BR112019002799B1 - COMPOUND, PHARMACEUTICAL COMPOSITION AND USE OF THE COMPOUND - Google Patents

Abstract

Amide compounds are described. Also described are pharmaceutical compositions comprising the compounds, as well as methods for treating neurodegenerative diseases that involve administering the compounds or pharmaceutical compositions to an individual.

Description

field of invention

[0001] Generally, the field involves medicinal compounds and pharmaceutical compositions. More specifically, the invention relates to medicinal amide compounds. Amide compounds may exhibit better transit to the central nervous system.

Related requests

[0002] This application claims priority to the U.S. provisional patent application. At the. 62/374,657, filed on August 12, 2017.

[0003] This application is related to document US 62/119.001, filed on February 20, 2015; PCT/US16/18732, filed February 19, 2016; US 15/048,672, filed February 19, 2016; US 62/338,178, filed May 18, 2016; US 61/819,467, filed May 3, 2013; PCT/US13/53640, filed on August 5, 2013; PCT/US14/14943, filed on February 5, 2014; and US 14/888,577, filed November 2, 2015. All of the above applications are incorporated herein by reference.

Fundamentals of the invention

[0004] There is growing interest in activating thyroid hormone signaling pathways in the brain for the treatment of certain CNS diseases, in particular those involving myelination problems (Fourcade S et al, Mol Pharmacol 63, 1296 1303 (2003 ) and Baxi EG et al, Glia 62, 1513-1529 (2014); both incorporated herein by reference). Thyroid hormones T4 and T3 are not suitable as therapy for these indications, as there is no therapeutic index for T4 and T3 separating the desired therapeutic effect from the adverse effects associated with hyperthyroidism, such as tachycardia, muscle wasting, and osteoporosis (Yen PM et al. , Physiol Rev 81, 1097-1142 (2001); Yen PM et al, Mol Cell Endocrinol 246, 121-127 (2006); Biondi B and Klein I, Endocrine 24, 1-13 (2004); and Klein I and Ojamaa K, Endocrinol Metab Clin North Am 27, 51-62 (1998; all incorporated herein by reference). This issue can potentially be addressed by certain synthetic T3 agonists that exhibit selective action on tissue thyroid hormones (Joharapurkar AA and et al., J Med Chem 55, 5649-5675 (2012); incorporated by reference herein).

[0005] Sobetiroma (also known as GC-1) is an example that has been studied extensively over the last 15 years (Scanlan TS, Heart Fail Rev 15, 177-182 (2010); incorporated by reference into this document). Sobethyroma and T3 are thought to affect LDL cholesterol by stimulating hepatic cholesterol clearance mechanisms. Advantageously, sobethyroma produces this effect with substantially no deleterious effect on heart, muscle or bone (Grover GJ et al, Endocrinology 145, 1656-1661 (2004); incorporated herein by reference). The use of sobethyroma in the treatment of neurodegenerative diseases has been previously disclosed (WO 2014/178931). Improvements in the efficiency of delivery to the CNS are usually desirable for therapeutic agents that target neurodegenerative diseases. There is a need for compounds with better distribution to the CNS for the treatment of neurodegenerative diseases (eg demyelinating diseases).

Summary of the invention

Fórmula I, ou um sal farmaceuticamente aceitável seu, em que R1 é uma amida.[0006] In one aspect, the invention features a compound of Formula I:

Formula I, or a pharmaceutically acceptable salt thereof, wherein R1 is an amide.

Fórmula II, ou um sal farmaceuticamente aceitável seu, em que R2 é alquilamino.[0007] In some embodiments of this aspect, the compound is

Formula II, or a pharmaceutically acceptable salt thereof, wherein R2 is alkylamino.

Fórmula II, ou um sal farmaceuticamente aceitável seu, em que R2 é amino.[0008] In some embodiments of this aspect, the compound is

Formula II, or a pharmaceutically acceptable salt thereof, wherein R2 is amino.

Fórmula III, ou um sal farmaceuticamente aceitável seu, em que cada um de R3 e R4 é, independentemente, H, alquila, cicloalquila, alquila substituída, alquila não substituída, heteroalquila, alquila saturado, alquila insaturado, arila, amino ou etoxil. Em algumas modalidades específicas, R3 é metila e R4 é metil.[0009] In some embodiments, the compound is a compound of Formula III:

Formula III, or a pharmaceutically acceptable salt thereof, wherein each of R3 and R4 is independently H, alkyl, cycloalkyl, substituted alkyl, unsubstituted alkyl, heteroalkyl, saturated alkyl, unsaturated alkyl, aryl, amino or ethoxyl. In some specific embodiments, R3 is methyl and R4 is methyl.

Fórmula IV, ou um sal farmaceutivamente seu, onde R3 é H, hidroxila, amino, metila, etila, propila, ciclopropila, 2- hidroxietila, 1-hidroxipropan-2-ila, 2-hidroxipropila, 2- aminoetila cetato, 2-fluoroetila, 2,2-difluoroetila, 2,2,2- trifluoroetila, fenila, (4-nitro)fenila, 2-feniletila 2-(2- hidroxifenila)etila, 2-(3-hidroxifenila)etila, 2-(3,4-di- hidroxifenila)etila, 3-fluoroetil; S-metilsulfonila, 1-(2- hidroxietila)-2-hidroxietila, 2-propenila, 2-propinila, metoxi, 2-etilsulfonato de sódio, cianometila ou oxetanil.[0010] In some embodiments, the compound is a compound of

Formula IV, or a pharmaceutically salt thereof, where R3 is H, hydroxyl, amino, methyl, ethyl, propyl, cyclopropyl, 2-hydroxyethyl, 1-hydroxypropan-2-yl, 2-hydroxypropyl, 2-aminoethyl acetate, 2-fluoroethyl , 2,2-difluoroethyl, 2,2,2-trifluoroethyl, phenyl, (4-nitro)phenyl, 2-phenylethyl 2-(2-hydroxyphenyl)ethyl, 2-(3-hydroxyphenyl)ethyl, 2-(3, 4-dihydroxyphenyl)ethyl, 3-fluoroethyl; S-methylsulfonyl, 1-(2-hydroxyethyl)-2-hydroxyethyl, 2-propenyl, 2-propynyl, methoxy, sodium 2-ethylsulfonate, cyanomethyl or oxetanil.

Fórmula III, ou um sal farmaceuticamente aceitável seu, onde R4 é selecionada dentre H e C1-6 alquil; e R3 é: (a) H, OH, NH2, -NH(C1-6 alquila), -N(C1-6 alquila)2, -SO2H, -SO2(C1-6 alquila), C2-6 alquenila, C2-6 alquinila, C3-6 cicloalquila ou um anel de heterociclila de 3 a 6 membros selecionado dentre O, N e S; ou (b) C1-6 alquila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente dentre OH, halogênio, NH2, -NH(C1-6 alquila), -N(C1-6 alquila)2, -SO2H, -SO2(C1-6 alquila), CN, C3-6 cicloalquila, um anel de heterociclila de 3 a 6 membros contendo um heteroátomo selecionado dentre O, N e S ou um grupo fenila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente do grupo que consiste em OH, NO2 e halogênio; ou (c) -O-C1-6 alquila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente dentre OH, halogênio, NH2, -NH(C1-6 alquila), -N(C1-6 alquila)2, -SO2H, -SO2(C1-6 alquila), CN, C3-6 cicloalquila, um anel heterociclila de 3 a 6 membros selecionado dentre O, N e S ou um grupo fenila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente do grupo que consiste em OH, NO2 e halogênio; ou (d) um grupo fenila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente do grupo que consiste em OH, NO2 e halogênio.[0011] In some embodiments, the compound is a compound of Formula III:

Formula III, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from H and C1-6 alkyl; and R3 is: (a) H, OH, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -SO2H, -SO2(C1-6 alkyl), C2-6 alkenyl, C2 -6 alkynyl, C3-6 cycloalkyl or a 3- to 6-membered heterocyclyl ring selected from O, N and S; or (b) C1-6 alkyl optionally substituted by 1, 2 or 3 substituents, each independently selected from OH, halogen, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -SO2H , -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a 3- to 6-membered heterocyclyl ring containing a heteroatom selected from O, N and S or a phenyl group optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and halogen; or (c) -O-C1-6 alkyl optionally substituted by 1, 2 or 3 substituents, each independently selected from OH, halogen, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2 , -SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a 3- to 6-membered heterocyclyl ring selected from O, N and S or a phenyl group optionally substituted by 1, 2 or 3 substituents each one independently selected from the group consisting of OH, NO2 and halogen; or (d) a phenyl group optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and halogen.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é: (a) H, OH, NH2, -NH(C1-6 alquila), -N(C1-6 alquila)2, - SO2H, -SO2(C1-6 alquila), C2-6 alquenila, C2-6 alquinila, C3-6 cicloalquila ou um anel heterociclila com 3 a 6 membros contendo um heteroátomo selecionado dentre O, N e S; ou (b) C1-6 alquila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente a partir do OH, halogênio, NH2, -NH(C1-6 alquila), -N(C1-6 alquila)2, - SO2H, -SO2(C1-6 alquila), CN, C3-6 cicloalquila, um anel heterociclila com 3 a 6 membros contendo um heteroátomo selecionado dentre O, N e S ou um grupo fenila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente do grupo que consiste em OH, NO2 e halogênio; ou (c) -O-C1-6 alquila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente dentre OH, halogênio, NH2, -NH(C1-6 alquila), -N(C1-6 alquila)2, -SO2H, -SO2(C1-6 alquila), CN, C3-6 cicloalquila, um anel heterociclila com 3 a 6 membros contendo um heteroátomo selecionado dentre O, N e S ou um grupo fenila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente do grupo que consiste em OH, NO2 e halogênio; ou (d) um grupo fenila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente do grupo que consiste em OH, NO2 e halogênio.[0012] In some embodiments, the compound is a compound of

Formula IV, or a pharmaceutically acceptable salt thereof, where R3 is: (a) H, OH, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -SO2H, -SO2(C1- 6 alkyl), C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or a 3- to 6-membered heterocyclyl ring containing a heteroatom selected from O, N and S; or (b) C1-6 alkyl optionally substituted by 1, 2 or 3 substituents, each independently selected from OH, halogen, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, - SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a 3- to 6-membered heterocyclyl ring containing a heteroatom selected from O, N and S or a phenyl group optionally substituted by 1, 2 or 3 substituents , each independently selected from the group consisting of OH, NO2 and halogen; or (c) -O-C1-6 alkyl optionally substituted by 1, 2 or 3 substituents, each independently selected from OH, halogen, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2 , -SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a 3- to 6-membered heterocyclyl ring containing a heteroatom selected from O, N and S or a phenyl group optionally substituted by 1, 2 or 3 substituents each independently selected from the group consisting of OH, NO2 and halogen; or (d) a phenyl group optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and halogen.

[0013] In particular embodiments of a compound of Formula IV, R3 is: (a) H, OH, NH2, -SO2H, -SO2(C1-3 alkyl), C23 alkenyl, C2-3 alkynyl, C3-6 cycloalkyl , a 3- to 6-membered heterocyclyl ring containing a heteroatom selected from O, N and S; or (b) C1-4 alkyl optionally substituted by 1, 2 or 3 substituents, each independently selected from OH, halogen, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -SO2H , -SO2(C1-3 alkyl), CN, C3-6 cycloalkyl, a 3 to 6 membered heterocyclyl ring containing a heteroatom selected from O, N and S or a phenyl group optionally substituted by 1, 2 or 3 substituents each one independently selected from the group consisting of OH, NO2 and halogen; or (c) -O-C1-4 alkyl optionally substituted by 1, 2 or 3 substituents, each independently selected from OH, halogen, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2 , -SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a 3- to 6-membered heterocyclyl ring containing a heteroatom selected from O, N and S or a phenyl group optionally substituted by 1, 2 or 3 substituents each independently selected from the group consisting of OH, NO2 and halogen; and (d) a phenyl group optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and halogen.

[0014] In specific embodiments of a compound of Formula IV, R3 is: (a) H, OH, NH2, -SO2H, -SO2(CH3), C2-3 alkenyl, C2-3 alkynyl, C3-6 cycloalkyl, a 3- to 6-membered heterocyclyl ring containing an oxygen heteroatom; or (b) C1-4 alkyl optionally substituted by 1, 2 or 3 substituents, each independently selected from OH, F, NH2, -SO2H, -SO2(CH3), CN, C3-6 cycloalkyl, a 3 to 6 heterocyclyl 6 members containing an oxygen heteroatom, or a phenyl group optionally substituted, by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and F; or (c) -O-C1-4 alkyl optionally substituted by 1, 2 or 3 substituents, each independently selected from OH, F, NH2, -SO2H, -SO2(CH3), CN, C3-6 cycloalkyl, a ring 3- to 6-membered heterocyclyl containing an oxygen heteroatom or a phenyl group optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and F; or (d) a phenyl group optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and F.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é -(CH2)n1-fenila e onde n1 é um número inteiro selecionado dentre 0, 1, 2, 3 ou 4 e o anel fenila é opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente a partir do grupo que consiste em OH, NO2 e halogênio.[0015] In some embodiments, the compound is a compound of

Formula IV, or a pharmaceutically acceptable salt thereof, where R3 is -(CH2)n1-phenyl and where n1 is an integer selected from 0, 1, 2, 3 or 4 and the phenyl ring is optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and halogen.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é -(CH2)n2-fenila, onde n2 é um número inteiro selecionado dentre 0, 1 ou 2 e o anel fenila é opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente do grupo que consiste em OH, NO2 e halogênio.[0016] In some embodiments, the compound is of Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, where R3 is -(CH2)n2-phenyl, where n2 is an integer selected from 0, 1 or 2 and the phenyl ring is optionally substituted by 1, 2 or 3 substituents, each one independently selected from the group consisting of OH, NO2 and halogen.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é -(CH2)n2-fenila, onde n2 é um número inteiro selecionado dentre 0, 1 ou 2 e o anel fenila é opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente do grupo que consiste em OH, NO2 e F.[0017] In some embodiments, the compound is of Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, where R3 is -(CH2)n2-phenyl, where n2 is an integer selected from 0, 1 or 2 and the phenyl ring is optionally substituted by 1, 2 or 3 substituents, each one independently selected from the group consisting of OH, NO2 and F.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, em que R3 é -(CH2)-fenila, em que o anel fenilo é opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente do grupo que consiste em de OH, NO2 e F.[0018] In some embodiments, the compound is of Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, wherein R3 is -(CH2)-phenyl, wherein the phenyl ring is optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and F.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é C1-6 alquila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente do grupo que consiste em OH, F, NH2, -SO2H, -SO2(CH3), CN, C3-6 cicloalquila e um anel heterociclila com 3 a 6 membros contendo um heteroátomo de oxigênio.[0019] In some embodiments, the compound is of Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, wherein R3 is C1-6 alkyl optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, F, NH2, -SO2H, -SO2(CH3) , CN, C3-6 cycloalkyl and a 3- to 6-membered heterocyclyl ring containing an oxygen heteroatom.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é C1-4 alquila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente do grupo que consiste em OH, F, NH2, -SO2H, -SO2(CH3), CN, C3-6 cicloalquila e um anel heterociclila com 3 a 6 membros contendo um heteroátomo de oxigênio.[0020] In some embodiments, the compound is of Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, wherein R3 is C1-4 alkyl optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, F, NH2, -SO2H, -SO2(CH3) , CN, C3-6 cycloalkyl and a 3- to 6-membered heterocyclyl ring containing an oxygen heteroatom.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é C1-6 alquila opcionalmente substituído por 1, 2 ou 3 substituintes, cada um selecionado independentemente do grupo que consiste em OH, F, NH2, CN, -SO2H e -SO2(C1-6 alquila).[0021] In some embodiments, the compound is a compound of Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, wherein R3 is C1-6 alkyl optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, F, NH2, CN, -SO2H and -SO2( C1-6 alkyl).

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é um C1-6 alquila opcionalmente substituído por 1, 2 ou 3 substituintes de OH.[0022] In some embodiments, the compound has Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, wherein R3 is a C1-6 alkyl optionally substituted by 1, 2 or 3 OH substituents.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, em que R3 é um C1-4 alquila opcionalmente substituído por 1, 2 ou 3 substituintes de OH.[0023] In some embodiments, the compound is a compound of Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, wherein R3 is a C1-4 alkyl optionally substituted by 1, 2 or 3 OH substituents.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é um C1-6 alquila opcionalmente substituído por 1, 2 ou 3 substituintes de F.[0024] In some embodiments, the compound has Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, where R3 is a C1-6 alkyl optionally substituted by 1, 2 or 3 substituents of F.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é um C1-4 alquila opcionalmente substituído por 1, 2 ou 3 substituintes de F.[0025] In some embodiments, the compound has Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, where R3 is a C1-4 alkyl optionally substituted by 1, 2 or 3 substituents of F.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é um -O-C1-6 alquila opcionalmente substituído por 1, 2 ou 3 substituintes de F.[0026] In some embodiments, the compound has Formula IV

Formula IV, or a pharmaceutically acceptable salt thereof, wherein R3 is an -O-C1-6 alkyl optionally substituted by 1, 2 or 3 substituents of F.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é um -O-C1-4 alquila opcionalmente substituído por 1, 2 ou 3 substituintes de F.[0027] In some embodiments, the compound has Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, wherein R3 is an -O-C1-4 alkyl optionally substituted by 1, 2 or 3 substituents of F.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é -O-C1-6 alquila.[0028] In some embodiments, the compound is of Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, wherein R3 is -O-C1-6 alkyl.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, onde R3 é um -O-C1-4 alquila.[0029] In some embodiments, the compound has Formula IV:

Formula IV, or a pharmaceutically acceptable salt thereof, where R3 is an -O-C1-4 alkyl.

