367C_D0144.tif" />

[00327] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl thiazole-2-carboxylate (300 mg, 1.49 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with brine (2 mL x 2), dried over Na?SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1 - 1:1 to yield the titled compound (200 mg, 62%) as ciystalline solids. ^]H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.06 (d, J= 2.8 Hz, 1 H), 7.67 (d, J= 3.2 Hz, 1 H), 4.49 (t, J = 6.2 Hz, 2 H), 2.58 (t, J= 7.2 Hz, 2 H), 2.19 - 2.12 (m, 2 H).

Example 1-52

[00328] Intermediate Compound 52 ’: 4-hydroxybutylfuran-3-carboxylate

<img file="CA2999367C_D0145.tif" />

[00329] Furan-3-carboxylic acid (224 mg, 2 mmol), DCC (453 mg, 2.2 mmol) and DMAP (24 mg) was added to a stirred solution of butane-1,4-diol (540 mg, 6 mmol) in DCM (10 mL). The reaction was stirred at 25 °C for 12 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with

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PCT/CN2016/099763 brine (10 mL), dried over Na2SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (270 mg, 73%) as a pale yellow oil. *Η NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.00 (s, 1 H), 7.42 (s, 1 H), 6.73 (s, 1 H), 4.28 (t, J = 6.4 Hz, 2 H), 3.70 (t, J = 6.4 Hz, 2 H), 1.83-1.67 (m, 4 H).

[00330] Compound 52: 4-(furan-3-carbonyloxy)butanoic acid

<img file="CA2999367C_D0146.tif" />

[00331] Jones reagent in portions was added to a stirred mixture of 4-hydroxybutyl furan-3-carboxylate (750 mg, 4.09 mmol) and Celite (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with brine (2 mL x 2), dried over Na2SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 3:1 to yield the titled compound (600 mg, 74%) as crystalline solids. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.01 (s, 1 H), 7.42 (s, 1 H), 6.73 (s, 1 H), 4.31 (t, J = 6.2 Hz, 2 H), 2.51 (t, J = 7.4 Hz, 2 H), 2.12 - 2.05 (m, 2H).

Example 1-53

[00332] Intermediate Compound 53 ’: 4-hydroxybutyl thiophene-3-carboxylate

O

<img file="CA2999367C_D0147.tif" />

[00333] Thiophene-3-carboxylic acid (1 g, 7.81 mmol), DCC (1.77 g, 8.59 mmol) and

DMAP (10 mg) was added to a stirred solution of butane-l,4-diol (2.1 g, 23.33 mmol) in DCM (50 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 7:1 to afford the crude product, which was further purified by prep-TLC with Hex/EA = 1:1 to yield the pure titled compound (600 mg, 38%) as

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PCT/CN2016/099763 crystalline solids. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.10 (d, J= 2.0 Hz, 1 H), 7.53 (d, J= 5.2 Hz, 1 H), 7.31 (dd, J= 3.2, 5.2 Hz, 1 H), 4.32 (t, J= 6.4 Hz, 2 H), 3.73 (t, J= 6.4 Hz, 2 H), 1.90 1.80 (m, 2 H), 1.76 - 1.68 (m, 2 H).

[00334] Compound 53: 4-(thiophene-3-carbonyloxy)butanoic acid O

<img file="CA2999367C_D0148.tif" />

[00335] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl thiophene-3-carboxylate (400 mg, 2 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with brine (2 mL x 2), dried over Na₂SO₄ and concentrated. The residue was purified by prep-HPLC to yield the titled compound (100 mg, 23%) as crystalline solids.¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.10 (d, J = 2.0 Hz, 1 H), 7.52 (d, J= 5.2 Hz, 1 H), 7.31 (dd, J = 3.0, 5.0 Hz, 1 H), 4.34 (t, J= 6.2 Hz, 2 H), 2.53 (t, J= 7.2 Hz, 2 H), 2.132.07 (m, 2 H).

Example 1-54

[00336] Intermediate Compound 54’:

(S)-l-tert-butyl 2-(4-hydroxybutyl) pyrrolidine-1,2-dicarboxylate

<img file="CA2999367C_D0149.tif" />

BOC

[00337] (S)-l-(ier/-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2 g, 9.3 mmol), DCC (2108 mg, 10.23 mmol) and DMAP (50 mg) was added to a stirred solution of butane1,4-diol (1674 mg, 18.6 mmol) in DCM (30 mL). The reaction was stirred at 25 °C for 3 h. After that, the reaction mixture was diluted with saturated aqueous NH₄C1 (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA =

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5:1 to yield the titled compound (1.4 g, 52%) as a colorless oil. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.32 - 4.12 (m, 3 H), 3.71 - 3.62 (m, 2 H), 3.58 - 3.35 (m, 2 H), 2.27 - 2.16 (m, 1 H), 2.02 1.60 (m, 8 H), 1.46 (s, 4 H), 1.41 (s, 5 H).

[00338] Compound 54:

(S)-4-(l-(tert-butoxycarbonyl)pyrrolidine-2-carbonyloxy)butanoic acid

<img file="CA2999367C_D0150.tif" />

[00339] Jones reagent was added in portions to a stirred mixture of (.^)-1-ZerZ-buty I 2(4-hydroxybutyl) pyrrolidine-1,2- dicarboxylate (400 mg, 1.39 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with DCM/MeOH = 120:1 to yield the titled compound (200 mg, 48%) as a colorless oil. ’H NMR was performed at 400MHz with CDChas solvent to characterize the titled compound, results are as follows: δ = 4.40 - 4.32 (m, 1 H), 4.26 - 4.07 (m, 2 H), 3.58 3.35 (m, 2 H), 2.45 (t, J= 7.0 Hz, 2 H), 2.33 - 2.12 (m, 2 H), 2.01 - 1.83 (m, 4 H), 1.46 (s, 5 H), 1.41 (s, 4 H).

Example 1-55

[00340] Intermediate Compound 55’:

4-hydroxybutyl 2-(tert-butoxycarbonylamino)acetate

<img file="CA2999367C_D0151.tif" />

[00341] 2-(/er/-butoxycarbonylamino)acetic acid (340 mg, 1.94 mmol), DCC (440 mg, 2.14 mmol) and DMAP (5 mg) was added to a stirred solution of butane-1,4-diol (350 mg, 3.89 mmol) in DCM (30 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with saturated aqueous NH₄C1 (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na₂SO₄ and

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PCT/CN2016/099763 evaporated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (200 mg, 42%) as a white solid. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.00 (br. s., 1 H), 4.20 (t, J = 6.6 Hz, 2 H), 3.90 (d, J= 5.2 Hz, 2 H), 3.68 (q, J = 6.0 Hz, 2 H), 1.79 1.72 (m, 2 H), 1.67 - 1.62 (m, 2 H), 1.45 (s, 9 H), 1.37 - 1.34 (m, 1 H).

[00342] Compound 55:4-(2-(tert-butoxycarbonylamino)acetoxy)butanoic acid o

<img file="CA2999367C_D0152.tif" />

[00343] Jones reagent was added in portions to a stirred mixture of 4-hydroxybutyl 2(tert-butoxycarbonylamino)acetate (200 mg, 0.81 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄and concentrated. The residue was purified by a flash column (silica gel, DCM/MeOH = 100:1 to yield the titled compound (150 mg, 71%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.03 (br. s., 1 H), 4.23 (t, J = 6.2 Hz, 2 H), 3.90 (d, J = 5.2 Hz, 2 H), 2.45 (t, J = 7.2 Hz, 2 H), 2.05 - 1.98 (m, 2 H), 1.45 (s, 9 H).

Example 1-56

[00344] Compound 56: 4-(2-aminoacetoxy)butanoic acid O

O

[00345] A solution of 4-(2-(tert-butoxycarbonylamino)acetoxy)butanoic acid (150 mg, 0.57 mmol) in HC1/EA (~ 2 M, 1.5 mL) was stirred at 25 °C for 24 h. After that, the reaction mixture was filtered and the resulting precipitate was collected, washed with Et20 (0.5 mL), dried in vacuo to yield the titled compound (82 mg, 89%) as a white solid in HC1 salt fonn. *H NMR was performed at 400MHz with CD3OD as solvent to characterize the titled compound, results are as follows: δ = 4.30 (t, 6.4 Hz, 2 H), 3.84 (s, 2 H), 2.42 (t, J=

Ί.2 Hz, 2 H), 2.03 - 1.94 (m, 2 H).

Example 1-57

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[00346] Intermediate Compound 57’:

(S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-phenylpropanoate

<img file="CA2999367C_D0153.tif" />

[00347] (0)-2-(/ez7-butoxycarbonylamino)-3-phenylpropanoic acid (1 g, 3.37 mmol), DCC (855 mg, 4.15 mmol) and DMAP (10 mg) was added to a stirred solution of butane-1,4diol (679 mg, 7.54 mmol) in DCM (20 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na2SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (700 mg, 55%) as a col oil ess oil. ^]H NMR was performed at 400MHz with CDCh as solvent to characterize the titled compound, results are as follows: Ô = 7.32 7.27 (m, 2 H), 7.26 - 7.21 (m, 1 H), 7.14 (d, ./ = 6 8 Hz, 2 H), 4.97 (d, J = 8.0 Hz, 1 H), 4.58 4.53 (m, 1 H), 4.19 - 4.08 (m, 2 H), 3.64 (q, J= 5.6 Hz, 2 H), 3.07 (t, J= 4.8 Hz, 2 H), 1.72 1.65 (m, 2 H), 1.56 - 1.51 (m, 2 H), 1.42 (s, 9 H).

[00348] Intermediate Compound 57”:

(S)-4-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)butanoic acid

<img file="CA2999367C_D0154.tif" />

O

[00349] Jones reagent was added in portions to a stirred mixture of (5)-4hydroxybutyl 2-(tert-butoxycarbonylammo)-3-phenyIpropanoate (600 mg, 1.78 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO4and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (220 mg, 35%) as a colorless oil. 'H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.34 - 7.27 (m, 2 H), 7.26 7.20 (m, 1 H), 7.14 (d, J = 6.8 Hz, 2 H), 4.99 (d, J = 8.0 Hz, 1 H), 4.61 - 4.51 (m, 1 H), 4.22

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4.09 (m, 2 H), 3.06 (d, J= 6.0 Hz, 2 H), 2.34 (t, J= 7.2 Hz, 2 H), 1.97 - 1.89 (m, 2 H), 1.42 (s, 9 H).

[00350] Compound 57: (S)~4-(2-amino-3-phenylpropanoyloxy)butanoic acid

<img file="CA2999367C_D0155.tif" />

[00351] A solution of (S)-4-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy) butanoic acid (180 mg, 0.51 mmol) in HC1/EA (~2 M, 2 mL) stirred at 25 °C for 24 h. After that, the reaction mixture was filtered and the resulting precipitate was collected, washed with Et₂O (0.5 mL), dried in vacuo to yield the titled compound (100 mg, 78%) as a white solid in HC1 salt form. *Η NMR was performed at 400MHz with CD3OD as solvent to characterize the titled compound, results are as follows: δ = 7.41 - 7.31 (m, 3 H), 7.27 - 7.25 (m, 2 H), 4.30 (t, J = 7.0 Hz, 1 H), 4.26 - 4.19 (m, 2 H), 3.25 - 3.15 (m, 2 H), 2.28 (t, J = 7.2 Hz, 2 H), 1.92- 1.86 (m, 2 H).

Example 1-58

[00352] Intermediate Compound 58’:

(S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate

<img file="CA2999367C_D0156.tif" />

[00353] (5)-2-(/er/-butoxycarbonylamino)-3-methylbutanoic acid (1 g, 4.61 mmol), DCC (1044 mg, 5.07 mmol) and DMAP (10 mg) was added to a stirred solution of butane1,4-diol (829 mg, 9.21 mmol) in DCM (20 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (10 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (15 mL), dried over anhydrous Na₂SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (700 mg, 53%) as a colorless oil. ^]H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.07 (d, J= 8.8 Hz, 1 H), 4.16 - 4.11 (m, 3 H), 3.62 (t, J= 6.2 Hz, 2 H), 2.32 (br. s., 1 H), 2.12 - 2.04 (m, 1 Η), 1.75 - 1.68 (m, 2 H), 1.62 - 1.56 (m, 2 H), 1.40 (s, 9 H), 0.92 (d, J = 7.2 Hz, 3 H), 0.85 (d, J= 7.2 Hz, 3 H).

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[00354] Intermediate Compound 58 ’’:

(S)-4-(2-(tert-butoxycarbonylanuno)-3-methylbutanoyloxy)butanoic acid

<img file="CA2999367C_D0157.tif" />

[00355] Jones reagent was added in portions to a stirred mixture of (5)-4hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (500 mg, 1.73 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of zPrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (170 mg, 32%) as a white solid. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.03 (d, J = 9.2 Hz, 1 H), 4.30 - 4.24 (m, 1 H), 4.22 - 4.13 (m, 2 H), 2.46 (t, J= 7.4 Hz, 2 H), 2.16 - 2.08 (m, 1 H), 2.06 -1.96 (m, 2 H), 1.45 (s, 9 H), 0.96 (d, J = 6.8 Hz, 3 H), 0.89 (d, J = 6.4 Hz, 3 H).

[00356] Compound 58: (S)-4-(2-amino-3-methylhutanoyloxy)bufanoic acid °

H₂N

[00357] A solution of (5)-4-(2-(Zerr-butoxycarbonylamino)-3methylbutanoyloxy)butanoic acid (104 mg, 0.34 mmol) in HC1/EA (~2 M, 1.5 mL) stirred at 25 °C for 24 h. After that, the reaction mixture was filtered and the resulting precipitate was collected, washed with Et₂O (0.5 mL), dried in vacuo to yield the titled compound (50 mg, 71%) as a white solid in HC1 salt form. *H NMR was performed at 400MHz with CD3OD as solvent to characterize the titled compound, results are as follows: δ = 4.33 - 4.26 (m, 2 H), 3.92 (d, J= 4.8 Hz, 1 H), 2.42 (t, J = 7.2 Hz, 2 H), 2.34 - 2.25 (m, 1 H), 2.05 - 1.94 (m, 2 H), 1.06 (d, J = 6.8 Hz, 6 H).

[00358] A suspension of the above white solid (800 mg, 3.3 mmol) in ethanol (4 mL) was stirred at 80 °C for around 30 min and a clear solution was formed. Then the solution was gradually cooled to 25 °C, propylene oxide (580 mg, 10 mmol) was added dropwise. The reaction was stirred at 25 °C for 16 h and then the resultant suspension was filtered. The

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WO 2017/050259 PCT/CN2016/099763 white solid was collected, washed with cold ethanol, dried in vacuo to afford the titled compound (510 mg, 75%) in free salt form. ’H NMR was performed at 400MHz with d^DMSO as solvent to characterize the titled compound, results are as follows: δ = 4.10 - 3.99 (m, 2 H), 3.11 (d, J= 5.2 Hz, 1 H), 2.29 (t, J= 7.4 Hz, 2 H), 1.90 - 1.74 (m, 3 H), 0.87 (d, J =

6.8 Hz, 3 H), 0.82 (d, J= 6.4 Hz, 3 H).

Example 1-59

[00359] Intermediate compound 59 ’: 4-hydroxybutyl 2-(p-tolyl)acetate

<img file="CA2999367C_D0158.tif" />

[00360] 2-(p-tolyl)acetic acid (1 g, 6.67 mmol), DCC (1.5 g, 7.33 mmol) and DMAP (10 mg) was added to a stirred solution of butane-1,4-diol (3 g, 33.33 mmol) in DCM (50 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was filtered and the filtrate was washed with saturated aqueous NH4CI (20 mL). The resultant organic phase was washed with brine (20 mL), dried over Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 3:1 to afford the titled compound (1.1g, 74%) as a colorless oil. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.18 - 7.12 (m, 4 H), 4.12 (t, J6.6 Hz, 2 H), 3.64 (t, J= 6.4 Hz, 2 H), 3.58 (s, 2 H), 2.33 (s, 3 H), 1.75 - 1.68 (m, 2 H), 1.62 1.55 (m, 2 H).