Fórmula III, ou um sal farmaceuticamente aceitável seu, onde cada um dentre R3 e R4 é, independentemente, H, um alifático substituído, um alifático não substituído, uma fenila não substituída, ORN1, -N(RN1)2 ou -SO2(RN2), onde cada RN1 é, independentemente, H, um alifático substituído ou um alifático não substituído e RN2 é OH, um alifático substituído ou não substituído; contanto que, caso um RN for ORN1, -N(RN1)2 ou -SO2(RN2), o outro RN é H, um alifático substituído, um alifático não substituído, uma fenila substituída ou uma fenila não substituída. Em modalidades específicas, R3 é H ou um alifático não substituído. Em modalidades específicas, R4 é H, um alifático substituído ou um alifático não substituído. Em modalidades específicas, R3 é metil. Em modalidades específicas, R4 é metil.[0030] In some embodiments, the compound is of Formula III

Formula III, or a pharmaceutically acceptable salt thereof, wherein each of R3 and R4 is independently H, a substituted aliphatic, an unsubstituted aliphatic, an unsubstituted phenyl, ORN1, -N(RN1)2 or -SO2(RN2 ), where each RN1 is independently H, a substituted aliphatic, or an unsubstituted aliphatic, and RN2 is OH, a substituted or unsubstituted aliphatic; provided that, if one RN is ORN1, -N(RN1)2, or -SO2(RN2), the other RN is H, a substituted aliphatic, an unsubstituted aliphatic, a substituted phenyl, or an unsubstituted phenyl. In specific embodiments, R3 is H or an unsubstituted aliphatic. In specific embodiments, R4 is H, a substituted aliphatic, or an unsubstituted aliphatic. In specific embodiments, R3 is methyl. In specific embodiments, R4 is methyl.

ou um sal farmaceuticamente aceitável seu.[0031] In another aspect, the invention features a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments of the first aspect of the invention, the compound is selected from the group consisting of: 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(2-hydroxyethyl) )acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(1-hydroxypropan-2-yl)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(2-hydroxypropyl)acetamide; 2-(2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamido)ethan-1-aminium acetate; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; N-(2,2-difluoroethyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(2,2,2-trifluoroethyl)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-methyl ketamide 2-(4-(4-hydroxy-3-isopropyl benzyl)-3,5-dimethylphenoxy)-N -(2-hydroxyphenyl)acetamide; 2-(4-(4-hydroxy-3-isopropyl benzyl)-N-(3-hydroxyphenyl)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-( 2-(methylsulfonamido)ethyl)acetamide; N-(1,3-dihydroxypropan-2-yl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide 2-( 4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-propyl ketamide; N-(2-fluoroethyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5 - dimethylphenoxy)acetamide; N-allyl-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5 -dimethylphenoxy)-N-(prop-2-yn-1-yl)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-methoxyacetamide; N-(3, 4-dihydroxyphenethyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy )-N-phenethyl ketamide; N-hydroxy-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3 2-(2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamido)ethane-1-sulfonate N-cyclopropyl-2-(4-(4- hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N,N-dimethylacetamide; N-ethyl-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; N-(cyanomethyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; N-(3-fluorophenyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(oxetan-3-yl)acetamide; and 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(4-nitrophenyl)acetamide; or a pharmaceutically acceptable salt thereof.

[0033] In another aspect, the invention features a pharmaceutical composition including a pharmaceutically effective amount of a compound described herein (e.g., a compound of any of the foregoing aspects) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers .

[0034] In another aspect, the invention features a method of treating a subject with a neurodegenerative disorder by administering a pharmaceutically effective amount of a compound described herein (e.g., a compound of any one of the foregoing aspects), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating neurodegenerative disease.

[0035] In some embodiments of this aspect, the neurodegenerative disease is a demyelinating disease. In some embodiments of this aspect, the neurodegenerative disease is X-linked adrenoleukodystrophy or multiple sclerosis.

[0036] In some embodiments of this aspect, the neurodegenerative disease is selected from the group consisting of acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, adult Refsum's disease, Alexander's disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, CPM, cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy, Devic's syndrome, myelinoclastic sclerosis, Guillain-Barré syndrome, diffuse, idiopathic inflammatory demyelinating disease, infantile Refsum's disease, Krabbe's disease, Leber's hereditary optic neuropathy, Marburg multiple sclerosis , Marchiafava-Bignami disease, metachromatic, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease, peroneal muscular atrophy, progressive multifocal leukoencephalopathy, transverse myelitis, tropical spastic paraparesis, van der Knaap disease, X-linked adrenoleukodystrophy and syndrome by Zellweger.

[0037] In another aspect, the invention features a method of treating an individual with Alzheimer's disease by administering a pharmaceutically effective amount of a compound described herein (e.g., a compound of any of the foregoing aspects), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating Alzheimer's disease.

[0038] In another aspect, the invention features a method of treating an individual having a disease or clinical condition selected from the group consisting of: acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), Refsum in adults, Infantile Refsum's disease, Alexander's disease, Alzheimer's disease, Balo's concentric sclerosis, Canavan's disease, CPM (CPM), Cerebral Palsy, Cerebrotendinous Xanthomatosis, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Devic's Syndrome, Myelinoclastic Sclerosis, Encephalomyelitis, Diffuse Guillain-Barré syndrome, Idiopathic inflammatory demyelinating disease (IIDD), Krabbe disease, Leber hereditary optic neuropathy, Leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraparesis (TSP), X-linked adrenoleukodystrophy (X-ALD, ALD, or X-linked ALD), and Zellweger syndrome by administering an effective amount of a compound described herein (e.g., a compound of any of the foregoing aspects), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein to the subject, thereby treating the condition or clinical condition

[0039] In another aspect, the invention features a compound described herein (for example, a compound of any of the preceding aspects), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in the treatment of a neurodegenerative disease (for example, a demyelinating disease, X-linked adrenoleukodystrophy or multiple sclerosis).

[0040] In some embodiments, the compound, pharmaceutically acceptable salt thereof or pharmaceutical composition is for use in treating a neurodegenerative disease and is selected from the group consisting of: acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, Refsum's disease in adults , Alexander's disease, Alzheimer's disease, Balo Concentric sclerosis, Canavan disease, CPM, cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy, Devic's syndrome, myelinoclastic sclerosis, Guillain-Barré syndrome, diffuse, idiopathic inflammatory demyelinating disease, infantile Refsum disease, Krabbe disease, Leber hereditary optic neuropathy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic, motor multifocal neuropathy, paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease, peroneal muscular atrophy, progressive multifocal leukoencephalopathy, transverse myelitis, tropical spastic paraparesis, van der Knaap disease, X-linked adrenoleukodystrophy, and Zellweger syndrome.

[0041] In another aspect, the invention features a compound described herein (for example, a compound of any of the preceding aspects), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in the treatment of disease of Alzheimer's.

[0042] In another aspect, the invention features a compound described herein (e.g., a compound of any of the preceding aspects) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for use in the treatment of a disease or condition clinic selected from the group consisting of acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), Refsum in adults, infantile Refsum disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, CPM ( CPM), Cerebral Palsy, Cerebrotendinous Xanthomatosis, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Devic's Syndrome, Myelinoclastic Sclerosis, Encephalomyelitis, Diffuse Guillain-Barré Syndrome, Idiopathic Inflammatory Demyelinating Disease (IIDD), Krabbe's Disease, Leber's Hereditary Optic Neuropathy , Leukodystrophy, multiple sclerosis of Marburg, Marchiafava-Bignami disease, metachromatic (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease (PMD), progressive multifocal leukoencephalopathy (PML ), tropical spastic paraparesis (TSP), X-linked adrenoleukodystrophy (X-ALD, ALD or X-linked ALD) and Zellweger syndrome.

Brief description of figures

[0043] FIG. 1 is a general approach to the CNS targeting compounds disclosed herein.

[0044] FIG. 2A is a graph of brain concentrations of sobethyroma (GC-1) or disclosed compounds following intraperitoneal administration to mice.

[0045] FIG. 2B is a graph of serum concentrations of sobethyroma (GC-1) or released compounds after intraperitoneal administration to mice.

[0046] FIG. 2C is a graph of the ratio of brain concentration to serum concentration of sobethyroma (GC-1) or the disclosed compounds after intraperitoneal administration to mice.

Detailed description of the invention Definitions

[0047] Unless specifically defined otherwise, technical terms, as used herein, have their normal meaning as understood in the art. The following explanations of terms and methods are provided to further describe the present compounds, compositions and methods, and to guide those skilled in the art in practicing the present disclosure. It should also be understood that the terminology used in this disclosure is for the purpose of describing particular embodiments and examples only and is not intended to be limiting.

[0048] As used herein, the singular terms "a", "an", and "the" include plural referents, unless the context clearly indicates otherwise. Likewise, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Furthermore, as used herein, the term "comprises" means "includes". Therefore, "comprising A or B" means including A, B, or A and B.

[0049] Variables such as R, including all its subvariables R1, R2, etc.) used throughout the disclosure are the same variables as previously defined unless otherwise indicated.

[0050] Administration: Refers to providing a compound, a prodrug of a compound, or a pharmaceutical composition comprising the compound or prodrug as described herein. The compound or composition can be administered by another person to the subject or can be self-administered by the subject. Non-limiting examples of routes of administration are: oral, parenteral (eg, intravenous) or topical.

[0051] Aliphatic: a branched, linear or cyclic, non-aromatic hydrocarbon group of 1 to 6 carbon atoms. An aliphatic group is either saturated or unsaturated. An unsaturated aliphatic group contains a carbon-carbon double or triple bond. A substituted aliphatic group is an aliphatic group substituted by 1 to 5 substituents, allowing for valence. Each substituent on the substituted aliphatic group is independently selected from the group consisting of halogen, -ORA, -N(RB)2, -SO2(RC), cyano, substituted phenyl, and unsubstituted phenyl; where RA is H, an unsubstituted aliphatic, unsubstituted phenyl, or substituted phenyl; each RB is independently an unsubstituted aliphatic, unsubstituted phenyl, substituted phenyl, or SO2(RC); and RC is independently -OH, an unsubstituted aliphatic, unsubstituted phenyl, or substituted phenyl.

[0052] Alkyl: a branched or unbranched saturated hydrocarbon group, such as, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. A lower alkyl group is a saturated branched or unbranched hydrocarbon having 1 to 6 carbon atoms (C1-6alkyl). The term alkyl also encompasses cycloalkyl. An unsaturated alkyl can be an alkenyl (for example, a group containing one or more carbon-carbon double bonds) or an alkynyl (for example, a group containing one or more carbon-carbon triple bonds). Alkyl also encompasses substituted alkyls which are alkyl groups where one or more hydrogen atoms are replaced by a substituent, such as, without limitation, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ether, ketone, aldehyde , hydroxyl, carboxyl, cyano, amido, haloalkyl, haloalkoxy or alkoxy. The term alkyl also encompasses heteroalkyls. A heteroalkyl contains at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus replacing one or more of the carbons. Substituted heteroalkyls are also encompassed by the term alkyl.

[0053] In some embodiments, an optionally substituted alkyl may contain, for example, 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1 -4, or 1-2 carbon atoms, not including the carbon atoms present in the substituents if the alkyl is substituted. In some embodiments, an optionally substituted alkenyl or an optionally substituted alkynyl can contain, for example, 2-20, 218, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms, not including carbon atoms present in substituents if alkenyl or alkynyl is substituted.

[0054] Alkylamino: a heteroalkyl in which one or more of the carbon atoms is replaced by a nitrogen. An alkylamino can be a straight chain, branched chain or a cycloalkylamino. An alkylamino generally has the structure -NX1X2 or -NX1X2X3+ in which X1, X2, and X3 are each independently selected from, for example, H, an optionally substituted alkyl (e.g., a substituted alkyl or a substituted alkyl , as the term is defined above), an optionally substituted alkenyl (for example, an optionally substituted C2-6 alkenyl), an optionally substituted alkynyl (for example, an optionally substituted C26 alkynyl), an optionally substituted cycloalkyl (for example, a optionally substituted C3-6 cycloalkyl), an optionally substituted heterocyclyl ring (for example, an optionally substituted 3- to 6-membered heterocyclyl ring containing a heteroatom selected from O, N, and S), an optionally substituted aryl (for example, a phenyl group optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and halogen), an optionally substituted -O-C1-6 alkyl (e.g., -O-C1-6 alkyl optionally substituted by 1 ,2 or 3 substituents, each selected from OH, halogen, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -SO2H, -SO2(C1-6 alkyl), CN, C3 -6 cycloalkyl, a 3-6 membered heterocyclyl ring containing a heteroatom selected from O, N and S or a phenyl group optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and halogen ), an acyl, OH, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -SO2H, or -SO2(C1-6 alkyl).

[0055] In some embodiments, u, alkylamino has the structure -NX1X2, where X1 is H or an optionally substituted C1-6 alkyl and X2 is a C1-6 alkyl optionally substituted by 1, 2 or 3 substituents, each selected independently from OH, halogen, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a heterocyclyl ring with 3 to 6 members containing a heteroatom selected from O, N and S or a phenyl group optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and halogen.

[0056] In some embodiments, an alkylamino has the structure -NX1X2, where X1 is H or an optionally substituted C1-6 alkyl and X2 is -O-C1-6 alkyl optionally substituted by 1, 2 or 3 substituted each independently selected from OH, halogen, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, one ring 3- to 6-membered heterocyclyl containing a heteroatom selected from O, N and S or a phenyl group optionally substituted by 1, 2 or 3 substituents selected, each independently from the group consisting of OH, NO2 and halogen.

[0057] In some embodiments, an alkylamino has the structure -NX1X2, where X1 is H or an optionally substituted C1-6 alkyl and X2 is a phenyl group optionally substituted by 1, 2 or 3 substituents, each selected independently of the group that consists of OH, NO2 and a halogen.

[0058] In some embodiments, an alkylamino has the structure -NX1X2, wherein X1 and X2 are each independently selected from H, a substituted aliphatic, an unsubstituted aliphatic, substituted phenyl, unsubstituted phenyl, ORN1, - N(RN1)2 or -SO2(RN2), where each RN1 is independently H, a substituted aliphatic or an unsubstituted aliphatic and RN2 is OH, an unsubstituted aliphatic or a substituted aliphatic. In some embodiments, if one RN is ORN1, -N(RN1)2, or -SO2(RN2), the other RN is H, a substituted aliphatic, an unsubstituted aliphatic, a substituted phenyl, or an unsubstituted phenyl.

[0059] In some embodiments, an alkylamino has the structure -NX1X2 where X1 is H and X 2 is H, hydroxyl, amino, methyl, ethyl, propyl, cyclopropyl, 2-hydroxyethyl, 1-hydroxypropan-2-yl, 2 -hydroxypropyl, 2-aminoethyl acetate, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, phenyl, (4-nitro)phenyl, 2-phenylethyl 2-(2-hydroxyphenyl)ethyl, 2- ( 3-hydroxyphenyl)ethyl, 2-(3,4-dihydroxyphenyl)ethyl, 3-fluoroethyl; S-methylsulfonyl, 1-(2-hydroxyethyl)-2-hydroxyethyl, 2-propenyl, 2-propynyl, methoxyl, sodium 2-ethylsulfonate, cyanomethyl or oxetanyl.

[0060] Examples of alkylamino groups include, without limitation, the following structures: -NHCH3, -N(CH3)2, -+++NH(CH3)2, -N(CH3)3, -NHCH2CH3, -NH2CH2CH3, -NCH3CH2CH3, -N(CH2CH3)2 and -NHCH3CH2CH3+. Alkylamino also encompasses heteroalkyls in which one or more of the carbon atoms are replaced by a nitrogen and/or, in addition, one or more other carbon atoms are replaced by another heteroatom, such as oxygen, sulfur or phosphorus.

[0061] The term alkylamino also contemplates alkyl groups attached to nitrogen forming a bond with non-terminal carbons to form a cycloalkylamino structure, for example: X1NHX3, where X1 and X3 are alkyl groups that form a covalent bond with each other. These include single 4-membered nitrogen (azetidinyl), single 5-membered nitrogen (pyrrolidinyl) or single 6-membered nitrogen (piperidinyl) structures, as well as double nitrogen structures and substituted cycloalkylamino structures, including X1NX2X3, where X1 and X3 form a covalent bond and X2 is alkyl. Alkylamino groups are also exemplified by a CH2CH2-NHR2 structure, where R2 is ethyl and forms a covalent bond with the first carbon to form a 4-membered ring.

[0062] Amide: a group of the structure -CH2-CONX1X2, where X1 and X2 are each independently H or an organic group such as an optionally substituted alkyl or an optionally substituted aryl group. In some embodiments, an amide has the structure -CH 2 - CONX1 X2 , where X1 and X2 are each independently H, an optionally substituted alkyl (e.g., a substituted alkyl or an unsubstituted alkyl, as the term is defined above), an optionally substituted alkenyl (for example, an optionally substituted C2-6 alkenyl), an optionally substituted alkynyl (for example, an optionally substituted C2-6 alkynyl), an optionally substituted cycloalkyl (for example, a C3- optionally substituted cycloalkyl), an optionally substituted heterocyclyl ring (for example, an optionally substituted 3- to 6-membered heterocyclyl ring containing a heteroatom selected from O, N, and S), an optionally substituted aryl (for example, a phenyl group optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and halogen), an -O-C1-6 alkyl (e.g. -O-C1-6 alkyl optionally substituted by 1, 2 or 3 substituents, each independently selected from OH, halogen NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a 3- to 6-membered heterocyclyl ring containing a heteroatom selected from O, N and S or a phenyl group optionally substituted by 1, 2 or 3 substituents, each independently selected from the group consisting of OH, NO2 and halogen), an acyl, OH, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -SO2H or -SO2(C1-6 alkyl).

[0063] Amino: a group with the structure -N(RN)2, where each RN is independently H, a substituted aliphatic, unsubstituted aliphatic, substituted phenyl, unsubstituted phenyl, -ORN1, -N(RN1)2 or - SO2(RN2), where each RN1 is independently H, a substituted aliphatic or an unsubstituted aliphatic and RN2 is -OH, an unsubstituted aliphatic or a substituted aliphatic; provided that, if one RN is -ORN1, -N(RN1)2, or -SO2(RN2), the other RN is H, a substituted aliphatic, an unsubstituted aliphatic, a substituted phenyl, or an unsubstituted phenyl.

[0064] Aryl: any carbon-based aromatic group, including, without limitation, benzene, naphthalene, and phenyl. The term aryl also contemplates substituted aryls in which one or more of the hydrogens is replaced by one or more groups, including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ether, ketone, aldehyde , hydroxy, carboxylic acid, cyano, amido, haloalkyl, haloalkoxy or alkoxy. The term aryl also encompasses heteroaryls in which one or more of the carbons is replaced by a heteroatom. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur and phosphorus. Substituted heteroaryls are also encompassed by the term aryl. A substituted phenyl is a phenyl group substituted by 1, 2, 3, 4 or 5 substituents independently selected from -OR, -NO2, an unsubstituted aliphatic and a halogen, where R is H or an unsubstituted aliphatic. An aryl refers to any monocyclic or fused bicyclic or tricyclic ring system that has the characteristics of aromaticity in terms of electron distribution through the ring system, for example, phenyl, naphthyl, or phenanthrene. In some embodiments, a ring system contains 5-15 ring member atoms or 5-10 ring member atoms. An aryl group can have, for example, between five and fifteen carbons (e.g. a C5-6, C5-7, C5-8, C5-9, C5-10, C5-11, C5-12, C5-13 , C5-14 or C5-15 aryl).

em que Rz é um alquila, alquenila, alquinila, cicloalquila, cicloalquenila, cicloalquinila, arila, heteroalquila, heteroalquenila, heteroalquinila, heterocicloalquila, heterocicloalquenila, heterocicloalquinila ou heteroarila opcionalmente substituídos.[0065] Acyl: a group with the structure:

wherein Rz is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl or heteroaryl.