[00361] Compound 59: 4-(2-(p-tolyl)acetoxy)butanoic acid

<img file="CA2999367C_D0159.tif" />

[00362] Jones reagent was added dropwise to a stirred mixture of 4-hydroxybutyl 2(p-tolyl)acetate (800 mg, 3.60 mmol) and Celite® (diatomaceous earth, 1.6 g) in acetone (15 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of isopropanol, diluted with EA (30 mL), and then filtered. The filtered cake was washed with EA (10 mL) and the combined filtrate was washed with brine (10 mL x 2), dried over Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 2:1 to afford the titled compound (500 mg, 59%) as crystalline solids. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ

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PCT/CN2016/099763 = 7.17 - 7.12 (m, 4 H), 4.14 (t, J = 6.2 Hz, 2 H), 3.57 (s, 2 H), 2.41 (t, J= 7.2 Hz, 2 H), 2.33 (s, 3 H), 1.99 - 1.93 (m, 2 H).

Example 1-60

[00363] Intermediate compound 60’:

(R)-4-hydroxyhutyl 2-(tert-htttoxycarbonyIamino)-3-methylhutanoate

<img file="CA2999367C_D0160.tif" />

[00364] DCC (3.1 g, 15.21 mmol) and DMAP (17 mg, 0.14 mmol) was added to a stirred suspension of (J?)-2-(ter/-butoxycarbonylamino)-3-methylbutanoic acid (3.0 g, 13 82 mmol) and butane-1,4-diol (3 7 g, 41.47 mmol) in DCM (40 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 25 °C for 16 h. After that, the reaction mixture was filtered and the filtered cake was washed with DCM (10 mL). The combined filtrate was washed with saturated aqueous NH4CI (10 mL x 2), dried over Na₂SÛ4 and evaporated. The residue was purified by a silica gel flash column with DCM/EA = 20:1 to afford the titled compound (2.5 g, 63%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.02 (d, J= 8.4 Hz, 1 H), 4.20 - 4.16 (m, 2 H), 3.68 (q, ./ = 6.0 Hz, 2 H), 2.16 - 2.08 (m, 1 H), 1.79 - 1.70 (m, 2 H), 1.69 - 1.64 (m, 2 H), 1.44 (s, 9 H), 0.96 (d, J = 6.8 Hz, 3 H), 0.89 (d, J= 6.8 Hz, 3 H).

[00365] Intermediate compound 60 ’ (R)-4-(2-(tert-butoxycarbonylaniino)-3-methylbutanoy!oxy)butanoic acid

O

<img file="CA2999367C_D0161.tif" />

[00366] Jones reagent was dropwise added to a stirred mixture of (J?)-4-hydroxybutyl 2-(ter/-butoxycarbonylamino)-3-methylbutanoate (2.5 g, 8.65 mmol) and Celite® (diatomaceous earth, 5.0 g) in acetone (25 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of isopropanol, diluted with EA (25 mL), and then filtered. The filtered cake was washed with EA (25 mL) and the combined filtrate was washed with brine (20 mL x 2), dried over Na₂SO4 and concentrated. The residue was purified by a silica gel flash column with DCM/EA = 20:1 -3:1 to afford the titled compound (1.1g, 42%) as a white solid.

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WO 2017/050259 PCT/CN2016/099763 *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.03 (d, J= 8.8 Hz, 1 H), 4.26 - 4.18 (m, 2 H), 2.45 (t, J = 7.4 Hz, 2 H), 2.14 - 2.10 (m, 1 H), 2.03 - 2.00 (m, 2 H), 1.45 (s, 9 H), 0.96 (d, J= 6.8 Hz, 3 H), 0.89 (d, 7= 6.8 Hz, 3 H).

[00367] Compound 60: (R)-4-(2-amino-3-methylbutanoyloxy)butanoic acid 'V ⁰

H₂N o

[00368] (/?)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid (400.0 mg, 1.32 mmol) was added to a stirred solution of HCI/EA (~2 M, 2 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 25 °C for 16 h. After that, the resulting suspension was filtered. The white precipitate was collected, washed with EA (2 mL) and dried in vacuo to afford the titled compound (184.0 mg, 58%) as a white solid in HC1 salt form. *H NMR was performed at 400MHz with D2O as solvent to characterize the titled compound, results are as follows: δ = 4.32 (t, J= 5.6 Hz, 2 H), 4.03 (d, J= 4.4 Hz, 1 H), 2.51 (t,7= 7.2 Hz, 2 H), 2.39 - 2.35 (m, 1 H), 2.03 (t, 7= 6.6 Hz, 2 H), 1.04 (t, 7= 7.2 Hz, 6 H).

Example 1-61

[00369] Intermediate compound 61 (S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)propanoate

<img file="CA2999367C_D0162.tif" />

[00370] A solution of (Boc)2O (13.5 g, 61.80 mmol) in 1,4-dioxane (56 mL) was added to a stirred solution (S)-2-aminopropanoic acid (5.0 g, 56.18 mmol) in water (56 mL) and aqueous NaOH (56.2 mL, 1 M) at 0 °C. The reaction was allowed to warm up gradually and stirred at 25 °C for 16 h. After that the reaction mixture was cooled to 0 °C, then acidified with HC1 (2 M) until pH = 2-3. The mixture was diluted with EA (56 mL), the aqueous phase was separated and extracted with EA (56 mL x 3). The combined organic phase was washed with brine (56 mL), dried over Na₂SO4 and evaporated to afford the crude (5)-2-(/er/-butoxycarbonylamino)propanoic acid (9.0 g) as a white solid, which was used directly for the next step without further purification.

[00371] DCC (4.4 g, 21.16 mmol) and DMAP (25 mg) was added to a stirred suspension of the above crude (S)-2-(/ez7-butoxycarbonylamino)propanoic acid (4.0 g) and

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WO 2017/050259 PCT/CN2016/099763 butane-1,4-diol (5.7 g, 63.49 mmol) in DCM (50 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 25 °C for 16 h. After that, the reaction mixture was filtered, the filtered cake was washed with DCM (10 mL). The combined filtrate was washed with saturated aqueous NH4CI (15 mL x 2), dried over Na2SO4 and evaporated. The residue was purified by a silica gel flash column with PE/EA = 4:1-1:1 to afford the titled compound (3.0 g, 55%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.02 (br. s., 1 H), 4.29 (t, J = 6.8 Hz, 1 H), 4.18 (t, J = 6.4 Hz, 2 H), 3 68 (q, J= 6.0 Hz, 2 Η), 1.79 - 1.72 (m, 2 H), 1.68 - 1.60 (m, 2 H), 1.44 (s, 9 Η), 1.38 (d, J = 7.2 Hz, 3 H).

[00372] Intermediate compound 61 ’ ’:

(S)-4-(2-(tert-butoxycarbonylamino)propanoyloxy)butanoic acid

<img file="CA2999367C_D0163.tif" />

[00373] Jones reagent was dropwise added to a stirred mixture of (5)-4-hydroxybutyl 2-(ter/-butoxycarbonylamino)propanoate (3.0 g, 11.49 mmol) and Celite® (diatomaceous earth, 6.0 g) in acetone (30 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of isopropanol, diluted with EA (100 mL), and then filtered. The filtered cake was washed with EA (20 mL) and the combined filtrate was washed with brine (30 mL x 2), dried over NaiSO4 and concentrated. The residue was purified by a silica gel flash column with DCM/EA = 20:1 to afford the titled compound (1.8 g, 57%) as a colorless oil. *11 NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.06 (br. s„ 1 H), 4.31 - 4.16 (m, 3 H), 2.45 (t, J= 7.2 Hz, 2 H), 2.02 - 1.97 (m, 2 H), 1.44 (s, 9 H), 1.38 (d, J= 7.2 Hz, 3 H).

[00374] Compound 61: (S)-4-(2-aminopropanoy!oxy)butanoic acid

I î h₂n 0

[00375] (5)-4-(2-(/er/-butoxycarbonylamino)propanoyloxy)butanoic acid (200.0 mg, 0.73 mmol) was added to a stirred solution of HC1ÆA (1.0 mL, -2 M) at 0 °C. The reaction was allowed to warm up gradually and stirred at 25 °C for 16 h. After that, the

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Example 1-62

[00376] Intermediate compound 62 ’: (S)-4-hydroxybutyl 2-acetanddopropanoate

<img file="CA2999367C_D0164.tif" />

[00377] Ac₂O (6.8 g, 66.67 mmol) was added to a stirred suspension of (5)-2aminopropanoic acid (5.0 g, 56.18 mmol) in HO Ac (25 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was evaporated to yield the crude (5)-2acetamidopropanoic acid as a white solid (8.0 g), which was used directly for next step without further purification.

[00378] DCC (3.1 g, 15.28 mmol) and DMAP (20 mg) was added to a stirred suspension of the above (5)-2-acetamidopropanoic acid (2.0 g, 15.28 mmol) and butane-1,4diol (4.1 g, 45.80 mmol) in DCM (50 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC to afford the titled compound (2.0 g, 67%) as a colorless oil.

NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 6.12 (br. s., 1 H), 4.59 - 4.52 (m, 1 H), 4.24 - 4.13 (m, 2 H), 3.67 (t, J= 6.4 Hz, 2 H), 2.01 (s, 3 H), 1.77 - 1.72 (m, 2 H), 1.66 - 1.59 (m, 2 H), 1.40 (d, J= 7.6 Hz, 3H).

[00379] Compound 62: (S)-4-(2-acetamidopropanoyloxy)butanoic acid

<img file="CA2999367C_D0165.tif" />

[00380] Jones reagent was dropwise added to a stirred mixture of (5)-4-hydroxybutyl A

2-acetamidopropanoate (660 mg, 3.25 mmol) and Celite (diatomaceous earth, 1.2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of

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WO 2017/050259 PCT/CN2016/099763 isopropanol, diluted with EA (10 mL), and then filtered. The filtered cake was washed with EA (10 mL) and the combined filtrate was washed with brine (10 mL x 2), dried over Na2SO₄and concentrated. The residue was purified by prep-HPLC to afford the titled compound (300 mg, 42%) as a colorless oil. 'H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 6.25 (d, J = 6.4 Hz, 1 H), 4.61 4.54 (m, 1 H), 4.28 - 4.15 (m, 2 H), 2.44 (t, J= 7.0 Hz, 2 H), 2.03 (s, 3 H), 2.07 - 1.97 (m, 2 H), 1.40 (d, J= 7 2 Hz, 3 H).

[00381] Scheme 3:

<img file="CA2999367C_D0166.tif" />

Pd/C, H₂

MeOH

<img file="CA2999367C_D0167.tif" />

Example 1-63 [00382] Intermediate compound 63 benzyl 4-(2-(tert-butoxycarbonyl)aminoacetoxy)butanoate

<img file="CA2999367C_D0168.tif" />

[00383] A mixture of /V-Boc glycine (2.0 g, 11.4 mmol), benzyl 4-hydroxybutanoate (2.7 g, 13.7 mmol), DCC (3.1 g, 14.8 mmol) and DMAP (5 mg) in DCM (20 mL) was stirred at 25 °C for 16 h. The reaction mixture was filtered and the filtrate was washed with aqueous saturated NH₄C1 (2 x 20 mL). The organic layer was dried over Na2SO₄, filtered and concentrated. The residue was purified by a silica gel flash column with PE/EA = 10:1-1:1 to afford the titled compound (2.0 g, 50%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.45 - 7.27 (m, 5 H), 5.13 (s, 2 H), 4.99 (br. s„ 1 H), 4.20 (t, J = 6.2 Hz, 2 H), 3.88 (d, J = 4.4 Hz, 2 H), 2.46 (t, J= 7.4 Hz, 2 H), 2.04 - 1.97 (m, 2 H), 1.45 (s, 9 H).

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[00384]

[00385]

Intermediate compound 63”: benzyl 4-(2-aminoacetoxy)butanoate o

ΝΗ₂

O'^Bn o

TFA (3.0 mL) was added to a solution of benzyl 4-(2-(tert butoxycarbonyl)aminoacetoxy)butanoate (1.60 g, 4.56 mmol) in DCM (15 mL) at 0 °C, and the reaction was stirred at the same temperature for 2 h. After that, solvent was evaporated to afford the titled compound (1.2 g), which was used directly for the next step without further purification.

[00386]

Intermediate compound 63”': benzyl 4-(2-propionamidoacetoxy)butanoate

<img file="CA2999367C_D0169.tif" />

[00387] Propionyl chloride (162 mg, 1.75 mmol) was dropwise added to a solution of benzyl 4-(2-aminoacetoxy)butanoate (400 mg, 1.59 mmol) and Et₃N (0.66 mL, 4.78 mmol) in DCM (10 mL) at 0 °C. The reaction was allowed to warm up and stirred at 25 °C for 16 h. After that, the reaction was quenched by water (10 mL) with stirring for 5 min. The aqueous phase was extracted with DCM (10 mL x 3), the combined organic phase was washed with brine (20 mL), dried over Na₂SO₄ and concentrated. The residue was purified by silica gel flash column with PE/EA = 1:1 to afford the titled compound (440 mg, 90%) as colorless oil.

[00388] Compound 63:4-(2-propionamidoacetoxy)butanoic acid

O O

NH y 0

[00389] Pd/C (50 mg) was added to a solution of benzyl 4-(2propionamidoacetoxy)butanoate (400 mg, 1.3 mmol) in MeOH (10 mL), and the mixture was stirred at 25 °C for 16 h under H₂ atmosphere. After that, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by a silica gel flash column with PE/EA = 1:50 to afford the titled compound (170 mg, 60%) as a white solid. *H NMR was performed at 400MHz with CD3OD as solvent to characterize the titled compound, results are as follows: 8 = 4.18 (t, J= 6.2 Hz, 2 H), 3.92 (s, 2 H), 2.39 (t, J= 7.4 Hz, 2 H), 2.27 (q, J =7.6 Hz, 2 H), 1.98-1.91 (m, 2 H), 1.14 (t, J = 7.6 Hz, 3 H).

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Example 1-64

[00390] Intermediate compound 64’: benzyl 4-(2-isobutyramidoacetoxy)butanoate

<img file="CA2999367C_D0170.tif" />

[00391] Isobutyryl chloride (0.8 g, 7.5 mmol) was added dropwise to a solution of benzyl 4-(2-aminoacetoxy)butanoate (1.57 g, 6.26 mmol) and Et3N (1.58 mL,15.7 mmol) in DCM (20 mL) at 0 °C. The reaction was stirred at 25 °C for 16 h and then washed with brine (2x10 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by prep-HPLC to afford the titled compound (0.8 g, 40%) as a colorless oil. 'H NMR was performed at 600MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.45 - 7.27 (m, 5 H), 5.93 (br. s., 1 H), 5.12 (s, 2 H), 4.20 (t, 6.3

Hz, 2 H), 4.00 (d, J= 4.8 Hz, 2 H), 2.50 - 2.37 (m, 3 H), 2.04 - 1.99 (m, 2 H), 1.18 (d, J= 7.2 Hz, 6 H).