[0066] Cycloalkyl: A non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyls also encompass substituted cycloalkyls and heterocycloalkyls (also referred to as "heterocyclyl" groups) in which at least one of the carbon atoms is replaced by a heteroatom, such as nitrogen, sulfur or phosphorus. A heterocycloalkyl in which one or more of the carbons is replaced by nitrogen is also referred to herein as cycloalkylamino. The term also encompasses substituted heterocycloalkyls.

[0067] Optionally substituted: a group (for example an alkyl, alkenyl, alkynyl, cycloalkyl or aryl) having 0, 1 or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, alkaryl, acyl, heteroaryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroalkaryl, halogen, oxo, cyano, nitro, amino, alkamino, hydroxy, alkoxy, alkanoyl, carbonyl, carbamoyl, guanidinyl, amidinyl, ureido, any of the groups or moieties described above, and hetero versions of any of the groups or moieties described above. Substituents include, without limitation, F, Cl, methyl, phenyl, benzyl, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl -OOCR, SO3R, CONR2, SO2NR2 , NRSO2NR2, CN, CF3, OCF3, R3Si and NO2, where each R is independently H, alkyl, alkenyl, aryl, heteroalkyl, heteroalkenyl or heteroaryl and where two of the optional substituents on the same or adjacent atoms may be joined together to form an optionally substituted 3-8 membered saturated or unsaturated, aromatic or non-aromatic ring.

[0068] Effective amount, therapeutically effective amount or pharmaceutically effective amount: a sufficient amount of a specified agent to obtain a desired effect in an individual being treated with that agent. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject. The effective amount of an agent will depend on the subject being treated, the severity of the condition and the mode of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed compound sufficient to achieve a desired effect in a subject will be understood by those skilled in the art in light of this disclosure.

[0069] Derivative: a compound or portion of a compound that is derived from or is theoretically derivable from a parent compound.

[0070] Hemorrhage: Bleeding or leakage of blood from a vessel.

[0071] Hypoxia: The lack of oxygen supply to body tissues below the normal level.

[0072] Heterocycle: A group encompassing heteroaryls and heterocycloalkyls Heterocycles may be monocyclic or polycyclic rings. Exemplary heterocyclics include, but are not limited to, azepinyl, oxide, azetyl, azetidinyl, diazepinyl, dithiadiazinyl, dioxazepinil, dioxolanyl, dithiazolyl, furanyl, isooxazolyl, isothiazolyl, imidazoles, morpholinyl, oxetanyl, oxadiazolyl, oxiranil, oxazinyl, oxazolyl, piperazin ila, pyrazinyl, pyridazinyl, pyrimidinyl, piperidine, piperidino, pyridyl, pyranyl, pyrazolyl, pyrrolyl, pyrrolidinyl, thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl, thiazoyl, thienyl, tetrazinyl, thiadiazinyl, triazinyl, thiazinyl, thiopyranyl, furoisoxazolyl, imidazothiazolyl, thienoisothia zolyl, thienothiazolyl, imidazopyrazolyl, cyclopentapyrazolyl, pyrrolopyrrolyl, thienotienyl, thiadiazolopyrimidinyl, thiazolothiazolyl, thiazolopyrimidinyl, thiazolopyridinyl, oxazolopyrimidinyl, oxazolopyridyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, imidazopyrazinyl, purinyl, pyrazolopyrimidinyl, imidazopyridin yl, benzimidazolyl, indazolyl, benzoxathiolyl, benzodioxolyl, benzodithiolyl, indolizinyl, indolinyl, isoindolinyl, furopyrimidinyl, furopyridyl, benzofuranyl, isobenzofuranyl, thienopyrimidinyl, thienopyridyl, benzothienyl, cyclopentaoxazinyl, cyclopentafuranyl, benzoxazinyl, benzothiazinyl, quinazolinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzopyranyl, pyridopyridazinyl and pyridopyrimidinyl groups. The term also encompasses substituted heterocycles, including substituted forms of all of the above species.

[0073] Injury: Refers to any type of physical damage to cells, tissues, or the body. In some cases, damage to the nervous system (eg, CNS or PNS) results in demyelination and/or demyelinating disease.

[0074] Ischemia: A vascular phenomenon in which a decrease in the blood supply to an organ, tissue, or part of the body is caused, for example, by constriction or obstruction of one or more blood vessels. Ischemia sometimes results from vasoconstriction, thrombosis, or embolism. Ischemia can lead to direct ischemic injury, tissue damage due to cell death caused by reduced oxygen supply. In some cases, ischemia can lead to demyelination.

[0075] Myelin: A lipid substance that forms a sheath (known as a myelin sheath) around the axons of certain nerve fibers. Myelin is an electrical insulator that serves to accelerate the conduction of nerve impulses in nerve fibers. “Myelination” (also “myelination”) refers to the development or formation of a myelin sheath around a nerve fiber. Similarly, "remyelination" (also, "remyelination") refers to the repair or reformation of the myelin sheath, such as after injury, exposure to a toxic agent, or an inflammatory response, or during the course of a demyelinating disease.

[0076] Pharmaceutical composition: A composition containing a pharmaceutically effective amount of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, formulated as a pharmaceutically acceptable carrier, which may also include other additives, and manufactured or sold with the approval by a government regulatory agency as part of a therapeutic regimen for the treatment of disease in mammals. Pharmaceutical compositions may be formulated, for example, for oral administration in unit dosage form (for example, a tablet, capsule, capsule, gelcap or syrup); for topical administration (eg, as a cream, gel, lotion or ointment); for intravenous administration (eg, as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein. Conventional procedures and ingredients for preparing suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0077] Pharmaceutically acceptable carrier: Any ingredient, other than the disclosed compounds, or a pharmaceutically acceptable salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being non-toxic and non-inflammatory to the patient . Excipients may include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrating agents, colorants (dyes), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, absorbents, suspending or dispersing agents, sweeteners or hydrating waters. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propyl paraben, retinol palmitate, shellac, silicon dioxide, cellulose Sodium carboxymethyl, sodium citrate, starch glycollate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C and xylitol.

[0078] Pharmaceutically acceptable salt: Salts prepared by conventional methods. These include basic salts of inorganic and organic acids, such as, without limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, acid lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid and mandelic acid. "Pharmaceutically acceptable salts" of the presently disclosed compounds also include those formed from cations such as, without limitation, sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl- glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane and tetramethylammonium hydroxide. These salts can be prepared by standard procedures, for example by reacting the free acid with a suitable organic or inorganic base. Any chemical compound described in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts are also inclusive of the free acid, base and zwitterionic forms of the disclosed compounds. Descriptions of exemplary pharmaceutically acceptable salts can be found in Stahl and Wermuth, Eds., Handbook of Pharmaceutical Salts; Properties, Selection and Use, Wiley VCH (2008). When the compounds disclosed herein include an acidic group such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxyl group are well known to those skilled in the art and include, without limitation, alkali, alkaline earth, ammonium cations and quaternary ammonium. Such salts are known to those skilled in the art. Likewise, when compounds described herein include a basic group, such as an amino group, then suitable pharmaceutically acceptable anion pairs for the basic group are equally well known and include halide, hydroxide, perhalate, halite, hypohalite, sulfate, sulfite , phosphate, phosphite, nitrate, nitrite and others known to those skilled in the art. For additional examples of pharmacologically acceptable salts, see Berge et al., J. Pharm. Sci. 66, 1 (1977).

[0079] Sobetiroma: A synthetic diarylmethane compound that has been clinically investigated as a potential therapeutic for hypercholesterolemia (see U.S. Patent No. 5,883,294, incorporated herein by reference). Sobertirome is 2-[4-[[4-hydroxy-3-(1-methylethyl)phenyl]methyl]3,5-dimethylphenoxyacetic acid. and GC-1.

[0080] Subject: An animal (eg, a mammal, such as a human). A subject to be treated in accordance with the methods described herein may be one who has been diagnosed with a neurodegenerative disease involving demyelination, insufficient myelination, or underdevelopment of a myelin sheath, for example, a subject diagnosed with multiple sclerosis or cerebral palsy, or a at risk of developing the condition. Diagnosis can be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated in accordance with the present disclosure may have undergone standard testing or may have been identified, without examination, as being at risk due to the presence of one or more risk factors associated with the disease or clinical condition.

[0081] Treatment: An intervention that improves a sign or symptom of a disease or pathological condition. As used herein, the terms "treatment", "treat" and "treat", with reference to a disease, pathological condition or symptom, also refer to any observable beneficial effect of the treatment. The beneficial effect may be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in the severity of some or all of the clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the subject's general health or well-being, or by other parameters well known in the art that are specific to the particular disease. A prophylactic treatment is a treatment administered to a subject who does not show signs of a disease or only shows early signs, with the purpose of decreasing the risk of developing pathology. A therapeutic treatment is a treatment administered to a subject after the development of signs and symptoms of the disease.

Neurodegenerative Diseases:

[0082] Acute disseminated encephalomyelitis (ADEM): Immune-mediated demyelinating disease of the central nervous system. ADEM usually occurs after a viral infection, but it can also appear after vaccination or after a bacterial or parasitic infection. In some cases, ADEM develops spontaneously. The disease involves autoimmune demyelination, similar to multiple sclerosis, and is therefore considered a borderline disease of multiple sclerosis. ADEM produces multiple inflammatory lesions in the brain and spinal cord, particularly in the white matter. Lesions are typically found in the subcortical and central white matter and cortical gray-white junction of both cerebral hemispheres, cerebellum, brainstem, and spinal cord, but the periventricular white matter and gray matter of the cortex, thalamus, and basal ganglia can also be found. be involved. When a patient has more than one demyelinating episode, the condition is referred to as recurrent disseminated encephalomyelitis or multiphasic disseminated encephalomyelitis.

[0083] Acute haemorrhagic leukoencephalitis (AHL or AHLE): A hyperacute and often fatal form of ADEM. This disease is also known as acute necrotizing encephalopathy (ANE), acute hemorrhagic encephalomyelitis (AHEM), acute necrotizing hemorrhagic leukoencephalitis (ANHE), Weston-Hurst syndrome or Hurst disease.

[0084] Refsum's disease in adults: An autosomal recessive neurological disease associated with overaccumulation of phytanic acid in cells and tissues. Adult Refsum disease is divided into the subtypes of adult Refsum disease 1 and adult Refsum disease 2. Individuals with Refsum disease have neurological damage, cerebellar degeneration, and peripheral neuropathy. Onset is most common in childhood/adolescence with a progressive course, although periods of stagnation or remission do occur. Symptoms also include ataxia, scaly skin (ichthyosis), difficulty hearing and eye problems, including cataracts and night blindness.

[0085] Alexander disease: A very rare congenital demyelinating disease. The disease mainly affects infants and children, causing developmental delay and changes in physical characteristics. Alexander's disease is a type of leukodystrophy.

[0086] Alzheimer's disease: The most common form of dementia. Symptoms of Alzheimer's disease include memory loss, confusion, irritability, aggression, mood swings and problems with speech. This disease is characterized by the loss of neurons and synapses in the cerebral cortex and in certain subcortical regions. The loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe, and parts of the frontal cortex and cingulate gyrus. Amyloid plaques and neurofibrillary tangles are visible microscopically in the brains of those suffering from this disease. The cause of Alzheimer's disease is unknown; however, there are several hypotheses, including that the disease is caused by age-related myelin degradation in the brain.

[0087] Balo's concentric sclerosis: A demyelinating disease similar to conventional multiple sclerosis, but with the particularity that the demyelinated tissues form concentric layers. Patients with this disease can survive and/or experience spontaneous remission. Typically, the clinical course is primary progressive, but a relapsing-remitting course has been reported.

[0088] Canavan Disease: An autosomal recessive degenerative disorder that causes progressive damage to nerve cells in the brain. Canavan's disease is a leukodystrophy and is one of the most common degenerative brain diseases of childhood. This disease is also called Canavan-Van Bogaert-Bertrand disease, aspartoacylse deficiency, and aminoacylse 2 deficiency.

[0089] Central pontine myelinolysis (CPM): Neurological disease caused by severe damage to the myelin sheath of nerve cells in the brainstem, more precisely in the area called the pons. The most common cause is the rapid correction of low blood sodium levels (hyponatremia). Symptoms often seen in this disorder are sudden paresthesia or quadraparesis, dysphagia, dysarthria, diplopia, and loss of consciousness. The patient may experience locked-in syndrome, where cognitive function is intact but all muscles are paralyzed with the exception of eye blinking.

[0090] Cerebral palsy: term used for a group of permanent, non-progressive movement disorders that cause physical disability. Cerebral palsy is caused by damage to the motor control centers in the developing brain and can occur during pregnancy, during childbirth or after birth up to the age of three. Patients with cerebral palsy have damage to their myelin sheaths.

[0091] Cerebrotendinous Xanthomatosis: An inherited disorder associated with the deposition of a form of cholesterol (cholestanol) in the brain and other tissues and with elevated levels of plasma cholesterol, but with a normal level of total cholesterol. It is characterized by progressive cerebellar ataxia beginning after puberty and by juvenile cataracts, chronic diarrhea of juvenile or infantile onset, infantile neurological deficit, and tendinous or tuberous xanthomas. This disorder is an autosomal recessive form of xanthomatosis. It is within a group of genetic disorders called leukodystrophies.

[0092] Chronic inflammatory demyelinating polyneuropathy (CIDP): An acquired immune-mediated inflammatory disorder of the peripheral nervous system. The disorder is sometimes called chronic relapsing polyneuropathy (CRP) or chronic inflammatory demyelinating polyradiculoneuropathy (because it involves the nerve roots). CIDP is closely related to Guillain-Barré syndrome and is considered the chronic equivalent of this acute illness. Its symptoms are also similar to progressive inflammatory neuropathy. An asymmetric variant of CIDP is known as Lewis-Sumner syndrome. The pathologic hallmark of the disease is loss of the myelin sheath.

[0093] Demyelinating Disease: Includes any disease of the nervous system in which myelin is damaged or lost, or in which the growth or development of the myelin sheath is impaired. Demyelination inhibits the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions for which the nerves are involved. Demyelinating diseases have many different causes and can be hereditary or acquired. In some cases, a demyelinating disease is caused by an infectious agent, an autoimmune response, a toxic agent, or traumatic injury. In other cases, the cause of the demyelinating disease is unknown ("idiopathic") or it develops from a combination of factors.

[0094] Devic Syndrome: An autoimmune and inflammatory disorder in which a person's immune system attacks the optic nerves and spinal cord, resulting in inflammation of the optic nerve (optic neuritis) and spinal cord (myelitis). Spinal cord injuries lead to varying degrees of weakness or paralysis in the legs or arms, loss of sensation, and/or bladder and bowel dysfunction. Although inflammation can also affect the brain, the lesions are different from those seen in MS. Devic syndrome is similar to MS in that the body's immune system attacks the myelin surrounding nerve cells. Unlike standard MS, the attacks are believed not to be mediated by the T cells of the immune system, but rather by antibodies called NMO-IgG. These antibodies target a protein called aquaporin 4 in the cell membranes of astrocytes, which acts as a channel for transporting water across the cell membrane. Devic syndrome is also known as Devic syndrome or neuromyelitis optica (NMO).

[0095] Diffuse myelinoclastic sclerosis: An uncommon neurodegenerative disease that presents clinically in the form of pseudotumoral demyelinating lesions. It usually starts in childhood, affecting children between 5 and 14 years of age; however, cases in adults are possible. This disease is considered one of the borderline forms of MS and is sometimes referred to as Schilder's disease.

[0096] Encephalomyelitis: Inflammation of the brain and spinal cord.

[0097] Experimental autoimmune encephalomyelitis (EAE): A disease model of MS (see, for example, Gold et al, Brain 129, 1953-1971 (2006). Animals with EAE exhibit plaques characteristic of widespread tissue damage throughout the central nervous system. Plates show infiltration of nerve tissue by lymphocytes, plasma cells, and macrophages, which cause destruction of the myelin sheaths surrounding the axons of nerve cells in the brain and spinal cord. In some cases, EAE is induced by immunization of susceptible animals, such as mice, rats, guinea pigs or non-human primates, with myelin or various myelin components. For example, EAE can be induced by immunization with myelin sheath components, such as basic protein myelin, proteolipid protein, or myelin oligodendrocyte glycoprotein (MOG) EAE is a useful and widely accepted model for studying mechanisms of CNS autoimmune tissue damage and for testing potential therapies for multiple sclerosis. EAE also includes “passive EAE” which is induced in the same way in donor animals but involves the transfer of activated T cells harvested from donor lymph nodes to pure recipient animals.

[0098] Guillain-Barré syndrome: Acute polyneuropathy, a disease that affects the peripheral nervous system. Ascending paralysis, weakness that begins in the feet and hands and migrates to the trunk, is the most typical symptom, and some subtypes cause altered sensation or pain, as well as autonomic nervous system dysfunction. It can cause life-threatening complications, particularly if the respiratory muscles are affected or the autonomic nervous system is involved. This disease is usually triggered by an infection. Acute inflammatory demyelinating polyneuropathy (AIDP) is the most common subtype of this disease. Other subtypes of Guillain-Barré syndrome include Miller Fischer syndrome, acute motor axonal neuropathy (Chinese paralytic syndrome), acute sensory motor axonal neuropathy, acute panutonic neuropathy, and Bickerstaff brainstem encephalitis.

[0099] Idiopathic Inflammatory Demyelinating Disease (IIDD): A broad spectrum of central nervous system disorders that can usually be differentiated on the basis of clinical, imaging, laboratory, and pathological findings. Idiopathic inflammatory demyelinating diseases are sometimes known as borderline forms of multiple sclerosis. IIDD generally refers to a collection of disease variants of multiple sclerosis, including, but not limited to, spinal-optic MS, Devic's disease, ADEM, acute hemorrhagic leukoencephalitis, Balo's concentric sclerosis, Schilder's disease, Marburg's multiple sclerosis, tumefactive multiple sclerosis and solitary sclerosis.

[0100] Infantile Refazum Disease: Disorder of peroxisomal biogenesis associated with deficiencies in catabolism of very long-chain and branched-chain fatty acids (such as phytanic acid) and plasminogen biosynthesis. Infantile Refsum disease is a rare, autosomal recessive congenital disorder and one of three peroxisomal biogenesis disorders that belong to the Zellweger spectrum of peroxisome biogenesis disorders.

[0101] Krabbe Disease: A rare, often fatal, degenerative disorder that affects the myelin sheath of the nervous system. It is a form of sphingolipidosis as it involves the dysfunctional metabolism of sphingolipids. This condition is inherited in an autosomal recessive pattern. Krabbe's disease is also known as globoid cell leukodystrophy or galactosylceramide lipidosis.

[0102] Leber's hereditary optic neuropathy: An inherited (passed from mother to offspring) mitochondrial degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this predominantly affects young adult males.

[0103] Leukodystrophy: Refers to a group of diseases that affect the growth or development of the myelin sheath.

[0104] Leukoencephalopathy: any of a group of diseases affecting the white matter of the brain; may specifically refer to a number of diseases, including, for example, “endangering white matter leukoencephalopathy” and “toxic leukoencephalopathy”. Leukoencephalopathies are diseases of the leukodystrophy type.

[0105] Multiple Sclerosis of Marburg: condition in which the central nervous system presents several demyelinating lesions with atypical characteristics in relation to those of standard multiple sclerosis. This disease is a borderline form of multiple sclerosis and is also known as tumefactive multiple sclerosis or fulminant multiple sclerosis. It is called tumefactive because the lesions are "tumor-like" and mimic tumors clinically, radiologically and sometimes pathologically.

[0106] Marchiafava-Bignami disease: A progressive neurological disease characterized by demyelination and necrosis of the corpus callosum and subsequent atrophy. It is classically associated with chronic alcoholics.

[0107] Metachromatic leukodystrophy (MLD): Lysosomal storage disease usually listed in the leukodystrophies family, as well as in the sphingolipidoses, as it affects the metabolism of sphingolipids. MLD is directly caused by a deficiency of the enzyme arylsulfatase A.

[0108] Multifocal Motor Neuropathy (MMN): A progressively worsening clinical condition in which the muscles in the extremities gradually weaken. This disorder, a motor neuropathy syndrome, is sometimes confused with amyotrophic lateral sclerosis (ALS) because of the similarity in the clinical picture, especially if muscle fasciculations are present. MMN is usually asymmetrical and is believed to be autoimmune.

[0109] Multiple sclerosis (MS): Disease of the CNS, slowly progressive, characterized by widespread patches of demyelination in the brain and spinal cord, resulting in diverse and varied neurological symptoms and signs, usually with remissions and exacerbations. The cause of MS is unknown, but an immune abnormality is suspected. An increased familial incidence suggests genetic susceptibility and females are affected slightly more than males. Symptoms of MS include weakness, lack of coordination, paresthesias, speech disturbances and visual disturbances, most commonly double vision. More specific signs and symptoms depend on the location of the lesions and the severity and destructiveness of the inflammatory and sclerotic processes. Relapsing-remitting multiple sclerosis (RRMS) is a clinical course of MS characterized by clearly defined acute attacks, with full or partial recovery and no disease progression between attacks. Secondary progressive multiple sclerosis (SPMS) is a clinical course of multiple sclerosis that is initially relapsing-remitting and then becomes progressive at a variable rate, possibly with an occasional relapse and minor remission. Primary-progressive multiple sclerosis (PPMS) initially presents in the progressive form. A clinically isolated syndrome is the first neurological episode, caused by inflammation/demyelination at one or more sites in the CNS. Relapsing-progressive multiple sclerosis (PRMS) is a rare form of multiple sclerosis (~5%) characterized by a progressively worsening disease state with acute relapses but no remissions.

[0110] Neurodegenerative disease: refers to any type of disease that is characterized by progressive deterioration of the nervous system.

[0111] Neuropathy: Functional disorder or pathological alteration of the peripheral nervous system. Axonal neuropathy refers to a disorder that interrupts the normal functioning of axons.

[0112] Paraproteinemic demyelinating polyneuropathy: Type of peripheral neuropathy characterized by autoantibodies directed against myelin-associated glycoproteins (MAG). Anti-MAG antibodies inhibit myelin production, leading to neuropathy.

[0113] Pelizaeus-Merzbacher Disease (PMD): Rare disorder of the central nervous system in which coordination, motor skills, and intellectual function are delayed to varying extents. The disease is one of a group of genetic diseases collectively known as the leukodystrophies.

[0114] Peroneal muscular atrophy (PMA): A genetically and clinically heterogeneous group of inherited disorders of the peripheral nervous system characterized by progressive loss of muscle tissue and sense of touch in various parts of the body. This disease is also known as Charcot-Marie-Tooth disease (CMT), Charcot-Marie-Tooth neuropathy, and hereditary motor and sensory neuropathy (HMSN).

[0115] Progressive multifocal leukoencephalopathy (PML): A rare and usually fatal viral disease characterized by progressive damage or inflammation of the white matter of the brain at various sites. PML occurs almost exclusively in people with severe immune deficiency. The cause of PML is a type of polyomavirus called the JC virus. The virus is widespread, with 86% of the general population having antibodies, but it usually remains latent, causing illness only when the immune system is severely weakened. PML is a demyelinating disease, in which the myelin sheath that covers the axons of nerve cells is gradually destroyed, impairing the transmission of nerve impulses. The disease can occur in individuals (eg, humans) with severe immune deficiency, such as transplant patients on immunosuppressant medications or those receiving certain types of medications. For example, PML has been associated with the administration of rituximab (off-label use in the treatment of multiple sclerosis). It affects the white matter, which is mainly composed of axons from the outermost parts of the brain (cortex). Symptoms include weakness or paralysis, vision loss, impaired speech and cognitive deterioration.

[0116] Transverse myelitis: Neurological disorder caused by an inflammatory process of the gray and white matter of the spinal cord, leading to axonal demyelination. Demyelination arises idiopathically after infections or vaccination, or due to multiple sclerosis. Symptoms include limb weakness and numbness, as well as motor, sensory, and sphincter deficits. Severe back pain may occur in some patients at the onset of the disease.

[0117] Tropical spastic paraparesis (TSP): Infection of the spinal cord by the human T lymphotropic virus, resulting in paraparesis and weakness of the legs. TSP is also known as HTLV-associated myelopathy or chronic progressive myelopathy. As the name suggests, this disease is most common in tropical regions, including the Caribbean and Africa.

[0118] Van der Knaap disease: a form of inherited demyelinating disease of the CNS. This disease is a type of leukodystrophy and is also known as megaencephalic leukoencephalopathy with subcortical cysts (MLC).

[0119] X-linked adrenoleukodystrophy (ALD-X, ALD, or X-linked ALD): Rare inherited metabolic disorder leading to progressive brain damage, mental deterioration, adrenal insufficiency, muscle spasms, blindness, and eventually death . ALD is one disease in a group of inherited disorders called leukodystrophies. Adrenoleukodystrophy progressively damages myelin. Patients with X-linked ALD can be divided into 7 phenotypes: infantile cerebral (progressive neurodegenerative decline leading to a vegetative state), adolescent (similar to childhood cerebral form but with slower progression), adrenomyeloneuropathy (progressive neuropathy, paraparesis, may progress to cerebral involvement), adult cerebral (dementia, evolution similar to the cerebral form in childhood), olivo-pontine-cerebellar (brain and cerebral disease), Addison's disease (adrenal insufficiency), asymptomatic (no clinical presentation, subclinical adrenal insufficiency or AMN phenotype). Female X-linked ALD carriers can be divided into 5 phenotypes: asymptomatic (without neurological or adrenal involvement), mild myelopathy, moderate to severe myelopathy (similar to the male AMN phenotype), cerebral (progressive dementia and decline) and adrenal (insufficiency primary adrenal). Patients with X-linked ALD may progress from one phenotype to another throughout their lifetime. ALD is also known as Addison-Schilder disease or Siemerling-Creutzfeldt disease.

[0120] Zellweger syndrome: Rare congenital disorder characterized by the reduction or absence of functional peroxisomes in an individual's cells. This disease is classified as a leukodystrophy and is one of three peroxisomal biogenesis disorders that belong to the peroxisome biogenesis spectrum of the Zellweger spectrum. Amide compounds of the invention

[0121] Systemically administered overthyroma is predominantly distributed in the liver. There is indirect evidence from several previous studies that sobethyroma is distributed in the CNS (Takahashi N et al., Biol Pharm Bull 37, 1103-1108 (2014); Trost S et al., Endocrinology 141, 30573064 (2000), Bernal J, Nat Clin Pract.Endrocrinol Metab 3, 249-259 (2007), Oppenheimer JH and Schwartz HL, Endocr Rev 18, 462-475 (1997) and Bernal J, J Endocrinol Invest 25, 268-288 (2002); are incorporated into this document by reference).

[0122] Generally, a brain/serum ratio in the range of 0.3-1.0 is usually preferred for CNS drugs (Doran A et al, Drug Metab Dispos 33, 165-174 (2005) and Reichel A, Curr Drug Metab 7, 183-203 (2006)), both incorporated herein by reference. A compound of the invention may exhibit increased penetration of the blood-brain barrier (BBB), as measured by the brain/serum ratio. In a non-limiting example, a compound of the invention can provide a brain/serum ratio of at least 0.3 (e.g., at least 0.4 or at least 0.5). These compounds may exhibit less, or absent, GC-1-like activity in peripheral tissue. Without being limited by theory, a compound of the invention can be unmasked in the CNS by resident hydrolases to produce GC-1, thereby producing high concentrations of GC-1 in the CNS (FIG. 1). GC-1 can become ionized in the CNS, thereby producing a therapeutic effect in the CNS (eg, remyelination). A higher brain/serum ratio for compounds of the invention may advantageously produce little or no peripheral action.

[0123] The non-provisional patent application US 15/048,672, incorporated herein by reference, describes ester compounds which, upon hydrolysis, can produce sobetiroma (GC-1). Ester compounds, including the 2-aminoethanol ester motif, have been observed to cross the blood brain barrier efficiently. Under certain physiological conditions, these compounds can undergo rearrangement to the corresponding amide product (Scheme 1). Analysis of the amide products revealed that the elevated levels of GC-1 in the brain were attributable to this amide conversion product rather than the major ester compounds. Compounds of the invention have been developed and are disclosed herein.

[0124] Scheme 1 - the aminoethanol ester sobetiroma

[0125] The compounds of the invention may have greater chemical and biological stability compared to esters. They are likely to be less prone to the spontaneous hydrolysis demonstrated by aqueous hydrolysis (for a discussion of hydrolysis rates, see Mabey W & Mill T, J. Phys Chem Ref Data 7, 383-415 (1978)). Furthermore, other compounds may be subjected to the action of broad families of enzymes in vivo (Fukami T and Yokoi T, Drug Metab Pharmacokinet 27, 466477 (2012); Casey Laizure S et al., Pharmacotherapy 33, 210222 (2013), all they are incorporated herein by reference) that can lead to premature hydrolysis. The hydrolysis of the compounds of the invention can be specific for certain amidases residing in the brain. Without wishing to be bound by theory, enzymatic cleavage of non-peptide amides may be more restricted in scope than other compounds.

Fórmula I, ou um sal farmaceuticamente aceitável seu, em que R1 é uma amida.[0125] Compounds of Formula I are disclosed:

Formula I, or a pharmaceutically acceptable salt thereof, wherein R1 is an amide.

Fórmula II, ou um seu sal farmaceuticamente aceitável, em que R2 é alquilamino ou amino.[0126] Compounds of Formula II are also disclosed:

Formula II, or a pharmaceutically acceptable salt thereof, wherein R2 is alkylamino or amino.

Fórmula III, ou um sal farmaceuticamente aceitável seu, em que cada um de R3 e R4 é conforme descrito neste documento.[0127] Compounds of Formula III are also disclosed:

Formula III, or a pharmaceutically acceptable salt thereof, wherein each of R3 and R4 is as described herein.

Fórmula IV, ou um sal farmaceuticamente aceitável seu, em que R3 é conforme descrito neste documento, em detalhes.[0128] Compounds of Formula IV are also disclosed:

Formula IV, or a pharmaceutically acceptable salt thereof, wherein R3 is as described herein in detail.

[0129] Furthermore, the disclosure includes a pharmaceutical composition, including a pharmaceutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

treatment methods

[0130] It is also understood that each of the compounds described herein, or a pharmaceutically acceptable salt thereof, may be used in a method of treating each of the diseases or ailments referred to herein. Each mode of treatment comprises administering to an individual in need, for example: a human in need, a pharmaceutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof.

[0131] For example, there is provided a method of treating a neurodegenerative disease in a subject, such as a human subject, the method comprising administering to the subject a pharmaceutically effective amount of a compound herein, or a pharmaceutically acceptable salt thereof.

[0132] Also provided is a method of treating a demyelinating disease in a subject, such as a human subject, the method comprising administering to the subject a pharmaceutically effective amount of a compound herein, or a pharmaceutically acceptable salt thereof.

[0133] For example, there is provided a method of treating X-linked adrenoleukodystrophy in a human subject, the method comprising administering to the subject a pharmaceutically effective amount of a compound herein, or a pharmaceutically acceptable salt thereof.

[0134] For example, there is provided a method of treating multiple sclerosis in a subject, such as a human subject, the method comprising administering to the subject a pharmaceutically effective amount of a compound herein, or a pharmaceutically acceptable salt thereof.

[0135] Also provided is a method of treating Alzheimer's disease in a subject, such as a human subject, the method comprising administering to the subject a pharmaceutically effective amount of a compound herein, or a pharmaceutically acceptable salt thereof.

[0136] Also provided is a method of treating a disease or clinical condition selected from the group consisting of: acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), Refsum in adults, Refsum disease in children, Refsum disease Alexander, Alzheimer's disease, Balo's concentric sclerosis, Canavan's disease, CPM (CPM), Cerebral Palsy, Cerebrotendinous Xanthomatosis, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Devic's Syndrome, Myelinoclastic Sclerosis, Encephalomyelitis, Diffuse Guillain-Barré Syndrome, Idiopathic inflammatory demyelinating disease (IIDD), Krabbe's disease, Leber's hereditary optic neuropathy, Leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), polyneuropathy paraproteinemic demyelinating disease, Pelizaeus-Merzbacher disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraparesis (TSP), X-linked adrenoleukodystrophy (X-ALD, X-linked ALD or ALD), and Zellweger syndrome. The method comprises administering to a subject in need, for example: a human subject, a pharmaceutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0137] It is also understood that each of the compounds described herein, or a pharmaceutically acceptable salt thereof, can be used in the preparation of a medicament useful in the treatment of each of the diseases or ailments referred to herein. Each mode of treatment comprises administering to a subject in need, for example: a human in need, a pharmaceutically effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof.

[0138] For example, there is provided the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament useful in the treatment of a neurodegenerative disease in an individual, for example: a human being.

[0139] For example, there is provided the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament useful in the treatment of a demyelinating disease in a subject, such as a human.

[0140] For example, there is provided the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament useful in the treatment of an adrenoleukodystrophy in an individual, for example: a human being.

[0141] For example, there is provided the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament useful in the treatment of multiple sclerosis in a subject, for example: a human being.

[0142] For example, there is provided the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament useful in treating Alzheimer's disease in a subject, such as a human.

[0143] Also provided is the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in treating a disease or medical condition in an individual, such as a human individual, selected from the group which consists of: acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), Refsum in adults, childhood Refsum disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, CPM (CPM) , Cerebral Palsy, Cerebrotendinous Xanthomatosis, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Devic's Syndrome, Myelinoclastic Sclerosis, Encephalomyelitis, Diffuse Guillain-Barré Syndrome, Idiopathic Inflammatory Demyelinating Disease (IIDD), Krabbe's Disease, Leber's Hereditary Optic Neuropathy, Leukodystrophy , Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraparesis (TSP), X-linked adrenoleukodystrophy (X-ALD, ALD, or X-linked ALD), and Zellweger syndrome.

Examples

[0144] The following examples are for illustration only. In light of this disclosure, those skilled in the art will recognize that variations on these examples and other examples of the disclosed invention are possible without undue experimentation. Example 1 - Animal Studies

[0145] The experimental protocols were in accordance with the Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Oregon Health & Science University Institutional Animal Care & Use Committee. Male wild-type C57BI/6 mice, aged 8 to 10 weeks, were housed in a climate-controlled room on a 12-hour light-dark cycle with ad libitum access to food and water. For time-point analysis of in vivo GC-1 concentrations, sobethyroma and prodrugs at 3.05 μmol/kg were injected intraperitoneally (i.p.) into mice. Euthanasia was performed on three rats after 1 hour and tissues and blood were collected. Tissues were immediately frozen and blood was kept on ice for a minimum of 30 minutes and then centrifuged at 7500 x G for 15 minutes. Serum (100 μL) was collected and stored with tissues at -80 °C until sample processing. Serum processing: Serum samples were warmed to room temperature and 10 µL of 2.99 µM internal standard (d6- sobetiroma) was added. Acetonitrile (500 µL) was added and the sample vortexed for 20 seconds. The sample was then centrifuged at 10,000 x G for 15 minutes at 4°C. Then, 90% of the upper supernatant was transferred to a glass test tube and concentrated for a speed of 1.5 hours at 45°C. The dried sample was then dissolved in 400 µl of 50:50 acetonitrile:H2O and subjected to the vortex for 20 seconds. The resulting mixture was transferred to an Eppendorf tube and centrifuged at 10,000 x G for 15 minutes. The supernatant was filtered with 0.22 μM centrifugal filters and subjected to LC-MS/MS analysis to quantify the amount of free subethyromes. The standard curve was made with 100 µL of serum from an 8-10 week old mouse that received a vehicle-only injection. Processing was carried out in exactly the same way, except for the fact that, after filtering, the sample was divided into 6 vials. To 5 of the 6 vials, sobetiroma was added to make final matrix concentrations of (0.1 pg/μL, 1 pg/μL, 10 pg/μL, 100 pg/μL, and 1000 pg/μL).

[0146] Brain processing: The brain samples were warmed to room temperature and transferred to a homogenizer tube with GoldSpec 1/8 chromed steel spheres (Applied Industrial Technologies). The resulting tube was weighed and then 1 mL of H2O was added, followed by 10 µL of 2.99 µM internal standard (d6-sobetiroma). The tube was homogenized with a Bead Bug® for 30 seconds and then transferred to a Falcon tube containing 3 mL of acetonitrile. Acetonitrile (1 mL) was used to wash the homogenizer tube and the solution was transferred back to the Falcon tube. The sample was then processed using the same method for processing the serum, except the sample was concentrated in a glass tube using a speedvac for 4 hours at 45°C. Samples were then processed using the serum processing method for LC-MS/MS analysis.