[00392] Compound 64:4-(2-isobutyramidoacetoxy)butanoic acid o 0 oh

I 0

[00393] Pd/C (75 mg) was added to a solution of benzyl 4-(2isobutyramidoacetoxy)butanoate (0.75 g, 2.3 mmol) in EA (10 mL). The reaction was stirred under H2 atmosphere for 16 h at 25 °C. The reaction was filtered and the filtrate was concentrated. The residue was purified by a silica gel flash column with PE/EA = 5:1 - 3:1 to afford the titled compound (270 mg, 50%) as a white solid. ²H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 6.04 (br. s., 1 H), 4.24 (t, J = 6.2 Hz, 2 H), 4.03 (d, J = 5.2 Hz, 2 H), 2.57 - 2.36 (m, 3 H), 2.06 - 1.99 (m, 2 Η), 1.18 (d, J= 7.2 Hz, 6 H).

Example 1-65

[00394] Intermediate compound 65 ’:

benzyl 4-(2-(tert-butoxycarbonyl)methylaminoacetoxy)butanoate

<img file="CA2999367C_D0171.tif" />

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[00395] A mixture of 2-((/er/-butoxycarbonyl)methylamino)acetic acid (5.0 g, 26.45 mmol), benzyl 4-hydroxybutanoate (4.6 g, 23.71 mmol), DCC (6.0 g, 29.07 mmol) and DMAP (cat.) in DCM (100 mL) was stirred at 25 °C for 16 h. After that, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by a silica gel flash column with PE/EA = 10:1 to afford the titled compound (8.0 g, 83%) as a colorless oil. *H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 7.35 - 7.26 (m, 5 H), 5.12 (s, 2 H), 4.17 (q, J = 5.6 Hz, 2 H), 3.94 (s, 1 H), 3.86 (s, 1 H), 2.90 (d, J= 6.8 Hz, 3 H), 2.45 (t, J = 7.4 Hz, 2 H), 2.02 - 1.97 (m, 2 H), 1.43 (d,J= 19.6 Hz, 9 H).

[00396] Intermediate compound 65 ’ ’:

benzyl 4-(2-(N-methylacetamido)acetoxy)butanoate

<img file="CA2999367C_D0172.tif" />

[00397] TFA (8.0 mL) was added to a solution of benzyl 4-(2-(tertbutoxycarbonyl)methylaminoacetoxy)butanoate (8.0 g, 21.89 mmol) in DCM (80 mL) at 0 °C, the reaction was stirred at the same temperature for 2 h. After that, solvent was evaporated, the residue (5.8 g) was used directly for next step.

[00398] The above residue (5.8 g) was dissolved in DCM (60 mL), to which EtsN (9.2 mL, 65.58 mmol) was added, followed by addition of acetyl chloride (3.4 g, 43.72 mmol) at 0 °C. The reaction was allowed to warm up and stirred at 25 °C for 16 h. After that, solvent was evaporated, and the residue was purified by prep-HPLC to afford the titled compound (4.0 g, 59%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.35 - 7.31 (m, 5 H), 5.10 (s, 2 H), 4.14 (t, J = 6.2 Hz, 2 H), 4.06 (s, 2 H), 3.03 (s, 3 H), 2.43 (t, J = 7.4 Hz, 2 H), 2.10 (s, 2 H), 2.11 -1.96 (m, 3 H).

[00399] Compound 65: 4-(2-(N-methylacetamido)acetoxy)butanoic acid

<img file="CA2999367C_D0173.tif" />

[00400] Pd/C (400 mg) was added to a solution of benzyl 4-(2-(^methylacetamido)acetoxy)butanoate (4.0 g, 13.01 mmol) in MeOH (40 mL), and the

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WO 2017/050259 PCT/CN2016/099763 reaction was stirred at 25 °C for 16 h under H₂ atmosphere. After that, the reaction mixture was filtered. The filtrate was concentrated and the residue was purified by a silica gel flash column with PE/EA = 1:10 to afford the titled compound (1.2 g, 42%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.92 (br. s„ 1 H), 4.20 (t, J = 6.2 Hz, 2 H), 4.11 (s, 2 H), 3.09 (s, 3 H), 2.42 (t, J = 7.2 Hz, 2 H), 2.16 (s, 3 H), 2.02 - 1.95 (m, 2 H).

[00401] Schemed:

<img file="CA2999367C_D0174.tif" />

Pd/C, H₂MeOH

<img file="CA2999367C_D0175.tif" />

Example 1-66

[00402] Intermediate compound 66’: benzyl 4-(2-acetanddoacetoxy)butanoate

<img file="CA2999367C_D0176.tif" />

[00403] 2-acetamidoacetic acid (362 mg, 3.09 mmol), DCC (584 mg, 2.83 mmol) and

DMAP (5 mg) was added to a stirred solution of benzyl 4-hydroxybutanoate (500 mg, 2.58 mmol) in DCM (20 mL), The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was filtered. The filtrate was washed with saturated aqueous NH4CI (15 mL), the organic phase was separated, washed with brine (10 mL), dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the titled compound (320 mg, 42%) as crystalline solids. NMR was performed at 400MHz with CD3OD as solvent to characterize the titled compound, results are as follows: δ = 7.36 - 7.31 (m, 5 H), 5.13 (s, 2 H), 4.17 (t, ./= 6.2 Hz, 2 H), 3.88 (s, 2 H), 2.48 (t, J= 7.4 H, 2 H), 2.01 - 1.94 (m, 5 H).

[00404] Compound 66: 4-(2-acetamidoacetoxy)butanoic acid

<img file="CA2999367C_D0177.tif" />

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[00405] Pd/C (30 mg) was added to a solution of benzyl 4-(2acetamidoacetoxy)butanoate (280 mg, 0.96 mmol) in methanol (10 mL), the reaction was stirred at 25 °C under H2 atmosphere for 16 h. After completion, the reaction mixture was filtered through Celite® (diatomaceous earth) and the filtrate was concentrated. The residue was purified by prep-HPLC to afford the titled compound (110 mg, 57%) as crystalline solids. *H NMR was performed at 400MHz with CD3OD as solvent to characterize the titled compound, results are as follows: δ = 4.18 (t, J = 6.4 Hz, 2 H), 3.92 (s, 2 H), 2.39 (t, J = ΊΑ Hz, 2 H), 2.00 (s, 3 Η), 1.98 - 1.91 (m, 2 H).

Example 1-67

[00406] Scheme 5:

<img file="CA2999367C_D0178.tif" />

<img file="CA2999367C_D0179.tif" />

[00407] Intermediate compound 67’:

(S)-4-hydroxybutyl 2-acetamido-3-methylbutanoate

<img file="CA2999367C_D0180.tif" />

[00408] HATU (5258 mg, 13.84 mmol) and DIPEA (3245 mg, 25.16 mmol) was added to a stirred solution of (5)-2-acetamido-3-methylbutanoic acid (2 g, 12.58 mmol) and butane-1,4-diol (3396 mg, 37.74 mmol) in DCM (50 mL). The reaction was stirred at 25 °C for 16 h. After that, the mixture was concentrated and the residue was purified by prep-HPLC to afford the titled compound (600 mg, 21 %) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.96 (d, J= 8.0 Hz, 1 H), 4.54 (dd, J = 5.0, 8.6 Hz, 1 H), 4.26 - 4.11 (m, 2 H), 3.69 (t, J = 6.4 Hz„ 2 H), 2.18 - 2.11 (m, 1 H), 2.05 (s, 3 H), 1.79 - 1.72 (m, 2 H), 1.69 - 1.65 (m, 2 H), 0.95 (d, J= 6.8 Hz, 3 H), 0.91 (d, 6.8 Hz, 3 H).

[00409] Compound 67: (S)-4-(2-acetanùdo-3-methylbutanoyloxy)butanoic acid

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<img file="CA2999367C_D0181.tif" />

[00410] Jones reagent was added dropwise to a stirred mixture of (5)-4-hydroxybutyl 2-acetamido-3-methylbutanoate (500 mg, 2.16 mmol) and Celite® (diatomaceous earth, 1 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction mixture was quenched by drops of isopropanol, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (10 mL), the combined filtrate was washed with brine (5 mL x 2), dried over NaiSO₄ and concentrated. The residue was purified by prep-HPLC to afford the titled compound (190 mg, 36%) as crystalline solids. *H NMR was performed at 400MHz with CDCL as solvent to characterize the titled compound, results are as follows: δ = 6 18 (d, .7 = 7.2 Hz, 1 H), 4.55 (dd, J = 4.8, 8.4 Hz, 1 H), 4.30 - 4.24 (m, 1 H), 4.20 - 4.14 (m, 1 H), 2.47 (t, J = 7.0 Hz, 2 H), 2.20 - 2.12 (m, 1 H), 2.09 (s, 3 H), 2.06 - 1.98 (m, 2 H), 0.95 (d, J = 6.8 Hz, 3 H), 0.91 (d, J = 6.8 Hz, 3 H).

[00411] Scheme 6:

h₂n

<img file="CA2999367C_D0182.tif" />

<img file="CA2999367C_D0183.tif" />

K₂CO₃, h₂o

<img file="CA2999367C_D0184.tif" />

<img file="CA2999367C_D0185.tif" />

DCC, DMAP, DCM

<img file="CA2999367C_D0186.tif" />

Example 1-68

[00412] Intermediate compound 68 2-(ethoxycarbonylamino)acetic acid

<img file="CA2999367C_D0187.tif" />

[00413] Ethyl carbonochloridate (3.8 g, 34.6 mmol) was dropwise added to solution of glycine (2.0 g, 26.6 mmol) and K2CO3 (9.6 g, 96.3 mmol) in water (40 mL) at 0 °C. The reaction was warmed up to 25 °C and stirred for 16 h. After that, the reaction mixture was extracted with EA (2 x 20 mL). The aqueous phase was separated and acidified with cold cone. HC1 until pH = 2, which was extracted with EA (2 x 40 mL). The combined organic

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WO 2017/050259 PCT/CN2016/099763 layer was dried over Na2SÛ4, filtered and concentrated to afford the titled compound (3.5 g 89%) as a white solid. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.16 (br. s., 1 H), 4.24 - 4.08 (m, 2 H), 4.07 - 3 .93 (m, 2 H), 1.41-1.14 (m, 3 H).

[00414] Intermediate compound 68 ’ ’:

4-hydroxybutyl 2-(ethoxycarbonylamino)acetate

<img file="CA2999367C_D0188.tif" />

[00415] A mixture of 2-(ethoxycarbonylamino)acetic acid (1.0 g, 6.8 mmol), butane1,4-diol (3.1 g 34.0 mmol), DCC (1.7 g, 8.2 mmol) and DMAP (10 mg) in DCM (30 mL) was stirred at 25 °C for 16 h. After that, the reaction mixture was filtered and the filtrate was washed with water (2 x 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by a silica gel flash column with ΡΕΈΑ = 5:1-2:1 to afford the titled compound (630 mg, 42%) as a colorless oil. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.16 (br. s., 1 H), 4.20 (t, J = 6.6 Hz, 2 H), 4.14 (t, J = 7.2 Hz, 2 H), 3.95 (d, J= 5.2 Hz, 2 H), 3.68 (t, J = 6.2 Hz, 2 H), 1.83 - 1.69 (m, 2 H), 1.69 - 1.52 (m, 2 H), 1.25 (t, .1=12 Hz, 3 H)

[00416] Compound 68: 4-(2-(ethoxycarbonyl)aminoacetoxy)butanoic acid

O O

<img file="CA2999367C_D0189.tif" />

[00417] Jones reagent was added in portions to a mixture of 4-hydroxybutyl 2(ethoxycarbonylaniino)acetate (500 mg 2.3 mmol) and Celite* (diatomaceous earth, 1.5 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 30 min and the reaction progress was monitored by TLC. After completion, the reaction mixture was quenched by drops of isopropanol, diluted with EA (20 mL) and filtered. The filtered cake was washed with EA (10 mL), the combined filtrate was washed with brine (5 mL x 2), dried over Na2SO₄ and concentrated. The residue was purified by a silica gel flash column with DCM/EA = 20:1-5:1 to afford the titled compound (190 mg, 36%) as a white solid. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results

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Example 1-69

[00418] Intermediate compound 69 2-(isopropoxycarbonylanuno)acetic acid

<img file="CA2999367C_D0190.tif" />

[00419] Isopropyl carbonochloridate (2.1 g, 17.3 mmol) was dropwise added to solution of glycine (1.0 g, 13.3 mmol) and K2CO3 (4.8 g, 34.6 mmol) in water (30 mL) at 0 °C. The reaction was warmed up to 25 °C and stirred for 16 h. After that, the reaction mixture was extracted with EA (2 x 20 mL). The aqueous phase was separated and acidified with cold cone. HC1 until pH = 2, which was extracted with EA (2 x 30 mL). The combined organic layer was dried over Na₂SO₄, filtered and concentrated to afford the titled compound (2.0 g, 93%) as a white solid. *H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 5.21 (br. s., 1 H), 4.98 - 4.89 (m, 1 H), 4.02 - 3.96 (m, 2 Η), 1.26 - 1.23 (m, 6 H).

[00420] Intermediate compound 69 ’ *;

4-hydroxybuty! 2-(isopropoxycarbony!amino)acetate

<img file="CA2999367C_D0191.tif" />

[00421] A mixture of 2-(isopropoxycarbonyIamino)acetic acid (500 mg, 3.1 mmol), butane-1,4-diol (839 mg, 9.3 mmol), DCC (768 mg, 3.7 mmol) and DMAP (10 mg) in DCM (10 mL) was stirred at 25 °C for 16 h. After that, the reaction mixture was filtered and the filtrate was washed with water (2 x 20 mL). The combined organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by a silica gel flash column with PE/EA = 10:1-1:1 to afford the titled compound (500 mg, 69%) as a colorless oil. ^]H NMR was perfonned at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.10 (br. s„ 1 H), 4.95 - 4.88 (m, 1 H), 4.20 (t, ./ = 6.4 Hz, 2 H), 3.95 (d, J = 5 .6 Hz, 2 H), 3.68 (t, J= 62 Hz, 2 H), 1.79 - 1.72 (m, 2 H), 1.67 - 1.57 (m, 2 H), 1.24 (d, J = 6.4 Hz, 6 H).

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[00422]

Compound 69:4-(2-(isopropoxycarbonyl)aminoacetoxy)butanoic acid

<img file="CA2999367C_D0192.tif" />

[00423] Jones reagent was added in portions to a mixture of 4-hydroxybutyl 2 (isopropoxycarbonylamino)acetate (500 mg, 2.1 mmol) and Celite* (diatomaceous earth,

1.5 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 30 min and the reaction progress was monitored by TLC. After completion, the reaction mixture was quenched by drops of isopropanol, diluted with EA (20 mL) and filtered. The filtered cake was washed with EA (10 mL), the combined filtrate was washed with brine (5 mL x 2), dried over Na₂SO₄ and concentrated. The residue was purified by prep-HPLC to afford the titled compound (220 mg, 42%) as a white solid. *H NMR was performed at 400MHz with CDCh as solvent to characterize the titled compound, results are as follows: δ = 5.13 (br s, 1 H),

4.95 - 4.89 (m, 1 H), 4.22 (t, J= 6.2 Hz, 2 H), 3.95 (d, J= 5.6 Hz, 2 H), 2.46 (t, J= 7.2 Hz, 2

H), 2.04 - 1.97 (m, 2 H), 1.24 (d, J= 6.4 Hz, 6 H).