Exemplo 2 - Química Geral[0147] The results are shown in Table 1.

Example 2 - General Chemistry

[0148] 1H NMRs were taken on a Bruker 400®. All 1H NMRs were calibrated to an NMR solvent reference peak (DMSO-d6, chloroform-d, methanol-d4). Electro-spray ionization high-resolution mass spectrometry (HRMS) was performed by the Bioanalytical EM Facility at Portland State University. Inert atmosphere reactions were performed under argon gas passed through a short column of drierite and were conducted in flame-dried RBFs. Anhydrous tetrahydrofuran (THF) and dichloromethane (DCM) and dimethylformamide (DMF) were obtained from a Seca Solvent System. All other solvents used were purchased from Sigma-Aldrich or Fisher. The synthesis of Sobetiroma (GC-1) has been previously described (Chiellini G et al, Bioorg Med Chem Lett 10, 2607-2611 (2000) and Placzek AT et al, Tetrahedron 71, 5946-5951 (2015); both are incorporated into this document by reference). The synthesis of O-benzyl-GC-1 (2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid) has been disclosed previously. All other reagents were purchased from Fisher, Sigma or TCI and used as received. Purity analysis of final compounds was determined to be >95% by HPLC. Analytical HPLC analysis was performed on a Varian ProStar HPLC with a Grace Alltima C18 column, 5 µm (4.6 x 250 mm) with a gradient (solvent A: 95:5 water: MeCN, 0.2% Et3NH3PO4, pH 2.5; solvent B: MeCN) to B from 40% to 100% over 20 minutes with a flow rate of 1 ml/min. Preparative HPLC was performed on a Varian Dynamax Microscrob 100-5 uM C18, 21.4x250 mm (Solvent A: Water +0.1% formic acid; Solvent B: MeCN +0.1% formic acid) using a gradient of 20-100% B for 20 minutes at a flow rate of 25 ml/min. Example 3-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(2-hydroxyethyl)acetamide (Compound 1)

[0149] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 130 mg, 0.31 mmol, 1 eq) in DCM (2 mL) at 0°C is treated with oxalyl chloride (110 µL, 1.23 mmol, 4 eq). DMF (1 drop) is added and the reaction is stirred for 3 hours while warming to room temperature. The solvent is removed under reduced pressure and the crude intermediate treated with DCM (5 mL), which is subsequently removed under reduced pressure. The crude intermediate treated with 1.5 mL of DCM followed by dropwise addition of ethanolamine (114 mg, 1.87 mmol, 6 eq). The reaction is stirred for 1 hour at room temperature. The reaction mixture purified by flash chromatography (25-100% EtOAc in hexanes) to give the intermediate product as a white solid (48 mg, 0.1 mmol, 33%). The benzyl-protected intermediate (48 mg, 0.104 mmol, 1 eq) is treated with 1:1 MeOH:EtOAc (1 mL) under argon. Palladium on carbon (10 wt%, 22 mg) is added to the reaction and triethylsilane (132 µL, 0.83 mmol, 8 eq) is added dropwise. The reaction is stirred overnight. An additional aliquot of triethylsilane (50 µL, 0.31 mmol, 3 eq) is added and the reaction is stirred for 1 hour. The reaction mixture is poured onto a pad of celite and washed with MeOH. The concentrated reaction solution is purified by flash chromatography (1-10% MeOH in DCM) to give the product as a white solid (29 mg, 0.076 mmol, 73%). 1H NMR (400 MHz, Chloroform-d) δ 7.11 (b, 1H), 6.93 (d, J = 2 Hz, 1H), 6.64-6.55 (m, 4H), 5.36 (b, 1H), 4.52 (s, 2H), 3.91 (s, 2H), 3.79 (t, J = 4.8 Hz, 2H), 3.55 (q, J = 5.5 Hz, 2H), 3.19 (sept, J = 6.9, 1H), 2.22 (s, 6H ), 1.25 (d, J = 6.8 Hz, 6H). HRMS (ESI) m/z [M+H+] C22H30NO4+ requires 372.2169, 372.2182 found. Example 4-2-(4-(4-'hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(1-hydroxypropan-2-yl)acetamide (Compound 2)

[0150] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 87 mg, 0.207 mmol, 1 eq) in DCM ( 1.3 mL) at 0oC is treated with oxalyl chloride (73 μl, 0.83 mmol, 4 eq). DMF (1 drop) is added and the reaction is stirred for 3 hours while warming to room temperature. The solvent is removed under reduced pressure and the crude intermediate treated with DCM (5 mL), which is subsequently removed under reduced pressure. The crude intermediate is treated with 1.5 mL of DCM followed by the dropwise addition of (+/-)-alaniol (93 mg, 1.24 mmol, 6 eq). The reaction is stirred for 1 hour at room temperature. The reaction mixture purified by flash chromatography (25-100% EtOAc in hexanes) to give the intermediate product as a white solid (48 mg, 0.1 mmol, 48%). The benzyl-protected intermediate (40 mg, 0.085 mmol, 1 eq) is treated with 1:1 MeOH:EtOAc (1 mL) under argon. Palladium on charcoal (10 wt%, 22 mg) is added to the reaction and triethylsilane (108 µL, 0.68 mmol, 8 eq) is added dropwise. The reaction is stirred overnight. An additional aliquot of triethylsilane (50 µL, 0.31 mmol, 3.7 eq) is added and the reaction is stirred for 1 hour. The reaction mixture is poured onto a pad of celite and washed with MeOH. The concentrated reaction solution purified by flash chromatography (1-10% MeOH in DCM) to give the product as a white solid (21 mg, 0.055 mmol, 64%). 1H NMR (400 MHz, Chloroform-d) δ 7.28 (b, 1H), 6.93 (d, J = 2 Hz), 6.73-6.53 (m, 4H), 5.04 (b, 1H), 4.50 (s, 2H) , 4.19 (m, 1H), 3.92 (s, 2H), 3.72-3.61 (m 2H), 3.19 (s, J = 6.9 Hz, 1H), 2.65 (s, 1H), 2.24 (s, 6H), 1.23 (m, 9H). HRMS (ESI) m/z [M+H+] C23H32NO4+ requires 386.2326, 386.2335 found. Example 5-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(2-hydroxypropyl)acetamide (Compound 3)

[0151] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 87 mg, 0.207 mmol, 1 eq) in DCM ( 1.3 mL) at 0oC is treated with oxalyl chloride (73 μl, 0.83 mmol, 4 eq). DMF (1 drop) is added and the reaction is stirred for 3 hours while warming to room temperature. The solvent is removed under reduced pressure and the crude intermediate treated with DCM (5 mL), which is subsequently removed under reduced pressure. The crude intermediate is treated with 1.5 mL of DCM followed by the dropwise addition of 1-amino-2-propanol (93 mg, 1.24 mmol, 6 eq). The reaction is stirred for 1 hour at room temperature. The reaction mixture purified by flash chromatography (25-100% EtOAc in hexanes) to give the intermediate product as a white solid (66 mg, 0.14 mmol, 68%). The benzyl-protected intermediate (40 mg, 0.085 mmol, 1 eq) is treated with 1:1 MeOH:EtOAc (1 mL) under argon. Palladium on charcoal (10 wt%, 22 mg) is added to the reaction and triethylsilane (108 µL, 0.68 mmol, 8 eq) is added dropwise. The reaction is stirred overnight. An additional aliquot of triethylsilane (50 µL, 0.31 mmol, 3.7 eq) is added and the reaction is stirred for 1 hour. The reaction mixture is poured onto a pad of celite and washed with MeOH. The concentrated reaction solution purified by flash chromatography (1-10% MeOH in DCM) to give the product as a white solid (43 mg, 0.11 mmol, 73%). 1H NMR (400 MHz, Chloroform-d) δ 7.11 (b, 1H), 6.93 (d, J = 2 Hz), 6.61-6.51 (m, 4H), 5.84 (b, 1H), 4.49 (s, 2H) , 3.96 (m, 1H), 3.91 (s, 2H), 3.51 (m, 1H), 3.19 (m, 2H), 2.27 (s, 6H), 1.20 (m, 9H). HRMS (ESI) m/z [M+H+] C23H32NO4+ requires 386.2326, found 386.2335. Example 6—2-(2-(4-(4-Hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamido)ethane-1-aminium acetate (Compound 4)

[0152] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 441 mg, 1.05 mmol, 1 eq) in DCM (7 mL) at 0°C is treated with oxalyl chloride (542 µL, 6.3 mmol, 6 eq). DMF (1 drop) is added and the reaction is stirred for 3 hours while warming to room temperature. The solvent is removed under reduced pressure and the crude intermediate treated with DCM (10 mL), which is subsequently removed under reduced pressure. The crude intermediate treated with 3 mL of DCM followed by the dropwise addition of 2-aminoethylbenzyl carbamate (408 mg, 2.1 mmol, 2 eq). The reaction is stirred for 1 hour at room temperature. The reaction mixture purified by flash chromatography (0-50% EtOAc in hexanes) to give the intermediate product as a white solid (380 mg, 0.643 mmol, 61%). The benzyl-protected intermediate (380 mg, 0.64 mmol, 1 eq) is treated with THF (2 mL) and acetic acid (0.2 mL) under argon. Palladium on carbon (10 wt%, 270 mg) is added to the reaction and triethylsilane (818 µL, 5.11 mmol, 8 eq) is added dropwise. The reaction is stirred overnight. The reaction mixture is poured onto a pad of celite and washed with MeOH. The solution is concentrated and then taken up in a minimum amount of DCM and MeOH and reconcentrated under reduced pressure. The crude product is recirculated with DCM (0.25 mL) with several drops of MeOH. Hexanes (3 mL) is slowly added to the solution, which leads to precipitation of the product. The hexane supernatant is removed by pipette and the white product is washed with hexanes and dried extensively under reduced pressure to give a white viscous solid product (57 mg, 0.132 mmol, 21%). 1H NMR (400 MHz, d6-DMSO) δ 8.40 (b, 1H), 6.83 (d, J = 2 Hz, 1H), 6.82-6.44 (m, 4H), 4.42 (s, 2H), 3.71 (s, 2H), 3.31 (t, J = 6 Hz, 2H), 3.19 (sept, J = 6.9 Hz, 1H), 2.79 (m, 2H), 2.16 (s, 6H), 1.83 (s, 3H), 1.09 ( d, J = 6.9 Hz, 6H). HRMS (ESI) m/z [M+H+] C22H31N2O3+ requires 371.2335, 371.2329 found. Example 7-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide (Compound 5)

[0153] GC-1 (250 mg, 0.76 mmol, 1 eq) is treated with MeOH (3 mL) in a sealed tube. Sulfuric acid (1 drop) is added and the reaction is sealed and then heated to 65oC for 1 hour while stirring. The reaction is allowed to come to room temperature. TLC analysis (1:30 MeOH:DCM) shows complete conversion to the intermediate methyl ester. To the intermediate reaction mixture, ammonia (7N in MeOH, 0.76 mL, 7 eq) is added. The reaction is resealed and reheated to 65oC for one hour. The reaction flask is allowed to come to room temperature and 0.5N NaOH (20 mL) is added into a separatory funnel and subsequently extracted with DCM (3 x 100 mL). The organic layers were combined, dried over Na2SO4 and concentrated. Purification by flash chromatography (0-6% MeOH in DCM) gave the product as a white solid (157 mg, 0.48 mmol, 63%). 1H NMR (400 MHz, Chloroform-d) δ 6.93 (b, 1H), 6.65-6.56 (m, 5H), 5.85 (b, 1H), 5.19 (s, 1H), 4.51 (s, 2H), 3.92 ( s, 2H), 3.19 (sept, J = 6.9, 1H), 2.24 (s, 6H), 1.23 (d, J = 6.9 Hz, 6H). HRMS (ESI) m/z [M+Na+]C20H25NNaO3+ requires 350.1727, 350.1737 found. Example 8—N-(2,2-difluoroethyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide (Compound 6)

[0154] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 300 mg, 0.72 mmol, 2 eq) treated with dry THF (5 mL) and CDI (140 mg, 0.86 mmol, 2.4 eq) followed by heating at 45 °C for 2 h. The reaction is concentrated under reduced pressure and dissolved in THF (5 mL). Half of the reaction is taken to the next step (0.36 mmol, 1 eq) and treated with THF (2.5 mL). Difluoroethylamine (87 mg, 1.075 mmol, 3 eq) is added as a solution in THF (0.2 mL). The reaction is stirred at room temperature for 1 h. The reaction solution is diluted with diethyl ether (20 mL) and washed with 0.5N HCl (2 x 20 mL) followed by brine (20 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The crude intermediate is taken up in DCM (3 mL) and placed under argon. Pentamethylbenzene (106 mg, 0.72 mmol, 2 eq) is added and the reaction is cooled to -78°C. A solution of BCl3 (1M DCM, 0.72 mL, 2 eq) is added slowly and the reaction stirred for 15 minutes. The reaction is quenched by adding a saturated NaHCO3 solution (2 mL) and the flask is allowed to warm to room temperature. The reaction mixture is diluted with water (10 mL) and extracted with DCM (2x 20 mL). The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (2-40% EtOAc in hexanes) gave the product as a crystalline solid (79 mg, 0.2 mmol, 56%). 1H NMR (400 MHz, Chloroform-d) δ 6.94 (m, 2H), 6.65-6.55 (m, 4H), 5.91 (tt, J = 55.8, 4.1 Hz, 1H), 5.19 (s, 1H), 4.55 ( s, 2H), 3.93 (s, 2H), 3.77 (m, 2H), 3.20 (sept, J = 6.9, 1H), 2.24 (s, 6H), 1.23 (d, J = 6.9 Hz, 6H). HRMS (ESI) m/z [M+H+] C22H28F2NO3+ requires 392.2032, 392.2040 found. Example 9-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(2,2,2-trifluoroethyl)acetamide (Compound 7)

[0155] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 300 mg, 0.72 mmol, 2 eq) treated with dry THF (5 mL) and CDI (140 mg, 0.86 mmol, 2.4 eq) followed by heating at 45 °C for 2 h. The reaction is concentrated under reduced pressure and dissolved in THF (5 mL). Half of the reaction is taken to the next step (0.36 mmol, 1 eq). Trifluoroethylamine hydrochloride (87 mg, 1.075 mmol, 3 eq) and DMAP (13 mg, 0.11 mmol, 0.3 eq) are added as a solution in THF (0.2 mL). The reaction is stirred at room temperature for 1 h. The reaction solution is diluted with diethyl ether (20 mL) and washed with 0.5N HCl (2 x 20 mL) followed by brine (20 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The crude intermediate is taken up in DCM (3 mL) and placed under argon. Pentamethylbenzene (106 mg, 0.72 mmol, 2 eq) is added and the reaction is cooled to -78°C. A solution of BCl3 (1M DCM, 0.72 mL, 2 eq) is added slowly and the reaction stirred for 15 minutes. The reaction is quenched by adding a saturated NaHCO3 solution (2 mL) and the flask is allowed to warm to room temperature. The reaction mixture is diluted with water (10 mL) and extracted with DCM (2x 20 mL). The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (2-40% EtOAc in hexanes) gave the product as a white solid (89 mg, 0.22 mmol, 61%). 1H NMR (400 MHz, Chloroform-d) δ 6.93 (m, 2H), 6.65-6.57 (m, 4H), 4.80 (s, 1H), 4.58 (s, 2H), 4.05 (m, 2H), 3.93 ( s, 2H), 3.18 (sept, J = 6.8, 1H), 2.24 (s, 6H), 1.23 (d, J = 6.8 Hz, 6H). HRMS (ESI) m/z [M+Na+] C22H26F3NNaO3+ requires 432.1757, 432.1762 found. Example 10—2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-methylacetamide (Compound 8)

[0156] 2-(4-(4-Hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (GC-1, 155 mg, 0.47 mmol) was dissolved in 3 mL of MeOH and 1 drop of sulfuric acid in a sealed tube. The sealed reaction mixture was then heated to 65°C with stirring for 1 hour. Upon cooling to room temperature, TLC of the mixture indicates complete conversion to the methyl ester intermediate. 610 µL (7.05 mmol, 15 eq.) of 40% methylamine in water was added and the reaction mixture was again heated at 65°C for 1 hour in a sealed tube. The reaction extracted 200 mL of 0.5 N NaOH in 3 x 50 mL of DCM. The organic layers were combined, dried over Na 2 SO 4 , filtered and concentrated, then purified on silica (10% MeOH in DCM) to give the product as a white solid (144 mg, 90%). 1H NMR (400 MHz, CD3CN): 6.98 (br, 1H), 6.89 (s, 1H), 6.68 (s, 2H), 6.62 (d, 1H, J = 8.6 Hz), 6.54 (dd, 1 H, J = 8.4, 2.4 Hz), 4.37 (s, 2 H), 3.87 (s, 2 H), 3.16 (septet, 1 H, J = 6.9 Hz), 2.75 (d, 3 H, J = 4.9 Hz), 2.20 (s, 6H), 1.12 (d, 6H, J = 6.9 Hz). HRMS exact mass calcd for C21H27NO3 [M + Na-]+: m/z 364.18831. Found m/z 364.18904. Example 11 - 2-(4-(4-hydroxy-3-isopropyl benzyl)-3,5-dimethylphenoxy)-N-(2-hydroxyphenyl)acetamide (Compound 9)

[0157] 2-[4-(4-(Benzyloxy)-3-isopropylbenzyl)-3, 5-dimethylphenoxy)acetic acid (250mg, 0.6 mmol) was dissolved in 6 ml of dry DMF in a round bottom flask . 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (230 mg, 1.2 mmol), 1-hydroxybenzotriazole (HOBt) (162 mg, 1.2 mmol) and diisopropylethylamine (DIEA) ( 418 uL, 2.4 mmol) and stirred. for 1 hour at room temperature. Then 2-aminophenol (130 mg, 1.2 mmol) was added in one batch and the reaction mixture was stirred overnight at room temperature. Ethyl acetate (15 ml) was then added and the reaction mixture was washed successively with 0.5N HCl (2x5 ml), saturated NaHCO 3 solution (2x5 ml) and saturated NaCl solution (1x10 ml). It was then dried over anhydrous MgSO4 and the solvent was removed in vacuo. The crude product was purified by Biotage flash chromatography, eluting with 10% to 40% ethyl acetate in hexane to give pure benzyl protected acetamide GC-1 (154 mg, 0.3 mmol). 1H NMR (400 MHz, CDCl3): δ 8.72(s, 1H), 8.573(s, 1H), 7.38-6.61(m, 14H), 5.30(s, 2H), 4.68(s, 2H), 3.95(s , 2H), 3.37 (m, 1H), 2.25(s, 6H), 1.22 (d, J=6.57Hz, 6H).

[0158] To a stirred suspension of this protected acetamide (150 mg, 0.29 mmol) and 10% Pd-C, moistened with about 55% water (60 mg) in 5 ml methanol was added triethylsilane ( 441uL, 2.9 mmol), dropwise, under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction (TLC), it was filtered through celite and the solvent was removed in vacuo. The crude product was purified by Biotage flash chromatography, eluting with 10% to 40% ethyl acetate in hexane to give the final acetamide (79 mg, 0.18 mmol, 64% yield and 98.9% pure by HPLC). 1HNMR (400MHz, CDCl3): δ 8.70(s, 1H), 8.57(s, 1H), 7.16(m, 1H), 7.08(m, 1H), 6.92(m, 2H), 6.72(s, 2H), 6.59(m, 2H), 4.68(s, 2H), 3.93(s, 2H), 3.13(m, 1H), 2.26(s, 6H), 1.22(d, J=6.98Hz, 6H). HRMS (M + Na) calcd for C26H29NO4 442.19888, 442.19903 found. Example 12-2-(4-(4-hydroxy-3-isopropylbenzyl)-N-(3-hydroxyphenyl)acetamide (Compound 10)

[0159] 2-[4-(4-(Benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (250 mg, 0.6 mmol) is dissolved in 6 ml of dry DMF. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (230 mg, 1.2 mmol), 1-hydroxybenzotriazole (HOBt) (162 mg, 1.2 mmol) and diisopropylethylamine (DIEA) ( 418 uL, 2.4 mmol) and stirred. for 1 hour at room temperature. To this solution, 2-aminophenol (130 mg, 1.2 mmol) was added in one batch and stirred overnight at room temperature. Ethyl acetate (15 ml) was then added and the reaction mixture was washed with 0.5N HCl (2x10 ml), saturated NaHCO 3 solution (2x10 ml) and saturated NaCl solution (1x10 ml). It was then dried over anhydrous MgSO4 and the solvent was removed in vacuo. The crude product was purified by Biotage flash chromatography, eluting with 10% to 40% ethyl acetate in hexane to give pure benzyl protected acetamide GC-1 (186 mg, 0.36 mmol). 1H NMR (400 MHz, CDCl3): δ 8.35(s, 1H), 7.64(s, 1H), 7.43-7.33(m, 5H), 7.21- 6.85(m, 4H), 6.76-6.61(m, 5H) , 5.0(s, 2H), 4.6(s, 2H), 3.97(s, 2H), 3.36(m, 1H), 2.25(s, 6H), 1.19(d, J=6.94Hz, 6H)

[0160] The protected acetamide (180 mg, 0.35 mmol) was dissolved in a mixture of methanol and THF (5 mL +6 mL) (11 mL) as it was not completely soluble in methanol alone. 10% Pd-C, wetted with about 55% water (72 mg, .035 mmol) and triethylsilane (532 uL, 3.5 mmol) was added dropwise to the suspension stirred under argon. After completion of the reaction in 2 hours (TLC), the mixture was filtered through celite and the solvent was removed in vacuo. The crude product was purified by Biotage flash chromatography, eluting with 20% to 60% ethyl acetate in hexane to give the final acetamide (75 mg, 0.17 mmol, 61% yield). 1HNMR (400MHz, CDCl3): δ 7.28(m, 1H), 7.16(t, J=7.89Hz, 1H), 6.88(m, 1H), 6.83(m, 1H), 6.67(s, 1H), 6.63( m, 1H), 6.59(d, J=7.89Hz, 1H), 6.49(m, 1H), 4.56(s, 2H), 3.88(s, 2H), 3.12(m, 1H), 2.22(s, 6H ), 1.16(d, J=6.85Hz, 6H). HRMS (M+Na) calcd for C26H29NO4 442.19888, 442.19939 found. Example 13—2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(2-(methylsulfonamido)ethyl)acetamide (Compound 11)

[0161] 2-(4-(4-(Benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (benzylated GC-1, 275 mg, 0.66 mmol) was dissolved in 1 mL of dry DMF. To this carboxylic acid solution was added DIEA (686 µL, 3.94 mmol), EDC HCl (253 mg, 1.31 mmol) and HOBt (178 mg, 1.31 mmol) and this solution was stirred for 1 hour at room temperature. The amine, N-(2-aminoethyl)methanesulfonamide (160 mg, 1.16 mmol) was then added and the reaction mixture was stirred at room temperature for 18 hours. Dilution of the reaction mixture with 10 mL of EtOAc was followed by washing with 2x 5 mL of 1N HCl, 1x with 5 mL of saturated aqueous sodium bicarbonate, and 2x with 5 mL of brine. The resulting organic layer was dried over MgSO4, filtered and concentrated to give the crude intermediate product (319 mg, 90%). The crude product was pure enough by 1H NMR to proceed without further purification.

[0162] The benzylated intermediate, 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(2-(methylsulfonamido)ethyl)acetamide (319 mg, 0.592 mmol) and pentamethylbenzene (292 mg, 1.97 mmol) was dissolved in 10 mL of dry DCM at -78 °C. To this stirred solution at -78 °C, BCl 3 (3.3 mL, 3.3 mmol) was added and the reaction mixture was stirred for 2 h before being quenched with 10 mL of 9:1 CHCl 3 :MeOH and evaporated to a residue. This residue was washed with hexanes to give a crude white solid which was chromatographically purified on silica (10% MeOH in DCM). The final product is an off-white solid (244 mg, 92%). 1H NMR (400 MHz, CD3CN): 7.29 (br, 1H), 6.89 (s, 1H), 6.69 (s, 2H), 6.62 (d, 1H, J = 8.2 Hz), 6.54 (d, 1H, J = 8.4, 2.0 Hz), 4.43 (s, 2H), 3.88 (s, 2H), 3.39 (m, 2H), 3.16 (m, 3H), 2.88 (s, 3H) , 2.20 (s, 6H), 1.12 (d, 6H, J = 6.9 Hz). HRMS exact mass calcd for C23H32N2O5S [M + Na]+: m/z 471.19241. m/z 471.19335 found. Example 14 - N-(1,3-dihydroxypropan-2-yl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide (Compound 12)

[0163] A stirred solution of GC-1 (411 mg, 1.25 mmol, 1 eq) treated with DCM (6 mL) followed by the addition of DCC (283 mg, 1.34 mmol, 1.1 eq) and N-hydroxysuccinimide (158 mg, 1.34 mmol, 1.1 eq). The reaction is stirred for 4 hours, during which time a white precipitate forms. The urea byproduct removed by filtration and the intermediate NHS ester purified by flash chromatography (0-80% EtOAc in hexanes) to give a white product (323 mg, 0.76 mol, 60%). The intermediate NHS ester (55 mg, 0.129 mmol, 1 eq) treated with THF (1 mL) and triethylamine (27μL, 0.19 mmol, 1.5 eq). The reaction is treated with (+/-)-serinol (17 mg, 0.19 mmol, 1.5 eq) and stirred for 30 min. The reaction mixture is purified directly by flash chromatography to give the product as a white solid (14 mg, 0.035 mmol, 27%). 1H NMR (400 MHz, Chloroform-d) δ 6.87 (s, 1H), 6.60-6.45 (m, 4H), 4.45 (s, 2H), 3.94 (m, 1H), 3.85 (s, 2H), 3.72- 3.61 (m 2H), 3.19 (s, J = 6.9 Hz, 1H), 2.65 (s, 1H), 2.24 (s, 6H), 1.23 (b, 8H). HRMS (ESI) m/z [M+Na+] C23H31NNaO5+ requires 424.2094, 424.2099 found. Example of 15-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-propyl ketamide

[0164] Dissolve 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-acetic acid (GC-1) (100 mg, 0.3 mmol) in methanol in a tube tight. H2SO4 (1 drop) was added and heated to 65°C. Full conversion to the methyl ester was observed within 1 hour (TLC). Propylamine (246 uL, 3 mmol) was added and then heat returned to 65°C for 1 hour. The reaction was not completed. Then another 100 uL of propylamine was added to it and the reaction was completed in 30 minutes (TLC). Cooled to 0 °C with an ice water bath and 0.5 N NaOH (10 mL) was added and the reaction mixture was extracted with dichloromethane (3 x 50 mL). The organic layers were combined and dried over anhydrous MgSO4. The crude product was purified by Biotage flash chromatography eluting with 20% to 60% ethyl acetate and pure propyl ketamide was obtained (46 mg, 0.12 mmol, 41% yield and 99.3% pure by HPLC ) 1HNMR (400MHz, CDCl3): δ 6.91(s, 1H), 6.63-6.53(m, 5H), 4.48(s, 2H), 3.90(s, 2H), 3.31(m, 2H), 3.15(m, 1H), 2.22(s, 6H), 1.59(m, 2H), 1.21(d, J=6.94Hz, 6H), 0.94(t, J=7.5Hz, 3H). HRMS (M+Na) calcd for C23H31NO3 392.21962, 392.22036 found. Example 16—N-(2-Fluoroethyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide (Compound 14)

[0165] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 150 mg, 0.36 mmol, 1 eq) treated with dry THF (5 mL) and CDI (140 mg, 0.86 mmol, 2.4 eq) followed by heating at 45 °C for 2 h. The reaction is concentrated under reduced pressure and dissolved in THF (2.5 mL). The reaction solution is treated with 2-fluoroethylamine hydrochloride (87 mg, 1.075 mmol, 3 eq) and stirred at room temperature for 1 h. The reaction solution is diluted with diethyl ether (20 mL) and washed with 0.5N HCl (2 x 20 mL) followed by brine (20 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The crude intermediate is taken up in DCM (3 mL) and placed under argon. Pentamethylbenzene (106 mg, 0.72 mmol, 2 eq) is added and the reaction is cooled to -78°C. A solution of BCl3 (1M DCM, 0.72 mL, 2 eq) is added slowly and the reaction stirred for 15 minutes. The reaction is quenched by adding a saturated NaHCO3 solution (2 mL) and the flask is allowed to warm to room temperature. The reaction mixture is diluted with water (10 mL) and extracted with DCM (2x 20 mL). The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (2-40% EtOAc in hexanes) gave the product as a white solid (70 mg, 0.19 mmol, 52%). 1H NMR (400 MHz, Chloroform-d) δ 7.03 (s, 1H), 6.94 (d, J = 2.1 Hz, 1H), 6.68 - 6.52 (m, 4H), 4.76 (s, 1H), 4.62 (dt, J = 47.4, 4.8 Hz, 1H), 4.53 (s, 2H), 3.93 (s, 2H), 3.71 (dq, J = 27.8, 5.0 Hz, 2H), 3.17 (hept, J = 7.0 Hz, 1H), 2.24 (s, 6H), 1.23 (d, J = 6.9 Hz, 6H). Example 17 - N-allyl-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide (Compound 15)

[0166] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 300 mg, 0.72 mmol, 2 eq) treated with dry THF (5 mL) and CDI (140 mg, 0.86 mmol, 2.4 eq) followed by heating at 45 °C for 2 h. The reaction is concentrated under reduced pressure and dissolved in THF (5 mL). Half of the reaction is taken to the next step (0.36 mmol, 1 eq) and treated with THF (2.5 mL). Allylamine hydrochloride (90 mg, 1.075 mmol, 3 eq) is added to the reaction solution, which is stirred at room temperature overnight. The reaction solution is diluted with diethyl ether (20 mL) and washed with 0.5N HCl (2 x 20 mL) followed by brine (20 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The crude intermediate is taken up in DCM (3 mL) and placed under argon. Pentamethylbenzene (106 mg, 0.72 mmol, 2 eq) is added and the reaction is cooled to -78°C. A solution of BCl3 (1M DCM, 0.72 mL, 2 eq) is added slowly and the reaction stirred for 15 minutes. The reaction is quenched by adding a saturated NaHCO3 solution (2 mL) and the flask is allowed to warm to room temperature. The reaction mixture is diluted with water (10 mL) and extracted with DCM (2x 20 mL). The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (2-40% EtOAc in hexanes) gave the product as a white solid (70 mg, 0.2 mmol, 55%). 1H NMR (400 MHz, Chloroform-d) δ 6.94 (d, J = 2.1 Hz, 1H), 6.75 (s, 1H), 6.68 - 6.52 (m, 4H), 5.96 — 5.81 (m, 1H), 5.27 - 5.14 (m, 2H), 4.96 (s, 1H), 4.54 (s, 2H), 4.02 (tt, J = 5.8, 1.6 Hz, 2H), 3.93 (s, 2H), 3.19 (hept, J = 6.9 Hz , 1H), 2.24 (s, 6H), 1.23 (d, J = 6.9 Hz, 6H). Example 18-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(prop-2-yn-1-yl)acetamide (Compound 16)

[0167] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 300 mg, 0.72 mmol, 2 eq) treated with dry THF (5 mL) and CDI (140 mg, 0.86 mmol, 2.4 eq) followed by heating at 45 °C for 2 h. The reaction is concentrated under reduced pressure and dissolved in THF (5 mL). Half of the reaction is taken to the next step (0.36 mmol, 1 eq) and treated with THF (2.5 mL). Propargylamine (90 mg, 1.075 mmol, 3 eq) is added to the reaction solution as a solution in THF (0.2 mL). The reaction is stirred at room temperature for 1 h. The reaction solution is diluted with diethyl ether (20 mL) and washed with 0.5N HCl (2 x 20 mL) followed by brine (20 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The crude intermediate is taken up in DCM (3 mL) and placed under argon. Pentamethylbenzene (106 mg, 0.72 mmol, 2 eq) is added and the reaction is cooled to -78°C. A solution of BCl3 (1M DCM, 0.72 mL, 2 eq) is added slowly and the reaction stirred for 15 minutes. The reaction is quenched by adding a saturated NaHCO3 solution (2 mL) and the flask is allowed to warm to room temperature. The reaction mixture is diluted with water (10 mL) and extracted with DCM (2x 20 mL). The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (2-40% EtOAc in hexanes) gave the product as an off-white solid (88 mg, 0.24 mmol, 67%). 1H NMR (400 MHz, Chloroform-d) δ 6.92 (t, J = 3.5 Hz, 2H), 6.63 (d, J = 8.1 Hz, 1H), 6.63 (s, 2H), 6.53 (dd, J = 8.2, 2.2 Hz, 1H), 5.69 (s, 1H), 4.51 (s, 2H), 4.16 (dd, J = 5.5, 2.6 Hz, 2H), 3.90 (s, 2H), 3.20 (hept, J = 6.9 Hz, 1H), 2.22 (s, 6H), 1.21 (d, J = 6.9 Hz, 6H). Example 19-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-methoxyacetamide (Compound 17)

[0168] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 300 mg, 0.72 mmol, 2 eq) treated with dry THF (5 mL) and CDI (140 mg, 0.86 mmol, 2.4 eq) followed by heating at 45 °C for 2 h. The reaction is concentrated under reduced pressure and dissolved in THF (5 mL). Half of the reaction is taken to the next step (0.36 mmol, 1 eq) and treated with THF (2.5 mL). Methoxylamine hydrochloride (83 mg, 1.075 mmol, 3 eq) is added to the reaction solution, which is stirred at room temperature overnight. The reaction solution is diluted with diethyl ether (20 mL) and washed with 0.5N HCl (2 x 20 mL) followed by brine (20 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The crude intermediate is taken up in DCM (3 mL) and placed under argon. Pentamethylbenzene (106 mg, 0.72 mmol, 2 eq) is added and the reaction is cooled to -78°C. A solution of BCl3 (1M DCM, 0.72 mL, 2 eq) is added slowly and the reaction stirred for 15 minutes. The reaction is quenched by adding a saturated NaHCO3 solution (2 mL) and the flask is allowed to warm to room temperature. The reaction mixture is diluted with water (10 mL) and extracted with DCM (2x 20 mL). The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (2-40% EtOAc in hexanes) gave the product as a white solid (94.5 mg, 0.26 mmol, 72%). 1H NMR (400 MHz, Chloroform-d) δ 9.06 (s, 1H), 6.93 (d, J = 2.1 Hz, 1H), 6.66 - 6.52 (m, 4H), 4.74 (s, 1H), 4.59 (s, 2H), 3.92 (s, 2H), 3.86 (s, 3H), 3.18 (hept, J = 6.9 Hz, 1H), 2.24 (s, 6H), 1.23 (d, J = 6.9 Hz, 6H). Example 20 - N-(3,4-dihydroxyphenethyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide (Compound 18)

[0169] 2-[4-(4-(Benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (200 mg, 0.48 mmol) was dissolved in 10 mL of dry THF in a vial of round fungus. 1,1'-Carbonyl diimidazole (CDI) (78 mg, 0.48 mmol) was added and stirred at 45°C for 3 hours. The reaction was monitored by TLC and when complete conversion to the acylimidazolide was observed, the mixture was concentrated to dryness in vacuo to remove all CO2. It was then dissolved in dry THF (8 mL) and a solution of dopamine hydrochloride (118.33 mg, 0.624 mmol, 1.3 eq) in 2 mL of dry MeOH was slowly added. The reaction mixture was stirred overnight at 45°C. It was then cooled and the solvent was evaporated in vacuo. Ethyl acetate (25 mL) was added and the reaction mixture was washed successively with 0.5N HCl (2 x 5 mL) and a saturated NaCl solution (1 x 10 mL). It was then dried over anhydrous MgSO4 and the solvent was removed in vacuo. The crude product was purified by Biotage flash chromatography, eluting with 10% to 40% ethyl acetate in hexane. The benzyl protected acetamide GC-1 was crystallized from chloroform (100 mg, 0.17 mmol)). 1H NMR (400 MHz, Methanol-d4): δ 7.48-7.26 (m, 3H), 6.93 (d, J = 2.3 Hz, 1H), 6.82 (dd, J = 8.5, 1.3 Hz, 1H), 6.71-6.62 (m, 3H), 6.51 (dd, J = 8.1, 2.0 Hz, 1H), 5.03 (s, 1H), 4.47 (d, J = 1.4 Hz, 1H), 3.95 (s, 1H), 3.45 (dd, J = 8.1, 6.7 Hz, 1H), 3.38-3.26 (m, 1H), 2.67 (t, J = 7.4 Hz, 1H), 2.22 (s, 3H), 1.16 (dd, J = 6.9, 1.3 Hz, 3H ).