[00424] Scheme 7:

<img file="CA2999367C_D0193.tif" />

H₂N

<img file="CA2999367C_D0194.tif" />

<img file="CA2999367C_D0195.tif" />

triphosgene, pyridine toluene

<img file="CA2999367C_D0196.tif" />

Example 1-70

[00425] Intermediate compound 70’: 2-((cyclohexyloxy)carbonylamino)acetic acid

<img file="CA2999367C_D0197.tif" />

[00426] Pyridine (1.2g, 15.0 mmol) was added dropwise to a solution of triphosgene (3.6 g, 12.0 mmol) in toluene (20 mL) at 0 °C, and the formed yellow slurry was stirred for 0.5 h. After that, a solution of cyclohexanol (1.0 g, 10.0 mmol) in toluene (10 mL) was added

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WO 2017/050259 PCT/CN2016/099763 dropwise at 0 °C. The reaction was allowed to warm up and stirred at 25 °C for additional 1 h, then was quenched by the addition of water (30 mL). The resulting aqueous phase was extracted with EA (2 x 20 mL). The combined organic layer was dried over MgSO₄, filtered and concentrated. The residue was used directly for the next step without purification.

[00427J The above crude cyclohexyl carbonochloridate was added dropwise to solution of glycine (675 mg, 9.0 mmol) and K₂CO₃ (3.5 g, 25.0 mmol) in water (20 mL) at 0 °C. The reaction was allowed to warm up and stirred at 25 °C for 16 h. After that, the reaction mixture was extracted with EA (2 x 30 mL). The aqueous phase was separated and acidified with cold cone. HC1 until pH = 2, which was extracted with EA (2 x 30 mL). The combined organic layer was dried over Na₂SO₄, filtered and concentrated to afford the titled compound (0.9 g, 45%) as a white solid. *H NMR was performed at 400MHz with CDChas solvent to characterize the titled compound, results are as follows: δ = 5.14 (br. s., 1 H), 4.79 - 4.59 (m, 1 H), 4.07 - 3.92 (m, 2 H), 1.95 - 1.80 (m, 2 H), 1.73 - 1.70 (m, 2 H), 1.61 - 1.14 (m, 6 H).

[00428] Intermediate compound 70 ’ V benzyl 4-(2-((cyclohexyloxy)carbonylamino)acetoxy)butanoate

<img file="CA2999367C_D0198.tif" />

[00429] A solution of 2-((cyclohexyloxy)carbonylamino)acetic acid (850 mg, 4.2 mmol), benzyl 4-hydroxybutanoate (985 mg, 6.3 mmol), HATU (1.9 g, 5.1 mmol) and DIPEA (819 mg, 6.3 mmol) in DCM (20 mL) was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with DCM (10 mL) and washed with water (2 x 20 mL). The combined organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by a silica gel column with PE/EA = 100:1-5:1 to afford the titled compound (0.9 g, 56%) as a colorless oil. NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.42 - 7.29 (m, 5 H), 5.12 (s, 2 H), 5.08 (br. s„ 1 H), 4.77 - 4.55 (m, 1 H), 4.20 (t, J = 6.4 Hz, 2 H), 3.93 (d, J = 5.6 Hz, 2 H), 2.45 (t, J = 7.6 Hz, 2 H), 2.04 - 1.97 (m, 2 H), 1.87 - 1.85 (m, 2 H), 1.78 - 1.64 (m, 2 H), 1.58 - 1.46 (m, 1 H), 1.46 - 1.14 (m, 5 H).

[00430] Compound 70:4-(2-(cyclohexyloxy)carbonylaminoacetoxy)butanoic acid

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<img file="CA2999367C_D0199.tif" />

[00431] Pd/C (90 mg) was added to a solution of benzyl 4-(2((cyclohexyloxy)carbonylamino)acetoxy)butanoate (900 mg, 2.4 mmol) in EA (10 mL). The reaction was stirred under H2 atmosphere at 25 °C for 16 h. After that, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by a silica gel flash column with PE/EA = 10:1-1:1 to afford the titled compound (220 mg, 32%) as a white solid. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.13 (br. s., 1 H), 4.67 - 4.62 (m, 1 H), 4.23 (t, 6.2

Hz, 2 H), 3.95 (d, 6.0 Hz, 2 H), 2.46 (t, 7.2 Hz, 2 H), 2.05 - 1.98 (m, 2 H), 1.88 - 1.86 (m,2H), 1.72- 1.70 (m, 2H), 1.59- 1.47 (m, 1 H), 1.46 - 1.12 (m, 5 H).

[00432] Scheme 8:

<img file="CA2999367C_D0200.tif" />

Example 1-71

[00433] Intermediate compound 71 (S)-2-(ethoxycarbonylamino)-3-methylbutanoic acid

<img file="CA2999367C_D0201.tif" />

[00434] Ethyl carbonochloridate (1.9 g, 17.3 mmol) was added dropwise to a solution of L-valine (1.0 g, 8.5 mmol) and K2CO3 (4.8 g, 34.6 mmol) in water (30 mL) at 0 °C. The reaction was allowed to warm up and stirred at 25 °C for 16 h. After that, the reaction mixture was extracted with EA (2 x 20 mL). The aqueous phase was separated and acidified with cold cone. HC1 until pH = 2, which was extracted with EA (2 x 30 mL). The combined organic layer was dried over Na2SO₄, filtered and concentrated to afford the titled compound (1.5 g, 60%) as a colorless oil. ’H NMR was performed at 400MHz with CDCI3 as solvent to

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WO 2017/050259 PCT/CN2016/099763 characterize the titled compound, results are as follows: δ = 5.12 (d, J = 9.2 Hz, 1 H), 4.33 (dd, J = 4.6, 9.0 Hz, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 2.32 - 2.11 (m, 1 Η), 1.26 (t, J = 7.2 Hz, 3 H), 1.01 (d, J = 6.4 Hz, 3 H), 0.94 (d, J= 7.2 Hz, 3 H).

[00435] Intermediate compound 71 ’ (S)-4-(benzyloxy)-4-oxobutyl 2-(ethoxycarbonylandno)-3-methylbutanoate

<img file="CA2999367C_D0202.tif" />

[00436] A solution of (5)-2-(ethoxycarbonylamino)-3-methylbutanoic acid (536 mg, 2.8 mmol), benzyl 4-hydroxybutanoate (500 mg, 2.6 mmol), HATU (1.2 g, 3.1 mmol) and DIPEA (499 mg, 3.9 mmol) in DCM (20 mL) was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with DCM (10 mL) and washed with water (2 x 20 mL). The organic layer was dried over Na₂SO4, filtered and concentrated. The residue was purified by silica gel flash column with PE/EA = 20:1 - 5:1 to afford the titled compound (370 mg, 39%) as a colorless oil. 'H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 7.45 - 7.46 (m, 5 H), 5.13 (s, 2 H), 4.26 (dd, J = 4.8, 8.8 Hz, 1 H), 4.17 (t, J= 6.4 Hz, 2 H), 4.11 (q, J = 7.2 Hz, 2 H), 2.46 (t, J= 7.6 Hz, 2 H), 2.21 - 2.07 (m, 1 H), 2.04 - 1.97 (m, 2 H), 1.24 (t, ./= 7.0 Hz, 3 H), 0.96 (d, ./= 6.8 Hz, 3 H), 0.87 (d, ./ = 6 8 Hz, 3 H).

[00437] Compound 71:

(S)-4-(2-((ethoxycarbonyl)amino)-3-methylbutanoyloxy)butanoic acid

<img file="CA2999367C_D0203.tif" />

[00438] Pd/C (40 mg) was added to a solution of (5)-4-(benzyloxy)-4-oxobutyl 2(ethoxycarbonylamino)-3-methyIbutanoate (350 mg, 1.0 mmol) in EA (10 mL). The reaction was stirred under H₂ atmosphere at 25 °C for 16 h. The reaction was filtered and the filtrate was concentrated to afford the titled compound (240 mg, 91%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.16 (d, J= 8.8 Hz, 1 H), 4.28 - 4.10 (m, 5 H), 2.46 (t, J= 7.2 Hz, 2 H), 2.25 - 2.08 (m, 1 H), 2.05 - 1.96 (m, 2 H), 1.25 (ζ J= 7.0 Hz, 3 H), 0.93 (dd, J = 7.0, 31.4 Hz, 6 H).

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[00439] Scheme 9:

<img file="CA2999367C_D0204.tif" />

<img file="CA2999367C_D0205.tif" />

Example 1-72

[00440] Intermediate compound 72 benzyl 4-hydroxybutanoate

<img file="CA2999367C_D0206.tif" />

[00441] A mixture of dihydrofuran-2(3//)-one (5.1 g, 59.2 mmol) and NaOH (2.37 g, 59.2 mmol) in H₂O (60 mL) was heated under 100 °C for 1 h. The clear solution was then cooled and concentrated The resultant solid was suspended in toluene and concentrated to remove H2O. The resultant solid was suspended in acetone (60 mL), to which TBAF (772 mg, 2.96 mmol) and (bromomethyl)benzene (12.2 g, 71.1 mmol) was added. The reaction was heated under reflux for 3 h. After that, the reaction mixture was partitioned between EA (150 mL) and H2O (100 mL). The organic layer was separated, dried over Na₂S0.4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 2:1-1:2 to afford the titled compound (8.5 g, 74%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.37 - 7.34 (m, 5 H), 5.13 (s, 2 H), 3.68 (t, J= 6.2 Hz, 2 H), 2.50 (t, J= Ί2 Hz, 2 H), 1.94 1.87(m,2H).

[00442] Intermediate compound 72 ’ (S)-4-(benzyloxy)-4-oxobutyl 5-oxopyrrolidine-2-carboxylate

<img file="CA2999367C_D0207.tif" />

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[00443] HATU (2.9 g, 7.7 mmol) and DIPEA (998 mg, 7.7 mmol) was added to a solution of L-pyroglutamic acid (731 mg, 5.7 mmol) and benzyl 4-hydroxybutanoate (1.0 g, 5.1 mmol) in DMF (20 mL). The mixture was stirred at 25 °C for 16 h. The reaction was concentrated and the residue was purified by prep-HPLC to afford the titled compound (0.9 g, 57%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.39 - 7.33 (m, 5 H), 6.34 (br. s., 1 H), 5.13 (s, 2 H), 4.21 (t, J = 6 0 Hz, 3 H), 2.53 - 2.28 (m, 5 H), 2.27 - 2.13 (m, 1 H),2.091.96 (m, 2 H).

[00444] Compound 72: (S)-4-(5-oxopyrrolidine-2-carbonyloxy)butanoic acid

ΛΊ ⁰

ST 0

[00445] Pd/C (90 mg) was added to a solution of (5)-4-(benzyloxy)-4-oxobutyl 5ox opy r r ol id ine-2-car boxy late (900 mg, 3.0 mmol) in EA (20 mL). The reaction was stirred under H₂ atmosphere at 25 °C for 16 h. After that, the reaction mixture was filtered and the filtrate was concentrated to afford the titled compound (580 mg, 91%) as a white solid. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.98 (br. s., 1 H), 4.31-4.16 (m, 3 H), 2.52 - 2.39 (m, 5 H), 2.35 2.19 (m, 1 H), 2.06 - 1.94 (m, 2 H).

[00446] Scheme 10:

<img file="CA2999367C_D0208.tif" />

<img file="CA2999367C_D0209.tif" />

R¹-OH, triphosgene

Et₃N, DCM

<img file="CA2999367C_D0210.tif" />

Example 1-73

[00447] Intermediate compound 73 4-hydroxybutyl (2-methoxyphenyl)carbonate

<img file="CA2999367C_D0211.tif" />

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[00448] A solution of 2-methoxyphenol (1 g, 8.06 mmol) and EtsN (977 mg, 9.68 mmol) in DCM (10 mL) was added dropwise to a stirred solution of triphosgene (788 mg, 2.66 mmol) in DCM (10 mL) at 0 °C during 10 min. After that, the reaction was allowed to warm up gradually and stirred at 25 °C for 2 h. The above reaction solution was added dropwise to a stirred solution of butane-1,4-diol (2.18 g, 24.19 mmol) in DCM (10 mL) at 0 °C during 10 min, and then the reaction mixture was stirred at 25 °C for 14 h. After that, the reaction mixture was diluted with water (10 mL), separated and the organic phase was washed with brine (10 mL), dried over Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with DCM/EA = 10:1 to afford the titled compound (350 mg, 27%) as a colorless oil. *Η NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.22 (ζ J= 8.0 Hz, 1 H), 7.13 (d, J= 6.8 Hz, 1 H), 6.99 - 6.93 (m, 2 H), 4.30 (t, J= 6.4 Hz, 2 H), 3.86 (s, 3 H), 3.72 (t, J= 6.2 Hz, 2 H), 1.89 - 1.82 (m, 2 H), 1.75 - 1.68 (m, 2 H).

[00449] Compound 73:4-((2-methoxyphenoxy)carbonyloxy)butanoic acid

Ο O

<img file="CA2999367C_D0212.tif" />

[00450] Jones reagent was added dropwise to a stirred mixture of 4-hydroxybutyl (2methoxyphenyl) carbonate (350 mg, 1.46 mmol) and Celite® (diatomaceous earth, 700 mg) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of isopropanol, diluted with EA (15 mL), and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with brine (5 mL x 2), dried over Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with DCM/EA = 10:1 to afford the titled compound (180 mg, 49%) as crystalline solids. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.22 (t, J= 8.0 Hz, 1 H), 7.13 (d, J = 6.8 Hz, 1 H), 6.99 - 6.93 (m, 2 H), 4.33 (t, J= 6.2 Hz, 2 H), 3.86 (s, 3 H), 2.55 (t, J = 7.4 Hz, 2 H), 2.12 - 2.05 (m, 2 H).

Example 1-74

[00451 ] Intermediate compound 74 ’:

4-hydroxybutyl (2-isopropyl-5-methylphenyl) carbonate

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<img file="CA2999367C_D0213.tif" />

[00452] A solution of 2-isopropyl-5-methylphenol (1 g, 6.67 mmol) and Et₃N (741 mg, 7.33 mmol) in DCM (10 mL) was added dropwise to a stirred solution of triphosgene (651 mg, 2.20 mmol) in DCM (10 mL) at 0 °C during 10 min. After that, the reaction was allowed to warm up gradually and stirred at 0-25 °C for 2 h. The above reaction solution was dropwise added to a stirred solution of butane-l,4-diol (1.8 g, 20 mmol) in DCM (10 mL) at 0 °C during 10 min, and then the reaction mixture was stirred at 0-25 °C for 14 h. After that, the reaction mixture was diluted with water (10 mL), separated and the organic phase was washed with brine (10 mL), dried over Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 3:1 to afford the titled compound (900 mg, 51%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.19 (d, J= 8.0 Hz, 1 H), 7.04 (d, J = 7.8 Hz, 1 H), 6.90 (s, 1 H), 4.30 (t, J= 6.4 Hz, 2 H), 3.72 (t, J= 6.2 Hz, 2 H), 3.10 - 3.03 (m, 1 H), 2.32 (s, 3 H), 1.89 - 1.82 (m, 2 H), 1.75 - 1.68 (m, 2 H), 1.20 (d, J= 7.2 Hz, 6 H).

[00453] Compound 74:4-((2-isopropyl-5-methylphenoxy)earbonyIoxy)butanoic add

<img file="CA2999367C_D0214.tif" />

[00454] Jones reagent was added dropwise to a stirred mixture of 4-hydroxybutyl (2isopropyl-5-methylphenyl) carbonate (900 mg, 3.38 mmol) and Celite® (diatomaceous earth, 1.8 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of isopropanol, diluted with EA (30 mL), and then filtered. The filtered cake was washed with EA (10 mL) and the combined filtrate was washed with brine (10 mL x 2), dried over Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with DCM/EA = 8:1 to afford the titled compound (500 mg, 53%) as a colorless oil. *11 NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 7.19 (d, J = 8.0 Hz, 1 H), 7.04 (d, J = 7.8 Hz, 1 H), 6.90 (s, 1 H), 4.32 (t, J =

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6.2 Hz, 2 H), 3.09 - 3.02 (m, 1 H), 2.55 (t, J= 7.2 Hz, 2 H), 2.32 (s, 3 H), 2.13 - 2.06 (m, 2 H),

1.20 (d, J =6.8 Hz, 6 H).

Example 1-75

[00455] Intermediate compound 75’:

benzo[dJ[l,3Jdioxol-5-yl (4-hydroxybutyl) carbonate

<img file="CA2999367C_D0215.tif" />

[00456] A solution of benzo[d][l,3]dioxol-5-ol (1 g, 7.25 mmol) and Et₃N (878 mg, 8.70 mmol) in DCM (10 mL) was added dropwise to a stirred solution of triphosgene (708 mg, 2.39 mmol) in DCM (10 mL) at 0 °C during 10 min. After that, the reaction was allowed to warm up gradually and stirred at 0-25 °C for 2 h. The above reaction solution was dropwise added to a stirred solution of butane-1,4-diol (1.96 g, 21.74 mmol) in DCM (10 mL) at 0 °C during 10 min, and then the reaction mixture was stirred at 0-25 °C for 14 h. After that, the reaction mixture was diluted with water (10 mL), separated and the organic phase was washed with brine (10 mL), dried over Na2SO₄ and concentrated, the residue was purified by a silica gel flash column with DCM/EA = 10:1 to afford the titled compound (500 mg, 27%) as a yellow oil. NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 6.75 (d, J- 8.4 Hz, 1 H), 6.67 (d, J= 2.0 Hz, 1 H), 6.60 (dd, J = 2.0, 8.4 Hz, 1 H), 5.97 (s, 2 H), 4.26 (t, J = 6.6 Hz, 2 H), 3.68 (t, J = 6.2 Hz, 2 H), 1.85 - 1.78 (m, 2 H), 1.71 - 1.64 (m, 2 H).

[00457] Compound 75: 4-((benzo[d][l,3]dioxol-5-yloxy)carbonyloxy)butanoic acid O

<img file="CA2999367C_D0216.tif" />

[00458] Jones reagent was added dropwise to a stirred mixture of benzo[&lt;Z|[13]dioxol5-yl (4-hydroxybutyl) carbonate (500 mg, 1.97 mmol) and Celite® (diatomaceous earth, 1 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of isopropanol, diluted with EA (30 mL), and then filtered. The filtered cake was washed with EA (10 mL) and the combined filtrate was washed with brine (10 mL x 2), dried over Na2SO₄and concentrated. The residue was purified by a silica gel flash column with DCM/EA = 8:1

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Example 1-76

[00459] Intermediate compound 76’: 4-methylbenzyl carbonochloridate

<img file="CA2999367C_D0217.tif" />

[00460] Pyridine (4.86 g, 61.48 mmol) was added to a stirred solution of triphosgene (14.5 g, 49.18 mmol) in toluene (100 mL) at 0 °C and the mixture was stirred for 30 min. After that, a solution of /Molylmethanol (5 g, 40.98 mmol) in toluene (50 mL) was dropwise added during 30 min, and then the reaction proceeded at 0 °C for additional 1 h. The reaction mixture was partitioned between water (50 mL) and EA (100 mL), the organic phase was separated and dried over MgSO4, filtered and concentrated. The residue was purified by a silica gel flash column with PE/EA = 10:1 to afford the titled compound (6 g, 79%) as a colorless oil.

[00461] Intermediate compound 76 ’ ’: 4-hydroxybutyl 4-methylbenzyl carbonate

<img file="CA2999367C_D0218.tif" />

[00462] 4-methylbenzyl carbonochloridate (3 g, 16.30 mmol) in DCM (20 mL) was dropwise added to a stirred solution of Et₃N (5 g, 49.50 mmol) and butane-1,4-diol (4.4 g, 48.89 mmol) in DCM (40 mL) at 0 °C during 15 min. The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with water (30 mL) and the aqueous phase was separated. The resulting organic phase was washed with brine (15 mL), dried over Na₂SÛ4 and concentrated, the residue was purified by a silica gel flash column with PE/EA = 3:1 to afford the titled compound (700 mg, 18%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.28 (d, J= 8.0 Hz, 2 H), 7.17 (d, J= 7.6 Hz, 2 H), 5.11 (s, 2 H), 4.18 (t, J= 6.4 Hz, 2 H), 3.67 (t, 6.4 Hz, 2 H), 2.35 (s, 3 H), 1.80 - 1.73 (m, 2 H), 1.68 - 1.61 (m, 2 H).

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[00463] Compound 76: 4-((4-methylbenzyl)oxycarbonyloxy)butanoic acid

O

<img file="CA2999367C_D0219.tif" />

[00464] Jones reagent was added dropwise to a stirred mixture of 4-hydroxybutyl 4methylbenzyl carbonate (700 mg, 2.94 mmol) and Celite® (diatomaceous earth, 1.4 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of isopropanol, diluted with EA (20 mL), and then filtered. The filtered cake was washed with EA (10 mL) and the combined filtrate was washed with brine (10 mL x 2), dried over Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with PE/EA = 2:1 to afford the titled compound (400 mg, 54%) as crystalline solids. *H NMR was performed at 400MHz with CDCb as solvent to characterize the titled compound, results are as follows: δ = 7.28 (d, J = 8.0 Hz, 2 H), 7.17 (d, J = 8.0 Hz, 2 H), 5.11 (s, 2 H), 4.20 (t, J = 6.4 Hz, 2 H), 2.47 (t, J = 7.2 Hz, 2 H), 2.35 (s, 3 H), 2.03 - 1.96 (m, 2 H).

Example 1-77

[00465] Intermediate compound 77':

4-hydroxybutyl (tetrahydro-2H-pyran-4-yl) carbonate

O

<img file="CA2999367C_D0220.tif" />

[00466] A solution of tetrahydro-2//-pyran-4-ol (1.0 g, 9.8 mmol) and EtjN (1.2 g, 11.8 mmol) in DCM (10 mL) was added dropwise to solution of triphosgene (1.0 g, 3.2 mmol) in DCM (10 mL) at 0 °C. After the addition is complete, the reaction was stirred at 0 °C for 1 h. After that, the above slurry was added dropwise.to the suspension of butane-1,4-diol (2.7 g, 29.4 mmol) in DCM (10 mL) at 0 °C. The resulting mixture was warmed up gradually to 25 °C and stirred for 16 h. The reaction was quenched by water (10 mL) and separated. The organic phase was dried over Na₂SO₄, filtered and concentrated. The residue was purified by a silica gel flash column with PE/EA = 10:1-1:1 to afford the titled compound (380 mg, 18%) as a colorless oil. ^]H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.82 - 4.78 (m, 1 H), 4.18 (t, J= 6.4 Hz, 2 H), 3.97 - 3.92 (m, 2 H), 3.69 (t, J = 6.2 Hz, 2 H), 3.70 - 3.53 (m, 2 H), 2.06 - 1.93 (m, 2 H), 1.87 - 1.59 (m, 6 H).

[00467] Compound 77: 4-((tetrahydro-2H-pyran-4-yl)oxycarbonyloxy)butanoic acid

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<img file="CA2999367C_D0221.tif" />

Ο

[00468] Jones reagent was added dropwise to a stirred mixtue of 4-hydroxybutyl (tetrahydro-2/f-pyran-4-yl) carbonate (300 mg, 1.4 mmol) and Celite® (diatomaceous earth, 0.6 g) in acetone (6 mL). The reaction proceeded at 0 °C over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of isopropanol, diluted with EA (20 mL), and then filtered. The filtered cake was washed with EA (20 mL) and the combined filtrate was washed with brine (10 mL x 2), dried over Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with PE/EA = 50:15:1 to afford the titled compound (110 mg, 34%) as crystalline solids. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.84 - 4.77 (m, 1 H), 4.20 (ζ J= 6.4 Hz, 2 H), 4.03 - 3.86 (m, 2 H), 3.64 - 3.44 (m, 2 H), 2.50 (t. J = Ί.6 Hz, 2 H), 2.05 - 1.88 (m, 4 H), 1.79 - 1.70 (m, 2 H).

[00469] Scheme 11:

<img file="CA2999367C_D0222.tif" />

<img file="CA2999367C_D0223.tif" />

(Boc)₂O

DMAP, DCM

<img file="CA2999367C_D0224.tif" />

Example 1-78

[00470] Intermediate Compound 78’: tert-butyl (4-hydroxybutyl) carbonate

<img file="CA2999367C_D0225.tif" />

[00471] (Boc)₂O (2.05 g, 9.4 mmol) and DMAP (100 mg) was added to a stirred solution of butane-l,4-diol (10 g, 111.11 mmol) in DCM (100 mL). The reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with saturated aqueous NH4CI (20 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (20 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na₂SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 10:1 to yield the titled compound (1 g, 56%) as a colorless oil. ’H NMR was

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[00472] Compound 78: 4-(tert-butoxycarbonyloxy)butanoic acid ⁰

<img file="CA2999367C_D0226.tif" />

[00473] Jones reagent was added in portions to a stirred mixture of tert-butyl (4hydroxybutyl) carbonate (800 mg, 4.21 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SÛ4 and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-6:1 to yield the titled compound (500 mg, 58%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.12 (t, J= 6.2 Hz, 2 H), 2.49 (t, J= 7.4 Hz, 2 H), 2.03 - 1.96 (m, 2 H), 1.48 (s, 9 H).

[00474] Scheme 12:

<img file="CA2999367C_D0227.tif" />

<img file="CA2999367C_D0228.tif" />

Example 1-79

[00475] Intermediate compound 79 ’: benzyl 4-(chlorocarbonyloxy)butanoate

<img file="CA2999367C_D0229.tif" />

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[00476] Pyridine (305 mg, 3.9 mmol) was slowly added to a solution of triphosgene (976 mg, 3.4 mmol) in toluene (10 mL) at 0 °C and stirred for 0.5 h. A solution of benzyl 4hydroxybutanoate (500 mg, 2.6 mmol) in toluene (5 mL) was added to the above formed slurry at 0 °C. The reaction was allowed to warm up and stirred at 25 °C for 1.5 h. After that, the reaction mixture was partitioned between water (15 mL) and EA (15 mL). The organic layer was separated, washed with brine (10 mL), dried over Na₂SO₄ and filtered. The filtrated was concentrated to yield a light yellow oil, which was purified by a silica gel flash column with PE/EA = 20:1-5:1 to afford the titled compound (490 mg, 74%) as colorless oil. *H NMR was performed at 400MHz with CDCh as solvent to characterize the titled compound, results are as follows: 5 = 7.43 - 7.27 (m, 5 H), 5.14 (s, 2 H), 4.37 (t, J= 6.2 Hz, 2 H), 2.50 (t, J= 7.2 Hz, 2 H), 2.12 - 2.05 (m, 2 H).

[00477] Intermediate compound 79’ V benzyl 4-((l-methylpiperidin-4-yl)oxycarbonyl oxy) butanoate o

<img file="CA2999367C_D0230.tif" />

[00478] A solution of benzyl 4-(chlorocarbonyloxy)butanoate (500 mg, 1.95 mmol) and Et₃N (395 mg, 3 .91 mmol) in DCM (5 mL) was added dropwise to a stirred solution of 1methylpiperidin-4-ol (225 mg, 1.96 mmol) in DCM (5 mL) at 0 °C during 10 min. After that, the reaction mixture was diluted with water (5 mL), the resulting aqueous phase was separated and extracted with DCM (5 mL). The combined organic phase was washed with brine (5 mL), dried over NazSO₄, filtered and concentrated. The residue was purified by prepHPLC to afford the titled compound (240 mg, 37%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.43 - 7.29 (m, 5 H), 5.12 (s, 2 H), 4.77 (br. s„ 1 H), 4.18 (t, J= 6.2 Hz, 2 H), 2.84 - 2.65 (m, 4 H), 2.51 - 2.47 (m, 5 H), 2.18 - 1.99 (m, 4 H), 1.98 - 1.83 (m, 2 H).

[00479]

Compound 79: 4-((l-methylpiperidin-4-yl)uxycurbonyloxy)butanoic acid

<img file="CA2999367C_D0231.tif" />

[00480] Pd/C (40 mg) was added to a solution of benzyl 4-((l-methylpiperidin-4 yl)oxycarbonyloxy)butanoate (200 mg, 0.6 mmol) in methanol (3 mL). The mixture was

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PCT/CN2016/099763 stirred at 25 ^CC under H₂ atmosphere for 16 h. After that, the mixture was filtered through Celite® (diatomaceous earth) and the filtered cake was washed with methanol (3 mL). The combined filtrate was concentrated, the residue was purified by prep-HPLC to afford the titled compound (15 mg, 10%) as crystalline solids. ’H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.92 (br. s., 1 H), 4.22 (t, J = 6.4 Hz, 2 H), 3.19 (br. s„ 4 H), 2.77 (s, 3 H), 2.44 (t, J = 7.2 Hz, 2 H), 2.35 - 2.20 (m, 2 H), 2.13 - 2.08 (tn, 2 H), 2.05 - 1.98 (m, 2 H).

[00481] Scheme 13:

oo ci 0Ji _ho-^s^\x^{OH 01} r ^{R3 OH} r ^Ho Et3N, DCM ⁰ Et3N, acetone ⁰ . ⁰II oxidation11 ^RV^O'R2^n^^^^OH *

[T K \J Γ| Γ\ U|T

000

Example 1-80

[00482] Intermediate Compound 80’: 4-hydroxybutyl 2-chloroacetate

Cl o

[00483] A solution of 2-chloroacetyl chloride (5 g, 44.25 mmol) in DCM (10 mL) dropwise during 10 min was added to a stirred solution of butane-1,4-diol (19.9 g, 221.11 mmol) and Et₃N (8.9 g, 88.5 mmol) in DCM (40 mL) at 0 °C. The reaction was allowed to warm up gradually and stirred at 0 - 25 °C over 16 h. After that, the reaction mixture was diluted with Η₂Ο (20 mL) and stirred for 5 min. The aqueous phase was separated and extracted with DCM (20 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4 and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 5:1 to yield the titled compound (3.2 g, 44%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 4.24 (t, J= 6.6 Hz, 2 H), 4.07 (s, 2 H), 3.69 (t, J= 6.4 Hz, 2 H), 1.82 - 1.75 (m, 2 H), 1.68 - 1.61 (m, 2 H).