[0170] To a stirred solution of this protected acetamide (75 mg, 0.13 mmol) and 10% Pd-C moistened with about 55% water (27.6 mg) in 5 mL of methanol was added triethylsilane ( 198 µL, 1.3 mmol), dropwise, under nitrogen. The reaction mixture was then stirred at room temperature for 3 hours. Upon completion of the reaction (TLC), it was filtered through celite and the solvent was removed in vacuo. The crude product was purified by Biotage flash chromatography, eluting with 30% to 80% dichloromethane in ethyl acetate to give the final acetamide (42 mg, 0.18 mmol, 67% yield and 99% purity by HPLC ). 1H NMR (400 MHz, CDCl3): δ 6.84 (d, J = 2.1 Hz, 1H), 6.69 (d, J = 6.8 Hz, 4H), 6.63 -6.49 (m, 3H), 4.48 (s, 2H) , 3.92 (s, 2H), 3.47 (t, J = 7.4 Hz, 2H), 3.22 (hept, J = 6.9 Hz, 1H), 2.69 (t, J = 7.4 Hz, 2H), 2.23 (s, 6H) , 1.32 (s, 1H), 1.15 (d, J = 6.9 Hz, 6H), 0.93 (t, J = 7.0 Hz, 2H). Example 21 - 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-phenethyl ketamide (Compound 19)

[0171] 2-[4-(4-(Benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (200 mg, 0.48 mmol) was dissolved in 10 mL of dry THF in a vial of round fungus. 1,1'-Carbonyl diimidazole (78 mg, 0.48 mmol) was added and stirred at 45°C for 3 hours. The reaction was monitored by TLC and when complete conversion to the acylimidazolide was observed, the mixture was concentrated to dryness in vacuo to remove all CO2. It was then dissolved in dry THF (8 mL) and a solution of 2-phenylethylamine (157.5 mg, 1.44 mmol, 1.33 eq) in 2 mL of dry THF was added dropwise. The reaction mixture was stirred at 45°C overnight. It was then cooled and the solvent was evaporated in vacuo. It was dissolved in ethyl acetate (25 mL) and washed successively with 0.5N HCl (2 x 5 mL) and a saturated NaCl solution (1 x 10 mL). It was then dried over anhydrous MgSO4 and the solvent was removed in vacuo. The crude product was purified by Biotage flash chromatography, eluting with 10% to 40% ethyl acetate in hexane. 1H NMR (400 MHz, Chloroform-d) δ 7.46 -7.14 (m, 11H), 6.98 (d, J = 2.1 Hz, 1H), 6.73 (dd, J = 8.4, 1.2 Hz, 1H), 6.70- 6.55 (m, 4H), 5.02 (s, 2H), 4.47 (s, 2H), 3.93 (s, 2H), 3.66-3.56 (m, 2H), 3.35 (hept, J = 6.9 Hz, 1H), 2.85 (t, J = 7.0 Hz, 2H), 2.23 (s, 6H), 1.20 (dd, J = 7.0, 1.2 Hz, 6H).

[0172] The deprotection of the benzyl group of the acetamide thus prepared was done with BCl3. Acetamide (220 mg, 0.42 mmol) is dissolved in dry dichloromethane (10 mL) and pentamethyl benzene (125 mg, 0.84 mmol) is added. The solution was then cooled to -78 °C using a dry ice/acetone bath and a 1M solution of BCl 3 in dichloromethane (117 mg, 1 mmol) was added very slowly. It was stirred at -78°C for 20 min and complete conversion to the product was observed by TLC. A saturated sodium bicarbonate solution (5 mL) was then added at -78°C. The reaction mixture was warmed to room temperature. Dichloromethane (25 mL) and water (5 mL) were then added and the organic layer was collected. The aqueous layer was extracted with dichloromethane (2 x 10 mL) and the combined organic layer was dried over anhydrous magnesium sulfate. The crude product was purified by Biotage flash chromatography, eluting with 20% to 60% ethyl acetate in hexane to give the final acetamide (134 mg, 0.31 mmol, 74% yield, 99.6% purity by HPLC). 1H NMR (400MHz, CDCl3): δ 7.34 - 7.12 (m, 5H), 6.92 (d, J=2.1 Hz, 1H), 6.67 (s, 1H), 6.62—6.50 (m, 4H), 4.67 (s , 1H), 4.46 (s, 2H), 3.90 (s, 2H), 3.61 (q, J=6.8 Hz, 2H), 3.15 (hept, J=6.9 Hz, 1H), 2.84 (t, J=7.0 Hz, 2H), 2.22 (5, 6H), 1.21 (d, J=6.9 Hz, 6H). Example 22 - N-'hydroxy-2-(4-(4-hydroxy-3-isopropylbenzyl)-20)

[0173] 2-(4-(4-(Benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (benzylated GC-1, 150 mg, 0.36 mmol) was dissolved in 6 mL of dry THF. To this carboxylic acid solution was added 1,1'-carbonyldiimidazole (70 mg, 0.43 mmol) under argon and this solution was stirred for 2 h at 50 °C. Then, hydroxylamine hydrochloride (30 mg, 0.43 mmol) in 3 mL of MeOH was added and the reaction mixture was stirred at 50 °C for 18 h. The reaction mixture was then evaporated to dryness in vacuo, dissolved in 10 mL DCM and washed with 2x 5 mL 1N HCl and 2x 5 mL brine. The resulting organic layer was dried over MgSO 4 , filtered and concentrated to give the crude intermediate product (139 mg, 90%). The crude product was pure enough by 1H NMR to proceed without further purification.

[0174] The benzylated intermediate, 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-hydroxyacetamide (139 mg, 0.321 mmol) and pentamethylbenzene (160 mg, 1, 07 mmol) was dissolved in 10 mL of dry DCM at -78 °C. To this stirred solution at -78°C, BCl3 (1.1 mL, 1.1 mmol) was added and the reaction mixture was stirred for 2h before being quenched with 10 mL of 9:1 CHCl3:MeOH and evaporated to a residue. This residue was washed with hexanes to give a crude white solid which was chromatographically purified on silica (10% MeOH in DCM). The final product is an off-white solid (51 mg, 46%). The tested product is positive (red-orange stain) with iron(III) chloride on TLC. 1H NMR (400 MHz, MeOD): 6.78 (s, 1H), 6.65 (s, 2H), 6.54 (d, 1H, J = 8.3 Hz), 6.48 (dd, 1H, J = 8.3, 2 Hz), 4.48 (s, 2 H), 3.85 (s, 2 H), 3.15 (sec. 1 H), 2.16 (s, 6 H), 1.08 (d, 6 H, J = 6.9 Hz). Example 23-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetohydrazide (Compound 21)

[0175] 2-(4-(4-Hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (sobetiroma, 50 mg, 0.15 mmol) was dissolved in 3 ml of MeOH and 1 drop of sulfuric acid in a sealed tube. The sealed reaction mixture was then heated to 65°C with stirring for 1 hour. Upon cooling to room temperature, TLC of the mixture indicates complete conversion to the methyl ester intermediate. To an intermediate solution was added 44μL (0.9 mmol, 6 eq.) of hydrazine monohydrate and the reaction mixture was stirred for 1 h in a sealed tube. The reaction was extracted from 50 mL of water in 3 x 20 mL of DCM. The organic layers were combined, dried over Na 2 SO 4 , filtered and concentrated, then purified on silica (10% MeOH in DCM) to give the product as a white solid (44 mg, 86%). The product shows positive results with ninhydrin on TLC. 1H NMR (400 MHz, MeOD): 6.77 (s, 1H), 6.64 (s, 2H), 6.53 (d, 1H, J = 8.2 Hz), 6.46 (dd, 1H, J = 8.3, 2 Hz), 4.48 (s, 2 H), 3.83 (s, 2 H), 3.16 (sec. 1 H), 2.16 (s, 6 H), 1.08 (d, 6 H, J = 6.9 Hz. Example 25 - Sodium 2-(2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamido)ethane-1-sulfonate (Compound 23)

[0176] GC-1 (100 mg, 0.3 mmol, 1 eq) is treated with MeOH (5 mL) in a sealed tube. Sulfuric acid (1 drop) is added and the reaction is sealed and then heated to 65oC for 1 hour while stirring. The reaction is allowed to come to room temperature. TLC analysis (1:30 MeOH:DCM) shows complete conversion to the intermediate methyl ester. To the intermediate reaction mixture, taurine (229 mg, 1.83 mmol, 6 eq) was added as a solution with sodium hydroxide (73 mg, 1.83 mmol, 6 eq) in water (2 mL). The reaction is resealed and reheated to 65°C overnight. A portion of the solvent is removed under reduced pressure and the total volume of the solution is adjusted to ~5 mL with additional water. The solution is filtered through a 0.22 µm filter and purified by preparative HPLC. The combined product fractions were combined and concentrated by a constant flow of air followed by reduced pressure to give a white solid (7.8 mg, 0.02 mmol, 5%). 1H NMR (400 MHz, 9:1 Chloroform-d: Methanol-d4) δ 6.85 (d, J = 2.2 Hz, 1H), 6.61 — 6.52 (m, 3H), 6.43 (dd, J = 8.2, 2.3 Hz, 1H), 4.40 (s, 2H), 3.83 (s, 2H), 3.72 (t, J = 6.0 Hz, 2H), 3.37 (s, 6H), 3.17 (hept, J = 6.9 Hz, 1H), 3.02 ( t, J = 6.0 Hz, 2H), 2.15 (s, 6H), 1.13 (d, J = 6.9 Hz, 6H). Example 2 6-N-cyclopropyl-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide (Compound 24)

[0177] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 300 mg, 0.72 mmol, 2 eq) treated with dry THF (5 mL) and CDI (140 mg, 0.86 mmol, 2.4 eq) followed by heating at 45 °C for 2 h. The reaction is concentrated under reduced pressure and dissolved in THF (5 mL). Half of the reaction is taken to the next step (0.36 mmol, 1 eq) and treated with THF (2.5 mL). Methoxylamine hydrochloride (60 mg, 1.075 mmol, 3 eq) is added to the reaction solution, which is stirred at room temperature overnight. The reaction solution is diluted with diethyl ether (20 mL) and washed with 0.5N HCl (2 x 20 mL) followed by brine (20 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The crude intermediate is taken up in DCM (3 mL) and placed under argon. Pentamethylbenzene (106 mg, 0.72 mmol, 2 eq) is added and the reaction is cooled to -78°C. A solution of BCl3 (1M DCM, 0.72 mL, 2 eq) is added slowly and the reaction stirred for 15 minutes. The reaction is quenched by adding a saturated NaHCO3 solution (2 mL) and the flask is allowed to warm to room temperature. The reaction mixture is diluted with water (10 mL) and extracted with DCM (2x 20 mL). The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (2-40% EtOAc in hexanes) gave the product as a white solid (63 mg, 0.17 mmol, 48%). 1H NMR (400 MHz, Chloroform-d) δ 6.93 (d, J = 2.1 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.62 (s, 2H), 6.54 (dd, J = 8.2, 2.2 Hz, 1H), 5.94 (s, 1H), 4.48 (s, 2H), 3.92 (s, 2H), 3.23 (hept, J = 6.9 Hz, 1H), 2.82 (tq, J = 7.2, 3.7 Hz, 1H), 2.23 (s, 6H), 1.23 (d, J = 6.9 Hz, 6H), 0.95 - 0.80 (m, 2H), 0.71 — 0.56 (m, 2H). Example 27-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N,N-dimethylacetamide

[0178] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 300 mg, 0.72 mmol, 2 eq) treated with dry THF (5 mL) and CDI (140 mg, 0.86 mmol, 2.4 eq) followed by heating at 45 °C for 2 h. The reaction is concentrated under reduced pressure and dissolved in THF (5 mL). Half of the reaction is taken to the next step (0.36 mmol, 1 eq) and treated with THF (2.5 mL). Dimethylamine hydrochloride (88 mg, 1.075 mmol, 3 eq) is added to the reaction solution, which is stirred at room temperature overnight. The reaction solution is diluted with diethyl ether (20 mL) and washed with 0.5N HCl (2 x 20 mL) followed by brine (20 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The crude intermediate is taken up in DCM (3 mL) and placed under argon. Pentamethylbenzene (106 mg, 0.72 mmol, 2 eq) is added and the reaction is cooled to -78 °C. A solution of BCl3 (1M DCM, 0.72 mL, 2 eq) is added slowly and the reaction stirred for 15 minutes. The reaction is quenched by adding a saturated NaHCO3 solution (2 mL) and the flask is allowed to warm to room temperature. The reaction mixture is diluted with water (10 mL) and extracted with DCM (2x 20 mL). The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (2-40% EtOAc in hexanes) gave the product as a white solid (38 mg, 0.11 mmol, 30%). 1H NMR (400 MHz, Chloroform-d) δ 6.95 (d, J = 2.1 Hz, 1H), 6.65 (d, J = 9.9 Hz, 3H), 6.53 (dd, J = 8.2, 2.2 Hz, 1H), 5.58 (s, 1H), 4.68 (s, 2H), 3.90 (s, 2H), 3.21 (h, J = 6.9 Hz, 1H), 3.13 (s, 3H), 3.02 (s, 3H), 2.20 (s, 6H), 1.23 (d, J = 6.8 Hz, 6H). Example 28 - N-ethyl-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide

[0179] GC-1 (100 mg, 0.304 mmol, 1 eq) is treated with MeOH (3 mL) in a sealed tube. Sulfuric acid (1 drop) is added and the reaction is sealed and then heated to 65oC for 1 hour while stirring. The reaction is allowed to come to room temperature. TLC analysis (1:30 MeOH:DCM) shows complete conversion to the intermediate methyl ester. To the intermediate reaction mixture, add ethylamine (33% in water, 0.25 mL, 1.84 mmol, 6 eq). The reaction is resealed and reheated to 65oC for one hour. The reaction flask is allowed to come to room temperature and 0.5N NaOH (20 mL) is added into a separatory funnel and subsequently extracted with DCM (3 x 100 mL). The organic layers were combined, dried over Na2SO4 and concentrated. Purification by flash chromatography (0-6% MeOH in DCM) gave the product as a white solid (82 mg, 0.23 mmol, 76%). 1H NMR (400 MHz, Chloroform-d) δ 6.94 (d, J = 2.2 Hz, 1H), 6.72 - 6.61 (m, 4H), 6.55 (dd, J = 8.1, 2.2 Hz, 1H), 5.77 (d, J = 17.7 Hz, 1H), 4.50 (s, 2H), 3.92 (s, 2H), 3.43 (qd, J = 7.3, 5.8 Hz, 2H), 3.22 (hept, J = 6.8 Hz, 1H), 2.24 ( s, 6H), 1.32 - 1.15 (m, 9H). Example 29-N-(cyanomethyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide (Compound 27)

[0180] 2-[4-(4-(Benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (200 mg, 0.48 mmol) was dissolved in 10 mL of dry THF in a vial of flame dried round fungus. 1,1'-Carbonyl diimidazole (85 mg, 0.52 mmol, 1.1 eq) was added and stirred at 45°C for 3 hours. The reaction was monitored by TLC and when complete conversion to the acylimidazolide was observed, the mixture was concentrated to dryness in vacuo to remove all CO2. It was then dissolved in dry THF (8 mL) and amino acetonitrile hydrochloride (133 mg, 1.44 mmol, 3 eq) was added in one portion. The reaction mixture was stirred at 45°C overnight. White solid precipitated from the reaction mixture. It was cooled and the THF was removed in vacuo. The solid was dissolved in ethyl acetate (25 mL) and the reaction mixture was washed successively with 0.5N HCl (2 x 5 mL) and a saturated NaCl solution (1 x 10 mL). It was then dried over anhydrous MgSO4 and the solvent was removed in vacuo. The resulting mixture solidified upon being kept in the refrigerator. It was washed with hexane and NMR showed it to be greater than 90% pure. 1HNMR (400MHz, Methanol-d4) δ 7.50 -7.27 (m, 5H), 6.94 (d, J = 2.3 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.74 (s, 2H), 6.69 (dd, J = 8.4, 2.3 Hz, 1H), 5.06 (s, 2H), 4.59 (s, 1H), 4.27 (s, 2H), 3.96 (s, 2H), 2.31 (s, 1H), 2.24 ( s, 6H), 1.18 (dd, J = 6.9, 1.5 Hz, 6H), 0.95 (d, J = 6.7 Hz, 1H).

[0181] The benzyl-protected group was cleaved by BCl3. Acetamide (175 mg, 0.38 mmol) was dissolved in dry dichloromethane (10 mL) and pentamethylbenzene (113 mg, 0.76 mmol) was added. The solution was then cooled to -78°C using a dry ice/acetone bath and a 1M solution of BCl 3 in dichloromethane (789uL, 89mg, 0.76mmol) was added very slowly. TLC showed a higher conversion to the product in 25 minutes of stirring at -78oC. A saturated sodium bicarbonate solution (5 ml) was then added at -78°C. The reaction mixture was warmed to room temperature. Dichloromethane (25 mL) and water (5 mL) were then added and the organic layer was collected. The aqueous layer was extracted with dichloromethane (2 x 10 mL) and the combined organic layer was dried over anhydrous magnesium sulfate. The crude product was purified by Biotage flash chromatography, eluting with 10% to 50% ethyl acetate in hexane to give the final acetamide (85 mg, 0.23 mmol, 60% yield, 99.6% purity by HPLC). 1H NMR (400 MHz, Methanol-d4) δ 6.83 (d, J=2.2 Hz, 1H), 6.72 (s, 2H), 6.62 -6.49 (m, 2H), 4.57 (d, J=1.6 Hz, 2H) , 4.25 (d, J = 1.6 Hz, 2H), 3.90 (s, 2H), 3.21 (hept, 1H), 2.22 (d, J = 1.5 Hz, 6H), 1.14 (dd, J = 7.0, 1.7 Hz, 6H). Example 30—N-(3-Fluorophenyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide (Compound 28)

[0182] 2-[4-(4-(Benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (200 mg, 0.48 mmol) was dissolved in 10 mL of dry THF in a vial of round fungus. 1,1'-Carbonyl diimidazole (78 mg, 0.48 mmol) was added and stirred at 45°C for 3 hours. The reaction was monitored by TLC and when complete conversion to the acylimidazolide was observed, the mixture was concentrated to dryness in vacuo to remove all CO2. It was then dissolved in dry THF (8 mL) and a solution of 3-fluoroaniline (144.4 mg, 1.44 mmol, 1.33 eq) in 2 mL of dry THF was added dropwise. The reaction mixture was then stirred at 45°C overnight. The reaction mixture was cooled and the solvent was evaporated in vacuo. Ethyl acetate (25 mL) was added and the reaction mixture was washed successively with 0.5N HCl (2 x 5 mL) and a saturated NaCl solution (1 x 10 mL). It was then dried over anhydrous MgSO4 and the solvent was removed in vacuo. The crude product was purified by Biotage flash chromatography, eluting with 10% to 40% ethyl acetate in hexane. 1H NMR (400 MHz, Chloroform-d) δ 8.34 (s, 1H), 7.56 (dt, J = 10.7, 2.3 Hz, 1H), 7.44 -7.18 (m, 7H), 6.95 (d, J = 2.3 Hz, 1H), 6.84 (tdd, J=8.2,2.5, 1.1Hz, 1H), 6.73 (d, J=8.4Hz, 1H), 6.68 (s, 2H), 6.60 (dd, J=8.4 , 2.3 Hz, 1H), 5.00 (s, 2H), 4.59 (s, 2H), 3.92 (s, 2H), 3.34 (hept, J=6.9 Hz, 1H), 2.23 (s, 6H), 1. 18 (d, J=6.9 Hz, 6H).