[00484] Intermediate Compound 80 ’ ’:

2-(4-hydroxyhutoxy)-2-oxoethyl 2-ethylhenzoate

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Ο

<img file="CA2999367C_D0232.tif" />

[00485] EtsN (365 mg, 3.61 mmol) and 4-hydroxybutyl 2-chloroacetate (300 mg, 1.81 mmol) was added to a stirred solution of 2-ethylbenzoic acid (542 mg, 3.61 mmol) in acetone (10 mL). The reaction was stirred at 50 °C for 5 h. After that, the reaction mixture was partitioned between DCM (20 mL) and HjO (10 mL). The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na^SCE and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 6:1 to yield the titled compound (175 mg, 35%) as a colorless oil. 'H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 8.02 - 7.95 (m, 1 H), 7.49 - 7.44 (m, 1 H), 7.32 7.24 (m, 2 H), 4.83 (s, 2 H), 4.25 (t, 6.4 Hz, 2 H), 3.67 (t, J= 6.4 Hz, 2 H), 3.08 - 2.97 (m,

H), 1.81 - 1.74 (m, 2 H), 1.67 - 1.60 (m, 2 H), 1.28 - 1.22 (m, 3 H).

[00486] Compound 80:4-(2-(2-ethylbenzoyloxy)acetoxy)butanoic acid

<img file="CA2999367C_D0233.tif" />

[00487] Jones reagent was added in portions to a stirred mixture of 2-(4hydroxybutoxy)-2-oxoethyl 2-ethylbenzoate (170 mg, 0.61 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (90 mg 51%) as a colorless oil. NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.96 (d, J= 7.6 Hz, 1 H), 7.46 (t, J= 7.0 Hz, 1 H), 7.31 - 7.25 (m, 2 H), 4.83 (s, 2 H), 4.28 (t, J= 6.2 Hz, 2 H), 3.00 (q, J= 7.6 Hz, 2 H), 2.47 (t, J= 7.4 Hz, 2 H), 2.06 - 1.99 (m, 2 H), 1.24 (t, J= 7.4 Hz, 3 H).

Example 1-81

[00488] Intermediate Compound 81 ’:

2-(4-hydroxybutoxy)-2-oxoethyl 2,4-dimethylbenzoate

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<img file="CA2999367C_D0234.tif" />

[00489] Et₃N (364 mg, 3.6 mmol) and 4-hydroxybutyl 2-chloroacetate (300 mg, 1.81 mmol) to a stirred solution of 2,4-dimethylbenzoic acid (405 mg, 2.7 mmol) in acetone (10 mL). The reaction was stirred at 50 °C for 5 h. After that, the reaction mixture was partitioned between DCM (20 mL) and H₂O (10 mL). The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 6:1 to yield the titled compound (350 mg, 69%) as a colorless oil. *H NMR was performed at 400MHz with CDClj as solvent to characterize the titled compound, results are as follows: δ = 7.92 (d, J= 8.0 Hz, 1 H), 7.08 - 7.06 (m, 2 H), 4.81 (s, 2 H), 4.24 (t, J= 6.6 Hz, 2 H), 3.67 (t, 6.2 Hz, 2 H), 2.59 (s, 3 H), 2.36 (s, 3 Η), 1.80 - 1.73 (m, 2 H),

1.66 - 1.60 (m, 2 H), 1.44 (br. s„ 1 H)

[00490] Compound 81:4-(2-(2,4-dimethylbcnzoyloxy)acetoxy)butanoic acid

<img file="CA2999367C_D0235.tif" />

[00491] Jones reagent was added in portions to a stirred mixture of 2-(4hydroxybutoxy)-2-oxoethyl 2,4-dimethylbenzoate (300 mg, 1.07 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (150 mg, 48%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.92 (d, J = 8.4 Hz, 1 H), 7.18 - 7.06 (m, 2 H), 4.81 (s, 2 H), 4.27 (t, J = 6.2 Hz, 2 H), 2.58 (s, 3 H), 2.47 (t, J = 7.4 Hz, 2 H), 2.36 (s, 3 H), 2.06 - 2.00 (m, 2 H).

Example 1-82

[00492] Intermediate Compound 82 ’:

2-(4-hydroxybutoxy)-2-oxoethyl 2,3-dimethoxybenzoate

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<img file="CA2999367C_D0236.tif" />

[00493] EtjN (364 mg, 3.6 mmol) and 4-hydroxybutyl 2-chloroacetate (300 mg, 1.81 mmol) was added to a stirred solution of 2,3-dimethoxybenzoic acid (655 mg, 3.6 mmol) in acetone (10 mL). The reaction was stirred at 50 °C for 5 h. After that, the reaction mixture was partitioned between DCM (20 mL) and H2O (10 mL). The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 2:1 to yield the titled compound (200 mg, 35%) as a colorless oil. ²H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ =7.43 (dd, ./= 2.4, 6.8 Hz, 1 H), 7.14 - 7.08 (m, 2 H), 4.84 (s, 2 H), 4.25 (t, J= 6.5 Hz, 2 H), 3.93 (s, 3 H), 3.89 (s, 3 H), 3.67 (t, J = 6.2 Hz, 2 H), 1.81-1.74 (m, 2 H), 1.67 - 1.60 (m, 2 H).

[00494] Compound 82:4-(2-(2,3-dimethoxybenzoyloxy)acetoxy)butanoic acid ^0 0 0

<img file="CA2999367C_D0237.tif" />

[00495] Jones reagent was added in portions to a stirred mixture of 2-(4hydroxybutoxy)-2-oxoethyl 2,3-dimethoxybenzoate (200 mg, 0.64 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was washed with saturated brine (2 mL x 2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 5:1-2:1 to yield the titled compound (100 mg, 48%) as a colorless oil. NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.43 (dd, J = 2.6, 7.0 Hz, 1 H), 7.14 - 7.09 (m, 2 H), 4.84 (s, 2 H), 4.27 (t, J= 6.0 Hz, 2 H), 3.93 (s, 3 H), 3.89 (s, 3 H), 2.47 (t, J = 7.2 Hz, 2 H), 2.06 - 1.99 (m, 2 H).

Example 1-83

[00496] Intermediate Compound 83 ’: 2-(4-hydroxybutoxy)-2-oxoethyl benzoate

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<img file="CA2999367C_D0238.tif" />

[00497] Et₃N (364 mg, 3.6 mmol) and 4-hydroxybutyl 2-chloroacetate (300 mg, 1.81 mmol) was added to a stirred solution of benzoic acid (439 mg, 3.6 mmol) in acetone (10 mL). The reaction was stirred at 50 °C for 5 h. After that, the reaction mixture was partitioned between DCM (20 mL) and H₂O (10 mL). The aqueous phase was separated and extracted with DCM (10 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO₄ and evaporated. The residue was purified by a silica gel flash column with Hex/EA = 6:1 to yield the titled compound (260 mg, 57%) as a colorless oil. *H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 8.10 (d, J = 7.2 Hz, 2 H), 7.60 (t, J = 7.4 Hz, 1 H), 7.47 (t, J= 7.8 Hz, 2 H), 4.85 (s, 2 H), 4.25 (t, 7 = 6 6 Hz, 2 H), 3.67 (t, 7 = 6.2 Hz, 2 Η), 1.80 - 1.73 (m, 2 H), 1.66 - 1.59 (m, 2 H).

[00498] Compound 83:4-(2-(benzoyloxy)acetoxy)butanoic acid

<img file="CA2999367C_D0239.tif" />

Jones reagent was added in portions to a stirred mixture of 2-(4-hydroxybutoxy)-2-oxoethyl benzoate (250 mg, 0.99 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0 °C. The reaction proceeded at 0 °C for over 1 h and the reaction progress was monitored by TLC. After completion, the reaction was quenched with drops of /PrOH, diluted with EA (10 mL) and then filtered. The filtered cake was washed with EA (5 mL) and the combined filtrate was w’ashed with saturated brine (2 mL x 2), dried over anhydrous Na2SO₄ and concentrated. The residue was purified by a silica gel flash column with Hex/EA = 10:1-5:1 to yield the titled compound (140 mg, 53%) as a white solid. *H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 8.10 (d, J = 7.2 Hz, 2 H), 7.60 (t, 7 = 7.4 Hz, 1 H), 7.47 (t, 7= 7.8 Hz, 2 H), 4.85 (s, 2 H), 4.27 (t, 7 = 6.2 Hz, 2 H), 2.46 (t, 7= 7.4 Hz, 2 H), 2.05 - 1.98 (m, 2 H).

[00499] Scheme 14:

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<img file="CA2999367C_D0240.tif" />

<img file="CA2999367C_D0241.tif" />

<img file="CA2999367C_D0242.tif" />

Example 1-84

[00500] Intermediate compound 84’: benzyl 4-(2-chloroacetoxy)butanoate o

UL ^Bn cr o o [00501] A solution of 2-chloroacetyl chloride (865 mg, 7.65 mmol) in DCM (10 mL) was added to a stirred solution of benzyl 4-hydroxybutanoate (1350 mg, 6.96 mmol) and Et₃N (1406 mg, 13.92 mmol) in DCM (10 mL) at 0 °C during 10 min. The reaction was stirred at 25 °C for 16 h. After completion, the reaction mixture was diluted with water (10 mL). The organic phase was collected, washed with brine (5 mL), dried over Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with PE/EA = 8:1 to afford the titled compound (977 mg, 52%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.41 - 7.30 (m, 5 H), 5.13 (s, 2 H), 4.24 (t, J = 6.4 Hz, 2 H), 4.02 (s, 2 H), 2.47 (t, J= 7.4 Hz, 2 H), 2.07 - 2.00 (m, 2 H).

[00502] Intermediate compound 84’:

benzyl 4-(2-2-(tert-butoxycarbonyl)aminoacetoxyacetoxy)butanoate

<img file="CA2999367C_D0243.tif" />

[00503] A solution of 2-(/er/-butoxycarbonylamino)acetic acid (654 mg, 3.74 mmol),

Et₃N (686 mg, 6.79 mmol) and benzyl 4-(2-chloroacetoxy)butanoate (917 mg, 3.40 mmol)

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[00504] Intermediate compound 84 * * *:

2,2-dimethyl-4,7,10-trioxo-3,8,ll-trioxa-5-azapentadecan-l5-oic acid

<img file="CA2999367C_D0244.tif" />

[00505] Pd/C (100 mg) was added to a stirred solution of benzyl 4-(2-2-(tertbutoxycarbonyl)aminoacetoxyacetoxy)butanoate (1 g, 2.44 mmol) in THF (10 mL), the mixture was stirred at 25 °C under H₂ atmosphere for 16 h. After that, the reaction mixture was filtered through Celite* (diatomaceous earth). The filtered cake was washed with EA (5 mL), the combined filtrate was concentrated. The residue was purified by prep-HPLC to afford the titled compound (600 mg, 77%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.11 (br. s., 1 H), 4.70 (s, 2 H), 4.24 (t, J = 5.8 Hz, 2 H), 4.11 (d, J= 6.0 Hz, 2 H), 2.46 (t, J = 6.8 Hz, 2 H), 2.10 - 2.02 (m, 2 H), 1.46 (s, 9 H).

[00506]

Compound 84: 4-(2-(2-aminoacetoxy)acetoxy)butanoic acid

<img file="CA2999367C_D0245.tif" />

[00507] 2,2-dimethyI-4,7,10-trioxo-3,8,ll-trioxa-5-azapentadecan-15-oic acid (600 mg, 1.88 mmol) was dissolved in HC1/EA (6 mL, ~2 M) and the solution was stirred at 25 °C for 16 h. After that, the reaction mixture was filtered, the collected solid was washed with Et₂O (5 mL) to afford the titled compound (450 mg, 94%) as crystalline solids in HC1 salt form. ’H NMR was performed at 400MHz with D₂O as solvent to characterize the titled

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[00508] Scheme 15:

<img file="CA2999367C_D0246.tif" />

<img file="CA2999367C_D0247.tif" />

Et₃N, DCM

<img file="CA2999367C_D0248.tif" />

<img file="CA2999367C_D0249.tif" />

Et₃N, Nai, DMF

<img file="CA2999367C_D0250.tif" />

Example 1-85

[00509] Intermediate compound 85’.· benzyl 4-(2-chloropropanoyloxy)butanoate

<img file="CA2999367C_D0251.tif" />

[00510] A solution of 2-chloropropanoyl chloride (1080 mg, 8.50 mmol) in DCM (10 mL) was dropwise added to a stirred solution of benzyl 4-hydroxybutanoate (1.5 g, 7.73 mmol) Et₃N (1562 mg, 15.47 mmol) in DCM (10 mL) at 0 °C, the reaction was stirred at 25 °C for 16 h. After that, the reaction mixture was diluted with water (10 mL), the aqueous phase was separated and the organic phase was washed with brine (10 mL), dried over Na₂SO₄ and concentrated. The residue was purified by a silica gel flash column with PE/EA = 8:1 to afford the tided compound (1.38 g, 63%) as a colorless oil. ’ll NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.41 - 7.30 (m, 5 H), 5.13 (s, 2 H), 4.36 (q, J = 7.0 Hz, 1 H), 4.22 (t, J = 6.0 Hz, 2 H), 2.48 (t, J= 7.4 Hz, 2 H), 2.07 - 2.00 (m, 2 H), 1.67 (d, J= 6.8 Hz, 3 H).

Intermediate compound 85”:

benzyl 4-(2-(2-(tert-butoxycarbonyl)amitwacetoxy)propanoyloxy)butanoate

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Ο

<img file="CA2999367C_D0252.tif" />

[00511] Et₃N (782 mg, 7.75 mmol) and Nai (20 mg) was added to a stirred solution of 2-(/er/-butoxycarbonylamino)acetic acid (746 mg, 4.26 mmol) and benzyl 4-(2chloropropanoyloxy)butanoate (1.1 g, 3.87 mmol) in DMF (15 mL), the reaction mixture was stirred at 70 °C for 16 h. After that, the mixture was concentrated, the residue was partitioned between EA (20 mL) and water (10 mL). The aqueous phase was separated, the organic phase was washed with brine (10 mL), dried over Na2SO₄ and concentrated. The residue was purified by a silica gel flash column with PE/EA = 5:1 to afford the titled compound (1.1 g, 69%) as a colorless oil ’H NMR was performed at 400MHz with CDCI₃as solvent to characterize the titled compound, results are as follows: δ = 7.43 - 7.29 (m, 5 H), 5.15 - 5.09 (m, 3 H), 5.00 (br. s„ 1 H), 4.19 (t, J= 6.2 Hz, 2 H), 4.06 (dd, J= 6.0, 18.4 Hz, 1 H), 3.93 (dd, J = 5.0, 14.2 Hz, 1 H), 2.44 (t. J= 7.2 Hz, 2 H), 2.03 - 1.97 (m, 2 H), 1.49 (d, J = 6.8 Hz, 3 H), 1.45 (s, 9 H).

[00512] Intermediate compound 85 2,2,9-trimethyl-4,7,10-trioxo-3,8,ll-trioxa-5-azapentadecan-15-oic acid 0

Boc.,,/-^ JD. /-. /-. ,OH N Y OY

H JIII

Pd/C (100 mg) was added to a stirred solution of benzyl 4-(2-(l-(tertbutoxycarbonyl)aniinoacetoxy)propanoyloxy)butanoate (1.1 g, 2.60 mmol) in THF (10 mL), the reaction mixture was stirred at 25 °C under H₂ atmosphere for 16 h. After that, the reaction mixture was filtered through Celite® (diatomaceous earth) and the filtered cake was washed with EA (5 mL). The combined filtrate was concentrated, the residue was purified by prep-HPLC to afford the titled compound (800 mg, 92%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 5.21 (q, J = 6.8 Hz, 1 H), 5.12 (br. s., 1 H), 4.29 - 4.09 (m, 3 H), 3.94 (dd, 4.6, 18 8 Hz, 1 H), 2.45 (t, J= 6.8 Hz, 2 H), 2.09 - 1 98 (m, 2 Η), 1.50 (d, J= 7.2 Hz, 3 H), 1.46 (s,9H).

[00513] Compound 85: 4-(2-(2-aminoacetoxy)propanoyloxy)butanoic acid

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Ο

<img file="CA2999367C_D0253.tif" />

[00514] 2,2,9-trimethyl-4,7,10-trioxo-3,8,l l-trioxa-5-azapentadecan-15-oic acid (770 mg, 2.31 mmol) was dissolved in HC1/EA (10 mL, -2 M) at 0 °C and the solution was stirred at 25 °C for 16 h. After that, the reaction mixture was concentrated, the residue was purified by prep-HPLC to afford the titled compound (48 mg, 9%) as a colorless oil in HC1 salt form. *H NMR was performed at 400MHz with D₂O as solvent to characterize the titled compound, results are as follows: δ = 5.26 (d, J= Ί.2 Hz, 1 H), 4.23 (dt, J= 2.8, 6.0 Hz, 2 H), 4.00 (d, J= 1.6 Hz, 2 H), 2.45 (t, J= 7.0 Hz, 2 H), 2.01 - 1.91 (m, 2 H), 1.50 (d, J= 7.2 Hz, 3 H).

<img file="CA2999367C_D0254.tif" />

Example 1-86 [00516] Intermediate compound 86 benzyl 4-(2-(2-acetanudoacetoxy)propanoyloxy)butanoate

<img file="CA2999367C_D0255.tif" />

[00517] A mixture of benzyl 4-(2-chloropropanoyloxy)butanoate (500 mg, 1.76 mmol), 2-acetamidoacetic acid (260 mg, 2.22 mmol), Nai (138 mg, 0.92 mmol) and Et?N (0.52 mL, 3.69 mmol) in DMF (5 mL) was stirred at 80 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel flash column with PE/EA = 5:1 to afford the titled compound (500 mg, 78%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.39 - 7.31 (m, 5 H), 6.01 (br. s., 1 H), 5.13 (s, 2 H), 5.10 (t, J= 3.2

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Hz, 1 H), 4.25 - 4.18 (m, 3 H), 4.03 (dd, J= 4.8, 18.8 Hz, 1 H), 2.44 (t, J= ΊΑ Hz, 2 H), 2.04 - 1.97 (m, 5 H), 1.50 (d, J= 7.2 Hz, 3 H).

[00518] Compound 86:4-(2-(2-acetamidoacetoxy)propanoyloxy)butanoic acid o o

<img file="CA2999367C_D0256.tif" />

[00519] Pd/C (150 mg) was added to a stirred solution of benzyl 4-(2-(2acetamidoacetoxy)propanoyloxy)butanoate (500 mg, 1.37 mmol) in THF (10 mL), the reaction was stirred at 25 °C for 16 h under H? atmosphere. After that, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by a silica gel flash column with PE/EA = 1:50 to afford the titled compound (280 mg, 74%) as a white solid. ¹H NMR was performed at 400MHz with rf₆-DMSO as solvent to characterize the titled compound, results are as follows: δ = 12.15 (s, 1 H), 8.34 (t, J- 5.6 Hz, 1 H), 5.02 (q, J- 6.8 Hz, 1 H), 4.12 - 4.06 (m, 2 H), 3.93 (dd, J = 6.2, 17.8 Hz, 1 H), 3.84 (dd, J= 6.0, 17.6 Hz, 1 H), 2.28 (t, J= 7.2 Hz, 2 H), 1.85 (s, 3 H), 1.84 - 1.77 (m, 2 H), 1.41 (d, J= 7.2 Hz, 3 H).

<img file="CA2999367C_D0257.tif" />

Example 1-87

[00521] Intermediate compound 87’:

benzyl 4-((l-chloroethoxy)carbonyloxy)butanoate

<img file="CA2999367C_D0258.tif" />

[00522] 1-chloroethyl carbonochloridate (1.0 g, 7.2 mmol) was added dropwise to a solution of benzyl 4-hydroxybutanoate (1.0 g, 5.2 mmol) and Et₃N (1.1 mL, 1.7 mmol) in DCM (10 mL) over 5 min at -5 - 0 °C. After that, the reaction was quenched by water (5 mL). The organic layer was separated, dried over Na₂SO₄ and filtered. The filtrate was

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[00523] Intermediate compound 87’ ’:

benzyl 4-((1 -acetoxyethoxy)carbonyloxy)butanoate

<img file="CA2999367C_D0259.tif" />

[00524] A solution of benzyl 4-((l-chloroethoxy)carbonyloxy)butanoate (180 mg, 598 μ mol ), acetic acid (720 mg, 12.0 mmol) and EtjN (151 mg, 1.5 mmol) in acetone (4 mL) was heated under reflux for 2 days. The reaction was diluted with EA (20 mL) and washed with water (10 mL). The organic layer was separated, dried over Na₂SO₄ and filtered. The filtrate was concentrated and the residue was purified by a silica gel flash column with PE/EA = 10:1-3:1 to afford the titled compound (120 mg, 64%) as a colorless oil. *Η NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.38 -7.33 (m, 5 H), 6.74 (q, J= 3.6 Hz, 1 H), 5.13 (s, 2 H), 4.21 (t, J~ 6.2 Hz, 2 H), 2.48 (t, J = 4.8 Hz, 2 H), 2.08 (s, 3 H), 2.06 - 2.01 (m, 2 Η), 1.51 (d, J = 3.6 Hz, 3 H).

[00525] Compound 87:4-((l-acetoxyethoxy)carbonyloxy)butanoic acid o

<img file="CA2999367C_D0260.tif" />

[00526] Pd/C (10 mg) was added to a mixture of benzyl 4-((1acetoxyethoxy)carbonyloxy)butanoate (110 mg, 339 pmol) in EA (2 mL). The reaction was stirred under H₂ atmosphere for 16 h at 25 °C. After that, the reaction mixture was filtered and the filtrate was concentrated to afford the titled compound (70 mg, 88%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 6.75 (q, J = 5.2 Hz, 1 H), 4.23 (t, J = 6.2 Hz, 2 H), 2.49 (t, J = 7.2 Hz, 2 H), 2.09 (s, 3 H), 2.06 - 1.99 (m, 2 Η), 1.52 (d, J= 5.2 Hz, 3 H).

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Example 1-88 [00527J Intermediate compound 88 benzyl 4-(1 -(isobutyryloxy)ethoxycarbonyloxy)butanoate

<img file="CA2999367C_D0261.tif" />

[00528] A solution of benzyl 4-((l-chloroethoxy)carbonyloxy)butanoate (300 mg, 998 pmol), isobutyric acid (879 mg, 10.0 mmol), Nai (179 mg, 1.2 mmol) and EtsN (121 mg, 1.2 mmol) in acetone (6 mL) was heated under reflux for 2 days. After that, the reaction mixture was diluted with EA (20 mL) and washed with saturated NaHCO₃ (10 mL). The organic layer was separated, dried over Na₂SO₄ and filtered. The filtrate was concentrated and the residue was purified by a silica gel column with PE/EA = 50:1-5:1 to afford the titled compound (300 mg, 85%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.42 - 7.29 (m, 5 H), 6.74 (q, J = 5.2 Hz, 1 H), 5.12 (s, 2 H), 4.21 (t, J= 6.2 Hz, 2 H), 2.58 - 2.51 (m, 1 H), 2.48 (t, J = 7.2 Hz, 2 H), 2.06 - 2.00 (m, 2 Η), 1.51 (d, J = 5.6 Hz, 3 H), 1.17 (d, J = 7.2 Hz, 6 H).

[00529] Compound 88: 4-(l-(isobutyryloxy)ethoxycarbonyloxy)butanoic acid

O

<img file="CA2999367C_D0262.tif" />

[00530] Pd/C (28 mg) was added to a mixture of benzyl 4-(1(isobutyryloxy)ethoxycarbonyloxy)butanoate (280 mg, 795 pmol) in EA (6 mL). The reaction was stirred under H₂ atmosphere for 16 h at 25 °C. After that, the reaction mixture was filtered and the filtrate was concentrated to afford the titled compound (200 mg, 96%) as a colorless oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 6.74 (q, J= 5.6 Hz, 1 H), 4.23 (t, J= 6.0 Hz, 2 H), 2.60 - 2.53 (m, 1 H), 2.49 (t, J = 12 Hz, 2 H), 2.06 - 1.99 (m, 2 H), 1.52 (d, J~ 5.2 Hz, 3 H), 1.18 (d, ./ = 6.8 Hz, 6 H).

Example 1-89

[00531] Intermediate compound 89 ’:

I-((4-benzyloxy-4-oxobutoxy)carbonyloxy)ethyl benzoate

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<img file="CA2999367C_D0263.tif" />

[00532] A solution of benzyl 4-((l-chloroethoxy)carbonyloxy)butanoate (300 mg, 998 μιηοΐ), benzoic acid (244 mg, 2.0 mmol), Nai (179 mg, 1.2 mmol) and Et₃N (121 mg, 1.2 mmol) in acetone (6 mL) was heated under reflux for 3 days. After that, the reaction was diluted with EA (20 mL) and washed with saturated NaHCO₃ (10 mL). The organic layer was separated, dried over Na^SCU and filtered. The filtrate was concentrated and the residue was purified by a silica gel flash column with PE/EA = 100:1-10:1 to afford the titled compound (240 mg, 62%) as a colorless oil. ^]H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 8.05 (d, J = 7.2 Hz, 2 H), 7.58 (t, J= 7.4 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.39 - 7.28 (m, 5 H), 7.02 (q, J= 5.6 Hz, 1 H), 5.11 (s, 2 H), 4.32 - 4.12 (m, 2 H), 2.48 (t, J= 7.6 Hz, 2 H), 2.07 - 1.97 (m, 2 H), 1.65 (d, J = 5.6 Hz, 3 H).

[00533] Compound 89:4-(l-(benzoyloxy)ethoxycarbonyloxy)butanoic acid

<img file="CA2999367C_D0264.tif" />

[00534] Pd/C (20 mg) was added to a mixture of l-((4-benzyloxy-4oxobutoxy)carbonyloxy)ethyl benzoate (200 mg, 518 pmol) in EA (4 mL). The reaction was stirred under H₂ atmosphere for 16 h at 25 °C. After that, the reaction mixture was filtered and the filtrate was concentrated to afford the titled compound (120 mg, 78%) as a sticky oil. *H NMR was performed at 400MHz with CDC1₃ as solvent to characterize the titled compound, results are as follows: δ = 8.06 (d, J- 7.2 Hz, 2 H), 7.59 (t, J=· 7.4 Hz, 1 H), 7.45 (t, J= 7.6 Hz, 2 H), 7.03 (q, J= 5.6 Hz, 1 H), 4 24 (t, J = 6 4 Hz, 2 H), 2.49 (t, J= 7.2 Hz, 2 H), 2.06 - 1.99 (m, 2 Η), 1.66 (d, J = 5.6 Hz, 3 H)

Example 1-90

[00535] Intermediate compound 90’:

benzyl 4-(3,10,10-trimethyl-5,8-dioxo-2,4,9-trioxa-7-azaundecan-l-oyloxy)butanoate

<img file="CA2999367C_D0265.tif" />

Roc N H

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[00536] A solution of benzyl 4-((l-chloroethoxy)carbonyloxy)butanoate (450 mg, 1.5mmol), 2-(/er/-butoxycarbonylamino)acetic acid (524 mg, 3.0 mmol), Nal (449 mg, 3.0 mmol) and Et₃N (182 mg, 1.8 mmol) in acetone (10 mL) was heated under reflux for 3 days. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by a silica gel flash column with PE/EA = 10:1-1:1 to afford the titled compound (390 mg, 59%) as a colorless sticky oil. *H NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 7.39 - 7.31 (m, 5 H), 6.80 (q, J = 5.6 Hz, 1 H), 5.12 (s, 2 H), 4.97 (br. s„ 1 H), 4.21 (t, J = 6.2 Hz, 2 H), 4.03 - 3.84 (m, 2 H), 2.48 (t, J= 7.4 Hz, 2 H), 2.06 - 2.00 (m, 2 H), 1.53 (d, J = 5.2 Hz, 3 H), 1.44 (s, 9 H).

[00537] Intermediate compound 90 ’ ’:

2,2,9-trimethyl-4,7,ll-trioxo-3,8,10,12-tetraoxa-5-azahexadecan-16-oic acid

O

<img file="CA2999367C_D0266.tif" />

[00538] Pd/C (38 mg) was added to a mixture of benzyl 4-(3,10,10-trimethyl-5,8dioxo-2,4,9-trioxa-7-azaundecan-l-oyloxy)butanoate (380 mg, 865 pmol) in EA (8 mL). The reaction was stirred under H₂ atmosphere for 16 h at 25 °C. After that, the reaction mixture was filtered and the filtrate was concentrated to afford the titled compound (280 mg, 93%) as a sticky oil. *Η NMR was performed at 400MHz with CDCI3 as solvent to characterize the titled compound, results are as follows: δ = 6.82 (q, J= 5.2 Hz, 1 H), 5.03 (br. s., 1 H), 4.34 - 4.15 (m, 2 H), 3.96 (d, J= 6.0 Hz, 2 H), 2.49 (t, J = ΊΛ Hz, 2 H), 2.13 - 1.96 (m, 2 H), 1.54 (d, J = 5.6 Hz, 3 Η), 1.45 (s, 9 H).

[00539] Compound 90:

4-(l-(2-aminoacetoxy)ethoxycarbonyloxy)butanoic acid

<img file="CA2999367C_D0267.tif" />

[00540] A solution of 2,2,9-trimethyl-4,7,ll-trioxo-3,8,10,12-tetraoxa-5azahexadecan-16-oic acid (280 mg, 802 pmol) in HCI/EA (5 mL, ~2 M) was stirred for 16 h at 25 °C. The precipitate was formed and filtered. The filtered cake was washed with EA (10 mL) and then dried in vacuo to afford the titled compound (168 mg, 84%) as a white solid in HC1 salt form. *H NMR was performed at 400MHz with D₂O as solvent to characterize the

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EXAMPLE 2: Metabolic stability assay of the test compounds

Rat Human Liver S9 Fractions Metabolic Stability Assay

[00541] The protocol for rat/human liver S9 fractions metabolic stability assay is employed to determine the half-life (T1/2) of the compounds of the present disclosure and their releasing efficiency of converting from the prodrugs to GHB in vitro.