[0183] Acetamide (200 mg, 0.39 mmol) was dissolved in dry dichloromethane (10 mL) and pentamethylbenzene (116 mg, 0.78 mmol) was added. The solution was then cooled to -78 °C using a dry ice/acetone bath and a 1M solution of BCl 3 in dichloromethane (777 µL, 91 mg, 0.78 mmol) was added very slowly. TLC showed full conversion to product within 15 minutes after stirring at -78°C. A saturated sodium bicarbonate solution (5 ml) was then added at -78°C. The reaction mixture was then warmed to room temperature. Dichloromethane (25 mL) and water (5 mL) were then added and the organic layer was collected. The aqueous layer was extracted with dichloromethane (2 x 10 mL) and the combined organic layer was dried over anhydrous magnesium sulfate. The crude product was purified by Biotage flash chromatography, eluting with 10% to 50% ethyl acetate in hexane to give the final acetamide (150 mg, 0.35 mmol, 91% yield and 96.8% purity by HPLC). 1H NMR (400 MHz, Chloroform-d) δ 8.34 (s, 1H), 7.34 -7.17 (m, 2H), 6.92 -6.79 (m, 2H), 6.68 (s, 2H), 6.61-6.49 (m, 2H), 4.58 (s, 3H), 3.90 (s, 2H), 3.13 (hept, J=6.8Hz, 1H), 1.19 (d, J=6.9Hz, 6H). Example 31—2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(oxetan-3-yl)acetamide (Compound 29)

[0184] 2-(4-(4-(Benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (benzylated GC-1, 200 mg, 0.48 mmol) was dissolved in 6 mL of dry THF. To this carboxylic acid solution was added 1,1'-carbonyldiimidazole (93 mg, 0.57 mmol) under argon and this solution was stirred for 2 h at 50 °C. Then, oxetan-3-amide (30 mg, 0.43 mmol) in 3 mL of THF was added and the reaction mixture was refluxed for 2 hours. The reaction mixture was then evaporated to dryness in vacuo, dissolved in 10 mL DCM and washed with 2x 5 mL 1N HCl and 2x 5 mL brine. The resulting organic layer was dried over MgSO 4 , filtered and concentrated to give the crude intermediate product (196 mg, 86%). The crude product was pure enough by 1H NMR to proceed without further purification.

[0185] The benzylated intermediate of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(oxetan-3-yl)acetamide (196 mg, 0.41 mmol ) was dissolved in 5 mL of dry methanol with 1 mL of THF and 10% Pd/C (100 mg) to generate a suspension. The reaction mixture was placed under vacuum for approximately 1 min, then placed under argon for approximately 1 min. This process was repeated three times to ensure the mixture was properly degassed. Triethylsilane (1 ml, 6.3 mmol) was then added dropwise to the suspension and the reaction mixture was stirred for 4 hours at room temperature. Filtration over a celite pad with methanol, concentration in vacuo and purification via flash chromatography (silica, 10% MeOH in DCM) gave the desired product as a white solid (121 mg, 77% yield) ). 1H NMR (400 MHz, CDCl3): 7.14 (d, J = 8.0 Hz, 1 H), 6.92 (s, 1 H), 6.65 (s, 2 H), 6.60 (d, 1 H, J = 8.2 Hz) , 6.54 (dd, 1 H, J = 8.1, 2.2 Hz), 5.18 (sext. 1 H, J = 7.6 Hz), 4.97 (t, 2 H, J = 7.2 Hz), 4.68 (s, 0H), 4.57 (t, 2H, J = 7.0 Hz), 4.49 (s, 2 H), 3.91 (s, 2 H), 3.15 (sept., 1 H, J = 6.9 Hz), 2.23 (s, 6 H), 1.21 (d, 6 H, J = 6.9 Hz). Example 32—2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(4-nitrophenyl)acetamide (Compound 30)

[0186] A stirred solution of 2-(4-(4-(benzyloxy)-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (O-benzyl GC1, 150 mg, 0.36 mmol, 1 eq) treated with dry THF (5 mL) and CDI (140 mg, 0.86 mmol, 2.4 eq) followed by heating at 45 °C for 2 h. The reaction is concentrated under reduced pressure and dissolved in THF (2.5 mL). The reaction solution is treated with 4-nitroaniline hydrochloride (150 mg, 1.075 mmol, 3 eq) and stirred at room temperature for 1 h. The reaction solution is diluted with diethyl ether (20 mL) and washed with 0.5N HCl (2 x 20 mL) followed by brine (20 mL). The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The crude intermediate is purified by flash chromatography (0-40% EtOAc in hexanes) to ensure removal of excess 4-nitroaniline. The purified intermediate is taken up in DCM (3 mL) and placed under argon. Pentamethylbenzene (106 mg, 0.72 mmol, 2 eq) is added and the reaction is cooled to -78°C. A solution of BCl3 (1M DCM, 0.72 mL, 2 eq) is added slowly and the reaction stirred for 15 minutes. The reaction is quenched by adding a saturated NaHCO3 solution (2 mL) and the flask is allowed to warm to room temperature. The reaction mixture is diluted with water (10 mL) and extracted with DCM (2x 20 mL). The organic layers are combined, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (7-60% EtOAc in hexanes) gave the product as a light yellow solid (22 mg, 0.05 mmol, 14%). 1H NMR (400 MHz, chloroform-d) δ 8.30 - 8.21 (m, 2H), 7.87 — 7.78 (m, 2H), 6.90 (d, J = 2.2 Hz, 1H), 6.71 (s, 2H), 6.66 — 6.49 (m, 2H), 4.64 (s, 2H), 3.91 (s, 2H), 3.20 (p, J = 6.9 Hz, 1H), 2.25 (s, 6H), 1.28 — 1.16 (m, 6H).

Claims (19)

1. Compound, characterized by the fact that it has formula I:

(Formula I), or a pharmaceutically acceptable salt thereof, wherein R1 is an amide. 2. Compound, according to claim 1, characterized in that the compound is of formula II:

(Formula II), or a pharmaceutically acceptable salt thereof, wherein R2 is alkylamino. 3. Compound, according to claim 1, characterized in that the compound is of formula II:

or a pharmaceutically acceptable salt thereof, wherein R2 is amino. 4. Compound, according to claim 1, characterized in that the compound is of formula III:

or a pharmaceutically acceptable salt thereof, each of R3 and R4 being independently H, alkyl, cycloalkyl, substituted alkyl, unsubstituted alkyl, heteroaryl, saturated alkyl, unsaturated alkyl, aryl, amino, or ethoxy. 5. Compound, according to claim 4, or a pharmaceutically acceptable salt thereof, characterized in that R3 is methyl and R4 is methyl. 6. Compound, according to claim 4, characterized in that the compound is of formula IV:

or a pharmaceutically acceptable salt thereof, wherein R3 is H, hydroxyl, amino, methyl, ethyl, propyl, cyclopropyl, 2-hydroxyethyl, 1-hydroxypropan-2-yl, 2-hydroxypropyl, 2-aminoethyl acetate, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, phenyl, (4-nitro)phenyl, 2-phenylethyl-2-(2-hydroxyphenyl)ethyl, 2-(3-hydroxyphenyl)ethyl, 2-( 3,4-dihydroxyphenyl)ethyl, 3-fluoroethyl; S-methylsulfonyl, 1-(2-hydroxyethyl)-2-hydroxyethyl, 2-propenyl, 2-propynyl, methoxy, sodium 2-ethylsulfonate, cyanomethyl, or oxetanyl. 7. Compound, according to claim 1, characterized in that the compound is of formula III:

(Formula III), or a pharmaceutically acceptable salt thereof, wherein R4 is selected from H and C1-6 alkyl; and R3 being: (a) H, OH, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -SO2H, -SO2(C1-6 alkyl), C2-6 alkenyl, alkynyl C2-6, C3-6 cycloalkyl, or a 3- to 6-membered heterocyclyl ring containing one heteroatom selected from O, N, and S; or (b) C1-6 alkyl optionally substituted with 1, 2, or 3 substituents, each independently selected from OH, halogen, NH2, -NH(C16 alkyl), -N(C1-6 alkyl)2, - SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a 3- to 6-membered heterocyclic ring containing a heteroatom selected from O, N and S or a phenyl group optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and halogen; or (c) -O-C1-6 alkyl optionally substituted with 1, 2, or 3 substituents, each independently selected from OH, halogen, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl) 6)2, -SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a 3- to 6-membered heterocyclic ring containing a heteroatom selected from O, N, and S, or a group phenyl optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and halogen, or (d) a phenyl group optionally substituted with 1, 2, or 3 substituents, each independently selected of the group consisting of OH, NO2, and halogen. 8. Compound, according to claim 7, characterized in that the compound is of formula IV:

(Formula IV), or a pharmaceutically acceptable salt thereof, R3 being: (a) H, OH, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -SO2H, -SO2( C1-6 alkyl), C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or a 3- to 6-membered heterocyclic ring containing a heteroatom selected from O, N, and S; or (b) C1-6 alkyl optionally substituted with 1, 2, or 3 substituents, each independently selected from OH, halogen, NH2, -NH(C16 alkyl), -N(C1-6 alkyl)2, - SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a 3- to 6-membered heterocyclic ring containing a heteroatom selected from O, N and S or a phenyl group optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and halogen; or (c) -O-C1-6 alkyl optionally substituted with 1, 2, or 3 substituents, each independently selected from OH, halogen, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl) 6)2, -SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a 3- to 6-membered heterocyclic ring containing a heteroatom selected from O, N, and S, or a group phenyl optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and halogen, or (d) a phenyl group optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and halogen; and/or wherein R3 is: (a) H, OH, NH2, -SO2H, -SO2(C1-6 alkyl), C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or a 3-membered heterocyclic ring - a 6-membered containing a heteroatom selected from O, N, and S; or (b) C1-6 alkyl optionally substituted with 1, 2, or 3 substituents, each independently selected from OH, halogen, NH2, -NH(C16 alkyl), -N(C1-6 alkyl)2, - SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a 3- to 6-membered heterocyclic ring containing a heteroatom selected from O, N and S or a phenyl group optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and halogen; or (c) -O-C1-6 alkyl optionally substituted with 1, 2, or 3 substituents, each independently selected from OH, halogen, NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl) 6)2, -SO2H, -SO2(C1-6 alkyl), CN, C3-6 cycloalkyl, a 3- to 6-membered heterocyclic ring containing a heteroatom selected from O, N, and S, or a group phenyl optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and halogen, or (d) a phenyl group optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and halogen; and/or wherein R3 is: (a) H, OH, NH2, -SO2H, -SO2(CH3), C2-3 alkenyl, C2-3 alkynyl, C36 cycloalkyl, or a 3- to 6-membered heterocyclic ring containing an oxygen heteroatom; or (b) C1-4 alkyl optionally substituted with 1, 2, or 3 substituents, each independently selected from OH, F, NH2, -SO2H, -SO2(C3), CN, C3-6 cycloalkyl, one ring 3- to 6-membered heterocyclic containing an oxygen heteroatom, a phenyl group optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and F; or (c) -O-C1-4 alkyl optionally substituted by 1, 2, or 3 substituents, each independently selected from OH, F, NH2, -SO2H, -SO2(CH3), CN, C3-6 cycloalkyl , a 3- to 6-membered heterocyclic ring containing an oxygen heteroatom, or a phenyl group optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and F, or ( d) a phenyl group optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and F. 9. Compound according to any one of claims 1 and 7, characterized in that the compound is of formula IV:

(Formula IV), or a pharmaceutically acceptable salt thereof, where R3 is -(CH2)n1-phenyl, and n1 being an integer selected from 0, 1, 2, 3, or 4, and the phenyl ring is , optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and halogen; or where R3 is -(CH2)n2-phenyl, and where n2 is an integer selected from 0, 1, or 2, and the phenyl ring is optionally substituted with 1, 2, or 3 substituents, each independently selected from from the group consisting of OH, NO2, and halogen; or where R3 is -(CH2)n2-phenyl, and where n2 is an integer selected from 0, 1, or 2, and the phenyl ring is optionally substituted with 1, 2, or 3 substituents, each independently selected from from the group consisting of OH, NO2, and F; or wherein R3 is -(CH2)-phenyl, and the phenyl ring being optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, NO2, and F; or wherein R3 is C1-6 alkyl, optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, F, NH2, -SO2H, -SO2(CH3), CN, C3 cycloalkyl -6, and a 3- to 6-membered heterocyclyl ring containing an oxygen heteroatom; or wherein R3 is C1-4 alkyl, optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, F, NH2, -SO2H, -SO2(CH3), CN, C3 cycloalkyl -6, and a 3- to 6-membered heterocyclyl ring containing an oxygen heteroatom; or wherein R3 is C1-6 alkyl, optionally substituted by 1, 2, or 3 substituents, each independently selected from the group consisting of OH, F, NH2, -SO2H, and -SO2(C1-6 alkyl); or wherein R3 is C1-6 alkyl, optionally substituted by 1, 2, or 3 OH substituents; or wherein R3 is C1-4 alkyl, optionally substituted by 1, 2, or 3 OH substituents; or wherein R3 is C1-6 alkyl, optionally substituted by 1, 2, or 3 substituents F; or wherein R3 is C1-4 alkyl, optionally substituted by 1, 2, or 3 substituents F; or wherein R3 is -O-C1-6 alkyl, optionally substituted by 1, 2, or 3 substituents F; or wherein R3 is -O-C1-4 alkyl, optionally substituted by 1, 2, or 3 substituents F; or wherein R3 is -O-C1-6 alkyl; or where R3 is -O-C1-4 alkyl. 10. Compound, according to claim 1, characterized in that the compound is of formula III:

(Formula III), or a pharmaceutically acceptable salt thereof, each of R3 and R4 being independently H, substituted aliphatic, unsubstituted aliphatic, substituted phenyl, unsubstituted phenyl, ORN1, -N(RN1)2, or -SO2(RN2), wherein each RN1 is independently H, substituted aliphatic, or unsubstituted aliphatic, and RN2 is OH, unsubstituted aliphatic, or substituted aliphatic; providing that, if one RN is ORN1, -N(RN1)2, or -SO2(RN2), the other RN is H, substituted aliphatic, unsubstituted aliphatic, substituted phenyl, or unsubstituted phenyl. 11. Compound, according to claim 10, or a pharmaceutically acceptable salt thereof, characterized in that R3 is H or unsubstituted aliphatic; and/or wherein R4 is H, substituted aliphatic, or unsubstituted aliphatic; or wherein R3 is methyl; and/or wherein R4 is methyl. 12. Compound, according to claim 1, characterized in that it is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. 13. Compound according to claim 1, characterized in that the compound is selected from the group consisting of: 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N- (2-hydroxyethyl)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(1-hydroxypropan-2-yl)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(2-hydroxypropyl)acetamide; ammonium 2-(2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamido)ethan-1-acetate; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; N-(2,2-difluoroethyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(2,2,2-trifluoroethyl)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-methylacetamide; 2-(4-(4-hydroxy-3-isopropyl benzyl)-3,5-dimethylphenoxyl)-N-(2-hydroxyphenyl)acetamide; 2-(4-(4-hydroxy-3-isopropyl benzyl)-N-(3-hydroxyphenyl)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-( 2-(methylsulfonamido)ethyl)acetamide N-(1,3-dihydroxypropan-2-yl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide 2-(4- (4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-propylacetamide; N-(2-fluoroethyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy) acetamide; N-allyl-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy) -N-(prop-2-yn-1-yl)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-methoxyacetamide; N-(3,4-dihydroxyphenethyl) )-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-phenethylacetamide ; N-hydroxy-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetohydrazide 2-(2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamido)ethane-1-sulfonate N-cyclopropyl-2-(4-(4-hydroxy-3-isopropylbenzyl) -3,5-dimethylphenoxy)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N,N-dimethylacetamide; N-ethyl-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; N-(cyanomethyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; N-(3-fluorophenyl)-2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetamide; 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(oxetan-3-yl)acetamide; and 2-(4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(4-nitrophenyl)acetamide, or a pharmaceutically acceptable salt thereof. 14. Pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of the compound, as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vehicles. 15. Use of the compound, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 13, or the pharmaceutical composition, as defined in claim 14, characterized in that it is for the manufacture of a drug for the treatment of a neurodegenerative disease. 16. Use according to claim 15, characterized in that the neurodegenerative disease is a demyelinating disease. 17. Use according to claim 15, characterized in that the neurodegenerative disease is X-linked adrenoleukodystrophy (X-ALD, ALD, or X-linked ALD). 18. Use, according to claim 15, characterized in that it is for the treatment of multiple sclerosis. 19. Use of the compound, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 13, or the pharmaceutical composition, as defined in claim 14, characterized in that it is for the manufacture of a drug for the treatment of a disease or condition selected from the group consisting of acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum's disease, infantile Refsum's disease, Alexander's disease, Alzheimer's disease, Balo's concentric sclerosis , Canavan disease, Central pontine myelinolysis (CPM), cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, Guillain-Barré syndrome, idiopathic inflammatory demyelinating disease (IIDD), Krabbe disease, Leber's hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), paraproteinemic demyelinating polyneuropathy, Pelizaeus- Merzbacher syndrome (PMD), progressive multifocal leukoencephalopathy (PML), spastic tropic paraparesis (TSP), and Zellweger syndrome.

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