[00542] The following is the study outline for S9 assay: 1) For GHB releasing efficiency assay, pooled liver S9 fractions (human or rat) in mixed gender were obtained from commercial vendors (e g., Xenotech) and stored at -80 °C prior to use. 2) A master solution in the incubation plate containing phosphate buffer, ultra-pure HiO, MgCb solution and liver S9 fraction was made to keep S9 fractions at 1 mg/mL final concentration. The mixture was pre-warmed at 37°C water bath for 5 minutes. 3) Add 4 pL of 500 pM test compound solution to the master solution plate at the final concentration of 5 pM test compound. The reaction was started with the addition of 40 pL of 10 mM NADPH and carried out at 37°C. 4) 50 pL aliquots of the reaction solution were taken out and put into new plates at different time points including 0, 15, 30, 45 and 60 minutes, and incubated at 37°C water bath with shaking at 60 rpm. The reaction was stopped by adding 200 pL of cold quench solution (methanol containing internal standards) at the appointed time points. The plates were centrifuged at 3220 g at 4 °C for 40 minutes to precipitate protein. 5) 100 pL of the supernatant was transferred to a new plate. The supernatant was diluted with water according to the LC/MS signal response and peak shape, mixed well and analyzed using LC/MS/MS for measurement of test compounds and GHB. The measurement results were then used for calculation of half-life (T1/2) of the test compounds and their conversion efficiency into GHB in S9 fractions. GHB releasing efficiency is calculated by dividing the detected amount of GHB by the total amount of GHB that can be released by the test compound. Data are shown as below in Table 1.

Table 1 : Metabolic Stability of Test Compounds in Human and Rat Liver S9 Fractions

<td> Test Compounds</td><td> Species</td><td> Timonin)</td><td> GHB releasing efficiency (%) at 60 min point</td>

<td> Compound 32</td><td> Human</td><td> 40.43</td><td> 47</td>

<td> 4-(phenoxycarbonyloxy)butanoicacid</td><td> Rat</td><td> 8.50</td><td> 74</td>

<td> hydrochloride salt of Compound 57</td><td> Human</td><td> 2.15</td><td> 61</td>

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<td> (5)-4-(2-amino-3-phenylpropanoyloxy) butanoic acid hvdrochloride</td><td> Rat</td><td> 2.48</td><td> 69</td>

<td rowspan="2"> Compound 66 4-(2-acetamidoacetoxy)butanoic acid</td><td> Human</td><td> 9.21</td><td> 78</td>

<td> Rat</td><td> 8.00</td><td> 71</td>

<td rowspan="2"> Compound 67 (5)-4-(2-acetamido-3- methylbutanoyloxy)butanoic acid</td><td> Human</td><td> 83.17</td><td> 35</td>

<td> Rat</td><td> 74.22</td><td> 32</td>

<td rowspan="2"> Compound 64 4-(2-isobutyramidoacetoxy)butanoic acid</td><td> Human</td><td> 58.01</td><td> 42</td>

<td> Rat</td><td> 62.66</td><td> 30</td>

<td rowspan="2"> Compound 89 4-( 1 -( bcnzoy loxy)cthoxy carbonyloxy )butanoic acid</td><td> Human</td><td> 10.54</td><td> 42</td>

<td> Rat</td><td> 17.48</td><td> 51</td>

[00543] The in vitro GHB releasing efficiency assay employing rat/liuman liver S9 fractions had shown that the prodrug compounds could be converted to GHB with variable releasing efficiencies, which suggested that they would be converted into GHB in the systemic circulation after being administered to rat/human.

[00544] Rat/Human Hepatocytes Metabolic Stability Assay

[00545] The protocol for rat/human hepatocytes metabolic stability assay is employed to determine the half-life (T_l2) of the compounds of the present disclosure and their releasing efficiency of converting from the prodrugs to GHB in vitro.

[00546] The following is the study outline for hepatocytes assay: 1) For GHB releasing efficiency assay, rat hepatocytes in male gender and human hepatocytes in mixed gender were obtained from commercial vendors (e.g., BioreclamationIVT) and stored at -150 °C prior to use. 2) 30 mM stock solutions of test compounds were prepared in DMSO. Thawing medium and supplement incubation medium (serum-free) were placed in a 37°C water bath for at least 15 minutes prior to use. Stock solutions were diluted to 500 pM by combining 295 pL acetonitrile and 5 pL of 30 mM stock solution. 3) Vials of cryopreserved hepatocytes were removed from storage, ensured that vials remain at cryogenic temperatures. The pressure was removed by loosening and re-tightening the cap. The vials were thawed in a 37 °C water bath with gently shaking. Vials were kept in water bath until all ice crystals had dissolved and were no longer visible. Vials were sprayed with 70% ethanol before being transferred to a biosafety cabinet. And then the contents were poured into the 50 mL thawing medium conical tube. Vials were centrifuged at 100 g for 10 minutes at room temperature. Thawing medium was aspirated and hepatocytes were resuspended with serum-free incubation medium to yield -1.5 ^x 10⁶ cells/mL. 4) Cell viability and density were counted using a Trypan Blue exclusion, and then cells were diluted with serum-free incubation medium to a working cell density of lx 10⁶ viable cells/ml. 5) A portion of the hepatocytes at

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PCT/CN2016/099763 x 10⁶ viable cells/mL was boiled for 10 min prior to adding to the plate as negative control to eliminate the enzymatic activity so that little or no substrate turnover should be observed. The inactivated hepatocytes were used to prepare negative samples, which were used to exclude the misleading factor that resulted from instability of chemical itself. 6) Aliquots of 247.5 pL hepatocytes were dispensed into each well of a 96-well non-coated plate. The plate was placed in the incubator on an orbital shaker at 500 rpm for approximately 10 minutes. 7) Aliquots of 2.5 pL of the 500 pM test compounds were added into respective wells of the non-coated 96-well plate to start the reaction. This assay was performed in duplicate. The plate was incubated in the incubator on an orbital shaker at 500 rpm for the designed time points. 8) 25 pL of contents were transferred and mixed with 6 volumes (150 pL) of cold acetonitrile with internal standard to terminate the reaction at time points of 0, 5, 15, 30, 60, 90 and 120 minutes. Samples were centrifuges for 25 minutes at 3220 g and aliquots of 100 pL of the supernatants were used for LC-MS/MS analysis for measurement of test compounds and GHB. The measurement results were then used for calculation of half-life (T1/2) of the test compounds and their conversion efficiency into GHB in hepatocytes. Data are shown as below in Table 2.

Table 2. Metabolic Stability of Test Compounds in Human and Rat Hepatocytes

<td> Test Compounds</td><td> Species</td><td> T_w (min)</td><td> GHB releasing efficiency (%) at 120 min point</td>

<td rowspan="2"> Compound 58 (,8)-4-(2-amino-3-methvlbutanoyloxy)butanoic acid</td><td> Human</td><td> 159.97</td><td> 73</td>

<td> Rat</td><td> 46.66</td><td> 46</td>

<td rowspan="2"> Compound 66 4-(2-acetamidoacetoxy)butanoic acid</td><td> Human</td><td> 24.95</td><td> 46</td>

<td> Rat</td><td> 16.68</td><td> 35</td>

<td rowspan="2"> Compound 67 (S)-4-(2-acetamido-3- methylbutanoyloxy)butanoic acid</td><td> Human</td><td> 219.89</td><td> 22</td>

<td> Rat</td><td> 130.66</td><td> 21</td>

[00547] The in vitro GHB releasing efficiency assay employing rat/human hepatocytes had shown that prodrug compounds could be converted to GHB with variable releasing efficiencies, which suggested that they would be converted into GHB in the systemic circulation after being administered to rat/human.

Rat/Human Whole Blood Metabolic Stability Assay

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[00548] The protocol for rat/human whole blood metabolic stability assay is employed to determine the releasing efficiency of the compounds of the present disclosure converting from the prodrugs to GHB in vitro.

[00549] The following is the study outline for whole blood assay: 1) For GHB releasing efficiency assay, rat whole blood in mixed gender was obtained from commercial vendors (e.g., SiBeiFu (Beijing) Laboratory Animal Science and Technology Co Ltd) and human whole blood was obtained from healthy volunteers in mixed gender, stored at 4 °C prior to use. 2) The stock solution of test compounds was prepared in DMSO and diluted at the final concentration of 500 μΜ. 3) 5 pL of 500 μΜ working solution was spiked to 495 pL whole blood to reach a final concentration of 5 pM. The final concentration of organic solvents was 1 %. The assay was performed in duplicate. The reaction samples were incubated at 37 °C at approximately 60 rpm in a water bath. 4) Aliquots of 50 pL were taken from the reaction samples at 0, 15, 30, 45, 60 and 120 minutes. The reaction was stopped by the addition of 7 volumes of cold methanol containing internal standards. 5) All samples were vortexed for 10 minutes, followed by centrifugation at 3220 g for 30 minutes to precipitate proteins. 100 pL of the supernatant was transferred to a new plate. The supernatant was diluted with ultra pure water according to the LC-MS signal response and peak shape. Samples were analyzed using LC/MS/MS for measurement of test compounds and GHB. The measurement results were then used for calculation of conversion efficiency the test compounds into GHB in whole blood. Data are shown as below in Table 3.

Table 3. Metabolic Stability of Test Compounds in Human and Rat Whole Blood

<td> Test Compounds</td><td> Species</td><td> GHB releasing efficiency (%) at 120 min point</td>

<td> Compound 58</td><td> Human</td><td> 42</td>

<td> (S)-4-(2-amino-3-methylbutanoyloxy)butanoic acid</td><td> Rat</td><td> 85</td>

<td> Compound 66</td><td> Human</td><td> 76</td>

<td> 4-(2-acetamidoacetoxy)butanoic acid</td><td> Rat</td><td> 100</td>

<td> Compound 67</td><td> Human</td><td> 45</td>

<td> (5)-4-(2-acetamido-3-methylbutanoyloxy)butanoicacid</td><td> Rat</td><td> 83</td>

[00550] The in vitro GHB releasing efficiency assay employing rat/human whole blood had shown that prodrug compounds could be converted to GHB with variable releasing efficiencies, which suggested that they would be converted into GHB in the systemic circulation after being administered to rat/human.

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EXAMPLE 3: Pharmacokinetic studies

[00551] For rat pharmacokinetic studies, male Sprague-Dawley rats were housed individually and fasted overnight before use. The animal dosing experiments were carried out in accordance to the National Institutes of Health Guide to the Care and Use of Laboratory Animals and the Animal Welfare Act. For GHB sodium salt, a single dose of 50 mg/kg was administered to each rat in two groups (n=3/group) via intravenous (TV) and oral (PO) administration, respectively. The vehicle used for GHB sodium salt is saline. For other test compounds, a single dose of each test compound was administered to each rat orally (n=3/group). The dosage of each test compound is listed in the Table 4. The vehicle used for dosing test compounds was 0.5% (w/v) Sodium Carboxyl Methyl Cellulose (CMC-Na) in saline. Blood samples were collected at specified time-points (pre-dose, 10 minutes, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours) following administration to individual rats within IV and PO group. Blood samples were clotted on ice immediately, plasma samples were then isolated by centrifugation and stored frozen (-80 °C) until further analysis. The concentrations of GHB and all other test compounds were individually determined by LC/MS/MS assay. Various pharmacokinetic parameters were calculated using Phoenix™ WinNonlin® software. To quantify the bioconversion efficiency of the test compounds in the circulation system, the relative bioavailability of GHB sodium salt after PO administration was calculated. The values of relative bioavailability were expressed as the ratio of the AL’C of GHB converted from the test compounds versus the AUC of GHB sodium salt administrated via IV alone adjusted by dose. Data are shown as below in Table 4.

Table 4. Rat pharmacokinetic parameters of GHB sodium salt and representative compounds

<td colspan="2"></td><td> AUC_last(h*pg/mL)</td><td> T ¹ max (min)</td><td> Cmax (pg/mL)</td><td> Bioavailabilitv F(%)</td>

<td rowspan="2"> GHB sodium salt @ 50 mg/kg</td><td> TV</td><td> 25.9</td><td></td><td></td><td> 100</td>

<td> PO</td><td> 6.7</td><td> 17</td><td> 7.6</td><td> 26</td>

<td> Compound 32 4-(phenox\ carbonyloxy)butanoic acid @ 89 mg/kg</td><td> PO*</td><td> 12.4</td><td> 10</td><td> 22.4</td><td> 48**</td>

<td> Compound 58 (5)-4-(2-amino-3- methylbutanoyloxy)butanoic acid i. 81 mg/kg</td><td> PO*</td><td> 14.3</td><td> 17</td><td> 18.5</td><td> 55**</td>

<td> Compound 67 (5)-4 -(2 -acetamido-3- methylbutanoyloxy /butanoic acid 97 mg/kg</td><td> PO*</td><td> 7.4</td><td> 10</td><td> 11.1</td><td> 29**</td>

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<td> Compound 64 4-(2-isobutyramidoacetoxy)butanoic acid '.a. 92 mg/kg</td><td> PO*</td><td> 11.8</td><td> 30</td><td> 8.6</td><td> 45**</td>

Note: * measured and calculated based on GHB, ** relative bioavailability

[00552] For dog pharmacokinetic studies, male Beagle dogs were housed individually. Dogs in oral administration groups were fasted overnight before use but with free access to water supply. Dogs in IV groups have free access to food and water. The animal dosing experiments were carried out in accordance with the National Institutes of Health Guide to the Care and Use of Laboratory Animals and the Animal Welfare Act. For GHB sodium salt, a single dose of 20 mg/kg was administered to each dog in two groups (n=3/group) via intravenous (FV) administration. The vehicle used for GHB sodium salt is saline. For other test compounds, a single dose of each test compound was administered to each dog orally (n=3/group). The dosage of each test compound is listed in the Table 5. The vehicle used for dosing test compounds was 0.5% (w/v) Sodium Carboxyl Methyl Cellulose (CMC-Na) in saline. Blood samples were collected at specified time-points (pre-dose, 5 min, 10 min, 20 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, post-dose) following administration to individual dogs within IV and PO group. Blood samples were clotted on ice immediately, plasma samples were then isolated by centrifugation and stored frozen (-80 °C) until further analysis. The concentrations of GHB and all other test compounds were individually determined by LC/MS/MS assay. Various pharmacokinetic parameters were calculated using Phoenix™ WinNonlin® software. To quantify the bioconversion efficiency of the test compounds in the circulation system, the bioavailability of GHB sodium salt after PO administration was calculated. Data are shown as below in Table 5.

Table 5 Dog pharmacokinetic parameters of GHB sodium salt and representative compound

<td colspan="2"></td><td> AUCto (h*pg/mL)</td><td> (min)</td><td> Cmax (pg/mL)</td><td> Bioavailabilitv F(%)</td>

<td> GHB sodium salt a 20 mg/kg</td><td> IV</td><td> 35.652</td><td></td><td></td><td> 100</td>

<td> Compound 58 (S)-4-(2-amino-3methylbutanoyloxy)butanoic acid (®. 32 mg/kg</td><td> PO*</td><td> 17.866</td><td> 13</td><td> 32.4</td><td> 51**</td>

Note: * measured and calculated based on GHB, ** relative bioavailability

EXAMPLE 4: Colonic absorption in rat

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[00553] The purpose of the colonic absorption trial is to evaluate the effect of the improved transport properties of prodrugs on the resulting pharmacokinetics and distribution of GHB. The study is to be conducted by the following general procedures: GHB and the compounds of the present invention are each administered to groups of three to seven male rats through a bolus injection directly into the colon via the indwelling cannula. Following dosing, blood samples are obtained at intervals over 24 hours and are immediately processed to obtain the plasma at 4 °C. The concentrations of GHB and all other test compounds are individually determined by HPLC-MS/MS assay. The compounds of the present disclosure demonstrate more effective colonic absorption than GHB.

[00554] While the present disclosure has been particularly shown and described with reference to specific embodiments (some of which are preferred embodiments), it should be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the present disclosure as disclosed herein.

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